hiv case study evolve

Skip to main content
Keyboard shortcuts for audio player

Goats and Soda

Infectious disease.

Development
Women & Girls
Coronavirus FAQ

Discovery of HIV variant shows virus can evolve to be more severe — and contagious

Melody Schreiber

A colorized electron microscope image from the National Institute of Allergy and Infectious Diseases shows a single human immunodeficiency virus budding from a human immune cell. AP hide caption

A colorized electron microscope image from the National Institute of Allergy and Infectious Diseases shows a single human immunodeficiency virus budding from a human immune cell.

A variant of HIV that is faster at progressing to serious illness and more contagious than other versions of the virus has been circulating in the Netherlands for decades, researchers have found.

The findings, which were published in the journal Science on Thursday, demonstrate how HIV can mutate to create more severe disease and more rapid transmission.

"Even after 100 years of HIV infecting humans, it still has the capacity to evolve and change," says Joel Wertheim , associate professor of medicine at the University of California, San Diego, who was not involved in the study but wrote a perspective about the research findings, also published in Science on Thursday.

Fact check: The theory that SARS-CoV-2 is becoming milder

The study serves as a reminder — in the age of COVID variants — that viruses don't always weaken over time. "We should never underestimate the potential for viral evolution," Wertheim says. "Let this study stand in stark contrast to the claim that all viruses will inevitably evolve to be benign."

A contagious new discovery

The discovery of the HIV variant was sparked by a curious set of samples.

In late 2018, Chris Wymant , the lead author of the study and senior researcher at the Big Data Institute at University of Oxford, noticed something interesting in a database for a project called BEEHIVE , which collects HIV samples from Uganda and several countries in Europe to help scientists understand how the virus is evolving.

There was a recent cluster of 17 samples that showed a lot of unusual mutations, he says — and 15 of the samples came from the Netherlands.

Wymant and his co-authors wanted to know more, so they dived into another Dutch study with more data. They discovered a total of 109 people who had this particular variant and never knew it, dating all the way back to 1992. The variant probably emerged in the late '80s, Wymant says, picking up steam around 2000 and then eventually slowing down around 2010.

People with this variant have a viral load that is three to four times higher than usual for those with HIV. This characteristic means the virus progresses into serious illness twice as fast — and also makes it more contagious, says Wymant.

History Repeats Itself: COVID-19 Vaccine Inequities Echo HIV Crisis

The good news: Existing medications work very well to treat even very virulent variants like this one, cutting down on transmission and reducing the chance of developing severe illness, he says.

"Nobody should be alarmed," Wymant says. "It responds exactly as well to treatment as HIV normally does."

There's no need to develop special treatments for this variant, he adds. It shows no signs at all of resisting medications, as some HIV variants do. But because the variant moves quickly, people need to receive medicine as fast as possible.

How to slow down the variant

This research was "nicely done" and "well-designed," says Adeeba Kamarulzaman , president of the International AIDS Society and professor of medicine at the University of Malaya, who did not work on the study.

It also helps answer a pressing question in the field of HIV research, she notes. Previously, researchers wondered whether people get sicker or are more contagious because of how their immune systems respond to the virus. The study found that individual responses are part of it but not all. It can also happen if a virus evolves to cause more severe illness and readier transmission.

Kamarulzaman warns that a mutation like this could happen in other places. If a number of HIV patients in a particular area have this kind of variant but isn't taking medication, "you are going to have a lot more people with advanced disease a lot more quickly," she says.

To prevent this from happening, she says, "early tests or frequent testing and immediate initiation of treatment is the way to go." The goal isn't to identify a specific variant but rather to diagnose new cases of HIV so that treatment may start as soon as possible. But some countries still struggle to do that, and they need more support, she adds.

Ambitious Plan To Stem HIV/AIDS Epidemic Meets None Of Its Goals

That's how this variant eventually slowed down in the Netherlands before researchers even identified it.

"The public health intervention that's been rolled out and expanded in the Netherlands over the last decade or so — improving access to treatments, getting people tested as soon as possible, getting them onto treatment as soon as possible — has helped reduce the numbers of this variant, even though we didn't know that it existed," Wymant says.

Rapid treatment also helps slow viral evolution, so variants like these are less likely to emerge.

"This doesn't mean we need to change strategy," Wertheim says. "It just means we need to do more of what we're already doing."

Melody Schreiber (@m_scribe) is a journalist and the editor of What We Didn't Expect: Personal Stories About Premature Birth .

Netherlands
researchers

Appointments
Our Providers
For Physicians
Understanding HIV’s evolutionary past — and future

Editor’s note: Although best known as a cancer research center, Fred Hutch also is a hub of HIV research. This is one of a series leading up to World AIDS Day on the breadth of our work, from investigating HIV at a molecular level to searching for a cure to running the world’s largest HIV vaccine clinical trial network.

We are all shaped by our past. It turns out that our viruses are too.

At approximately 100 years old, HIV is a relatively recent arrival on the human virus scene. But its roots stretch back much farther. Understanding where the virus has come from can help us understand where it’s going — and how to stop it — say evolutionary biologists.

HIV’s “ancestors go back many, many millions of years,” said Fred Hutchinson Cancer Research Center virologist Dr. Michael Emerman .

Emerman leads a research team studying the evolutionary events that allowed HIV to come into being. Before HIV was a human virus, its predecessors were shaped by the immune systems of the other primates they infected. And before humans were ever infected with HIV, our immune system and defense proteins were shaped by other, older viruses.

Understanding both sides of that history is key to understanding the virus and why it’s so dangerous to humans, Emerman said.

HIV’s ancient past

HIV arose from a monkey virus known as SIV, or simian immunodeficiency virus, which is approximately 10 million years old. At least 40 different African monkey species carry their own version of SIV, and for the most part, the animals and viruses exist together peacefully because they’ve adapted together over so many years. SIV is far less dangerous to its monkey hosts than HIV is to us.

Sometime in the more recent evolutionary past — between a thousand and 20,000 years ago — an African chimpanzee ate some SIV-infected monkeys and got infected with a super-strain of the monkey virus, known as SIVcpz, which formed from two SIV strains combining and rearranging. This new combination of genes allowed the monkey virus to adapt to the immune system of the chimpanzee.

Then, about a century ago in Central Africa, SIVcpz jumped from chimps to humans and, with a few more changes, morphed into the virus we now know as HIV.

More than 30 years after scientists discovered HIV as the cause of the then-unfolding AIDS pandemic, there’s much we still don’t understand about the virus. Emerman and his research team study how HIV evolved to adapt to the human immune system, but much of their work is focused on the human and other primate genes that produce proteins that defend — or fail to defend — against the virus.

His laboratory team is conducting a systematic hunt to uncover all the human proteins that can act defensively against HIV. Many of these proteins are known, but Emerman thinks there are more to find and more to understand about those scientists have already discovered. His team is also working to understand variations in these antiviral proteins among people — what might make one person intrinsically more able to fight HIV? Such work could inform HIV cure research by pointing to the gaps in our immune systems cure approaches need to plug, Emerman said.

“We learn how [HIV] adapted to humans. We learn why humans aren’t all equal, so what are the differences in genes between people in the population?” he said. “We learn what factors are missing from humans, so what are the holes in the human innate immune system that other primates do have?”

Along with Fred Hutch evolutionary biologist Dr. Harmit Malik , Emerman is also working on developing “super-restriction factors” — proteins engineered in the lab by optimizing existing antiviral proteins with the hopes of making a protein that’s more powerful against HIV than the ones we already have.

HIV’s future

Emerman’s Fred Hutch colleague, evolutionary biologist Dr. Jesse Bloom , is taking a different tack on laboratory manipulations to better understand HIV. Together with Hutch virologist Dr. Julie Overbaugh and doctoral students Hugh Haddox and Adam Dingens, Bloom is creating libraries of mutant HIVs to help predict the virus’s evolutionary future.

In two recent studies , the research team created genetic mutations in HIV to change each single amino acid — the 20 different building blocks of proteins — to every other possible amino acid in the viral protein known as envelope, or Env. The researchers are using that mutant library to ask how different mutations affect HIV’s ability to infect human cells in the lab.

So far, they’ve found that mutations in the region of Env where a type of immune protein known as a broadly neutralizing antibody attaches to the viral protein weaken the virus’s ability to infect cells. That’s good news for HIV vaccine researchers, including those at the Hutch, who are exploring the potential of broadly neutralizing antibodies to prevent HIV infection.

Their goal in this line of research is to predict the evolutionary paths HIV might take in the future — especially in the presence of an HIV vaccine. If researchers can predict whether the virus is likely to mutate away from certain types of immune proteins, they might be able to design better vaccines to stay one step ahead of the virus.

rachel-tompa

Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa .

Related News

Help us eliminate cancer.

Every dollar counts. Please support lifesaving research today.

Jesse Bloom
Harmit Malik
Michael Emerman
hiv vaccine
Basic Sciences
Human Biology
viral evolution
World AIDS Day 2017
world aids day

For the Media

Contact Media Relations
News Releases
Media Coverage
About Fred Hutch
Fred Hutchinson Cancer Center

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

View all journals
Explore content
About the journal
Publish with us
Sign up for alerts
Review Article
Published: 01 January 2004

The causes and consequences of HIV evolution

Andrew Rambaut 1 ,
David Posada 2 ,
Keith A. Crandall 3 &
Edward C. Holmes 1

Nature Reviews Genetics volume 5 , pages 52–61 ( 2004 ) Cite this article

28k Accesses

383 Citations

40 Altmetric

Metrics details

The present genetic diversity of HIV is the result of multiple cross-species transfers to humans from African non-human primates.

HIV-1 has its origin in chimpanzees and is the result of three separate transfers to humans; by contrast, HIV-2 is most closely related to strains in the sooty mangabey and is the result of at least four transfers.

The most recent common ancestor of HIV-1 group M (the virus that causes the vast majority of infections globally) is estimated to have existed in the 1930s, although more 'fossil' viruses are needed to confirm this.

HIV-1 subtypes arise as the consequence of founder events and incomplete sampling.

Over the course of an infection, positive natural selection is the dominant mode of HIV evolution within a single patient.

Over the epidemic as a whole, stochastic processes are more important for the evolution of the virus between patients. There is little evidence that fitness differences among strains determine their population structure and distribution.

Genetic recombination is a fundamental mechanism for the evolution of HIV.

The development of drug treatments has greatly extended life expectancy and quality of life for those who are HIV positive but the development of drug resistance has been a major setback.

Recombination can rapidly bring together resistance mutations for multiple drugs during combination therapy.

The development of a vaccine for HIV has been a frustratingly slow process with the few candidate vaccines that have made it to phase III trials demonstrating no efficacy.

The high rate of evolution means that the pattern of diversity of HIV is changing at an alarming rate.Vaccines are therefore aiming at a constantly moving target.

Understanding the evolution of the human immunodeficiency virus (HIV) is crucial for reconstructing its origin, deciphering its interaction with the immune system and developing effective control strategies. Although it is clear that HIV-1 and HIV-2 originated in African primates, dating their transmission to humans is problematic, especially because of frequent recombination. Our ability to predict the spread of drug-resistance and immune-escape mutations depends on understanding how HIV evolution differs within and among hosts and on the role played by positive selection. For this purpose, extensive sampling of HIV genetic diversity is required, and is essential for informing the design of HIV vaccines.

HIV-1 and human genetic variation

Transmission dynamics of HIV-1 subtype B strains in Indonesia

Common evolutionary features of the envelope glycoprotein of HIV-1 in patients belonging to a transmission chain

AIDS is arguably the most serious infectious disease to have affected humankind. Not only are an estimated 42 million people carrying the virus at present 1 , but its case fatality rate is close to 100%, making it an infection of devastating ferocity. In 2002 alone, 5 million people became infected with the causative agent — the human immunodeficiency virus (HIV) — and, of these, 70% live in sub-Saharan Africa. Although a succession of antiviral agents has made HIV/AIDS a more manageable disease in some industrialized nations, and several vaccines are about to enter Phase III clinical trials, HIV will doubtless continue to impose a terrible burden of morbidity and mortality ( Box 1 ).

Although the development of anti-HIV drugs and vaccines has often been a frustrating exercise, and many aspects of HIV pathogenesis remain unclear, research into the origins and evolution of the virus has proven more fruitful. Ironically, one of the main reasons that successful treatment of HIV infection is so difficult — its rapid rate of evolutionary change — has allowed us to reconstruct the evolutionary history of HIV with great precision. More importantly, establishing the ground rules that underpin the evolution of HIV will lead to better vaccines and antiviral agents. Here, we review the current evidence documenting the origin of HIV, discuss how the virus evolves in relation to the human immune system and argue that evolutionary ideas are essential for the successful control of the virus. Basic aspects of the biology of HIV are illustrated in Fig. 1 .

Although the human immunodeficiency virus (HIV) is able to infect a variety of cell types, AIDS results from the depletion of CD4 + T-HELPER LYMPHOCYTE CELLS , a key component of the human immune system. The env ( envelope ) gene encodes the proteins of the outer envelope of the virus, the gag ( group-specific antigen ) gene encode the components of the inner capsid protein, whereas the pol (polymerase) gene codes for the enzymes (such as REVERSE TRANSCRIPTASE ) that are used in viral replication.

The origins of HIV

The key to understanding the origin of HIV was the discovery that closely related viruses — the simian immunodeficiency viruses (SIVs) — were present in a wide variety of African primates 2 . Collectively, HIV and SIV comprise the primate lentiviruses, and SIVs have been isolated in more than 20 African primate species. Importantly, in no case (other than laboratory-associated infections of Asian macaque monkeys) has it been shown that the SIVs cause disease in their hosts, although only a few studies of their natural history in wild populations have been undertaken.

Molecular phylogenies of HIV and SIV. The evolutionary history of HIV-1 and HIV-2 has been reconstructed in great detail by inferring phylogenetic trees of the primate lentiviruses. It was soon discovered that the two human viruses are related to different SIVs and therefore have different evolutionary origins ( Fig. 2 ). Specifically, HIV-1 is most closely related to SIVcpz , which is found in some sub-species of chimpanzee ( Pan troglodytes troglodytes and Pan troglodytes schweinfurthii ) that inhabit parts of equatorial Western and Central Africa, respectively 3 , 4 . SIVcpz from P. t. troglodytes is of most interest because it shares the closest relationship with the abundant HIV-1 M group. The geographical range of P. t. troglodytes also encompasses the region in Africa that has the greatest genetic diversity of HIV-1, containing groups M, N and O; such a distribution is expected if this was where HIV-1 first emerged. By contrast, HIV-2 is most closely related to SIVsm 5 , which is found at high prevalence in sooty mangabey monkeys ( Cercocebus atys ). As with HIV-1, sooty mangabeys are most frequent in the regions of West Africa where HIV-2 is likely to have emerged.

Because both the human immunodeficiency virus type 1 (HIV-1) and HIV-2 lineages (red branches) fall within the simian immunodeficiency viruses (SIVs) that are isolated from other primates, they represent independent cross-species transmission events. The tree and other evidence also indicate that HIV-1 groups M, N and O represent separate transfers from chimpanzees (SIVcpz), again because there is a mixing of the HIV-1 and SIV lineages. Similarly, HIV-2 seems to have been transferred from sooty mangabey monkeys (SIVsm) on many occasions, although this is best documented in other phylogenetic analyses 2 . The tree was reconstructed using a MAXIMUM LIKELIHOOD METHOD on an alignment of 34 published nucleotide sequences of the viral polymerase ( pol ) gene ( Fig. 1 ), excluding third codon positions (full details from the authors on request). Other abbreviations for viruses and their primate hosts are as follows: SIVcol, black and white colobus; SIVdrl, drill; SIVgsn, greater spot-nosed monkey; SIVlhoest, L'Hoest monkey; SIVmac, macaque; SIVmnd, mandrill; SIVmon, Campbell's mona monkey; SIVrcm, red-capped monkey; SIVsab, Sabaeus monkey; SIVsun, sun-tailed monkey; SIVsyk, Sykes' monkey; SIVtan, tantalus monkey; SIVver, vervet monkey. For clarity, only some subtypes of HIV-1 and HIV-2 are shown. All gene sequences were taken from GenBank (see online links box).

Molecular phylogenies also show that there have been many cross-species transmissions to humans, because there is a mixing of HIV and SIV lineages ( Fig. 2 ). Although the vagaries of sampling make it difficult to determine exactly how many cross-species transfers have occurred, for HIV-2 this number might be at least four 2 , whereas three jumps from chimpanzees to humans are thought to explain the current diversity of HIV-1, such that groups M, N and O each have an independent origin 3 , 6 . However, inter-specific recombination, which might be common among the primate lentiviruses, greatly complicates this analysis 7 . For example, HIV-1 group N seems to be a recombinant between a SIVcpz strain and a virus related to the ancestor of group M (Ref. 3 ), but this event occurred before the establishment of group M and N in humans. SIVcpz is itself a composite of viruses, the descendants of which are now found in red-capped mangabeys ( Cercocebus torquatus , SIVrcm) and greater spot-nosed monkeys ( Cercocebus nictitans , SIVgsn ) 8 .

Dating the evolution of primate lentiviruses. To fully understand the evolutionary history of HIV, it is also necessary to determine its timescale. At face value, the wide host-species range of the SIVs, as well as their low VIRULENCE and strong association with specific species 9 , argues for an ancient evolutionary history, perhaps representing virus–host co-divergence over several million years. Indeed, in some cases the phylogeny of the SIVs matches that of their primate hosts, as expected under a co-divergence model 10 . However, there are an increasing number of instances in which host and virus phylogenies are mismatched, implying more recent cross-species transfer in the SIVs 8 , 11 , 12 . If cross-species transfer is in fact the main mode of evolution, then any resemblance between host and virus trees might be because related primate species are often found in adjacent geographical ranges, or because host switching is most likely to occur between closely related host species 13 .

The timescale of evolution inferred from viral MOLECULAR CLOCKS also seems incompatible with long-term co-divergence. If co-divergence were true, then the divergence times of SIVs should broadly match those of their hosts, going back millions of years. However, all molecular clock estimates of primate lentivirus evolution are orders of magnitude more recent than this 14 , and the rates of mutation and replication are similar among these viruses 15 , 16 . Therefore, if molecular clocks are accurate, then the evolutionary timescale for each epidemic of HIV-1 and HIV-2 is measured only in decades. Several methods are available to measure substitution rates, and therefore divergence times, in RNA viruses, although the most reliable estimates come from analysing the temporal distribution of nodes on trees ( Box 2 ). Application of these (and similar) methods have led to suggestions that the M group of HIV-1 originated in the 1930s, with a range of ∼ 10 years on either side 17 , 18 , 19 (but see Box 2 ). A broadly similar evolutionary timescale has been proposed for HIV-2 (Ref. 20 ).

Although most estimates for the time of origin of HIV-1 are consistent, all can be subject to the same systematic bias. Once again, recombination might contribute to this error. Recombination has complex effects on the estimation of divergence times, by increasing apparent variation in rates among nucleotide sites and reducing genetic distances between sequences 21 , 22 . In these circumstances, perhaps the only reliable indicators of the timescale of HIV evolution are archival viral samples. The earliest HIV-1 M group sequence that is available was sampled in the Democratic Republic of Congo in 1959 (Ref. 23 ). That this sequence falls some distance from the root of the M group tree is strong evidence that the diversification of these viruses occurred before this time ( Box 2 ). Accurately dating HIV evolution will require the analysis of more such 'fossil' viruses.

Emergence of the human diseases. By what mechanisms did HIV jump to humans? Although several theories have been proposed, there is little evidence to suggest that anything other than entirely 'natural' processes are responsible for its emergence 2 . In particular, given the frequency with which primate bushmeat that is sold in African markets is infected with SIV 24 , it is easy to envisage how individuals that are involved in the slaughter of animals or the preparation of food could become infected. Indeed, it is likely that SIV jumped into humans many times before the transmission pathways leading to the current AIDS epidemics were established, and that these incipient infections occurred in isolated rural communities and soon burnt out because of a lack of susceptible hosts.

It is also important to explain why HIV-1 forms subtypes, such that virus sequences tend to fall into distinct clusters with approximately equal genetic distances between them (10–30%, depending on the genes compared). These clusters are most likely to be produced by a combination of FOUNDER EFFECTS and incomplete sampling. In particular, intensive viral collection from West and Central Africa has now uncovered strains that fall between the previously described subtypes 25 . This indicates that these parts of Africa were the source of the strains that ignited successful epidemics in other localities, in Africa and beyond, and that the subtype structure of the HIV-1 tree to a large extent reflects sampling bias 26 . For example, most HIV-1 strains that were isolated in North America and Europe fall into subtype B, and their relative similarity reflects their recent common origin from a founder in, or from, Africa. Under the evolutionary timescale proposed for group M, the individual subtypes would have diversified in the last 40 years or so 17 , 27 , although there is debate as to whether subtype B originated in the 1960s or the 1970s 28 .

The phylogenesis of HIV-1 is therefore a dynamic process, such that subtypes will disappear and new epidemics arise ( Fig. 3 ). More importantly, the current recommendations of what constitutes a subtype will become meaningless as phylogenetic complexity increases through the continued spread of the epidemic, with recombination among currently recognized types and more widespread sampling. The mean genetic divergence of subtype A, B, C and D genomes isolated in 1999 (9.8%, 10.0%, 7.9% and 8.5%, respectively) each equal that of the whole group M epidemic in 1985 (8.8%). The genetic divergence of the entire group M has increased to 14.9% in the same period (data from the HIV Database ; see online links box). Although some of this increase can be ascribed to increased sampling, the substitution rate that this implies ( ∼ 0.002 substitutions per site, per year) lies within the range calculated previously for the viral env (envelope) and gag (group-specific antigen) genes (0.0028 and 0.0019, respectively) 17 .

The current global genetic diversity of HIV-1 group M is the result of several historical events in which geographically isolated epidemics (lower coloured triangles) were founded from strains that were present in a source population (large base triangle), most likely in the west of Central Africa 25 . Within each of these epidemics, frequent mixing of strains results in a complex recombinant structure (arrows within triangles). Subsequently, owing to global travel, the geographical ranges of these epidemics have increasingly overlapped, resulting in inter-subtype circulating recombinant forms (arrow between triangles), the number and mosaic complexity of which has steadily been increasing.

Evolutionary processes

Within-host evolution. One of the earliest and most striking observations made about HIV is the extensive genetic variation that the virus has within individual hosts, particularly in the hypervariable regions of the env gene 29 ; this variation makes HIV one of the fastest evolving of all organisms. Such rapid evolution is the result of an explosive combination of factors. First, the virus experiences a high rate of mutation, with reverse transcriptase making ∼ 0.2 errors per genome during each replication cycle 30 , and further errors occurring during transcription from DNA by RNA Pol II polymerase. Second, HIV has remarkable replicatory dynamics: it has a viral generation time of ∼ 2.5 days and produces ∼ 10 10 –10 12 new VIRIONS each day 31 . Finally, frequent recombination and natural selection further elevate its rate of evolutionary change.

Two key evolutionary questions arise when considering within-host genetic variation; how much of this diversity is shaped by IMMUNE SELECTION , and what is the relationship between genetic diversity and clinical outcome? Although it is possible that stochastic forces ( GENETIC DRIFT ) are involved in intra-host evolution, especially when the viral EFFECTIVE POPULATION SIZE is small (perhaps owing to population subdivision 32 ), and when advantageous mutations are at low frequency, there is strong evidence that natural (positive) selection is the driving force of intra-host evolution. So, HIV successively FIXES mutations that allow it to evade immune responses, especially in the env gene. Host immune-selection pressure could be generated by neutralizing antibodies 33 — for example, in the guise of an evolving GLYCAN SHIELD 34 , by T-helper cells 35 or by CYTOTOXIC T LYMPHOCYTES (CTLs) 36 , 37 , 38 , 39 . CTL escape has been particularly well characterized, especially in SIV models 40 , 41 , where it can have a large impact on disease outcome 42 . Positive selection is also easily detectable in computational analyses of HIV gene sequences, in which the per site rate of NONSYNONYMOUS SUBSTITUTION ( d N ) exceeds that of SYNONYMOUS SUBSTITUTION ( d S ) 35 , 43 , 44 , and in the structure of intra-host phylogenies (see below). The remarkable strength of immune selection was revealed in a recent analysis of evolutionary dynamics in 50 HIV-1 patients 45 . Most fixed env amino-acid changes in these patients confer a selective advantage, with an average of one adaptive fixation event every ∼ 2.5 months. Under these criteria, HIV shows stronger positive selection than any other organism studied so far.

AIDS pathogenesis. Less clear is the role, if any, played by viral evolution in the development of AIDS in HIV-infected individuals. One early hypothesis was that there was a direct link between genetic (or, more specifically, antigenic) variation and pathogenesis, such that the immune system was unable to suppress each replicating variant and the patient succumbed to AIDS 46 . However, studies on larger numbers of patients have painted a far more complex picture of the relationship between genetic diversity and disease status. Although there is some evidence that rates of nonsynonymous substitution vary according to disease status, the direction of the correlation and its underlying causes are more uncertain 47 , 48 , 49 . This could, in part, be because analyses of intra-host sequence variation have failed to distinguish between total genetic variation and selectively advantageous changes, the latter being key to understanding the interaction between host and virus. Moreover, recombination again complicates the analysis, as it might produce false-positive evidence for natural selection in measures of d N / d S 50 , 51 . How to tease apart the respective roles of selection and recombination in shaping genetic diversity is a key area for future research in evolutionary genetics.

It is also important to determine whether the evolution of virulent viruses within each host tips the balance towards AIDS. The first indication that this might be the case was that AIDS patients more frequently harboured viruses that formed SYNCYTIA in vitro (SI strains) than those who were asymptomatic 52 . More recently, the development of SI strains has been associated with a broadening of co-receptor usage. Although HIV preferentially infects CD4 + cells, it also utilizes CHEMOKINE co-receptors, most notably CCR5 and CXCR4 . Viral strains that infect macrophages use the CCR5 receptor (known as R5 strains), dominate during the early years of HIV infection and do not induce syncytia in vitro (NSI strains) 53 . A broadening of co-receptor usage — so that strains also using the CXCR4 receptor emerge (known as X4 strains) — generally occurs later in infection 48 . These T-cell tropic SI strains are associated with a higher rate of CD4 + cell decline and therefore a more rapid progression to AIDS 54 . However, many HIV-infected patients progress to AIDS without the appearance of X4 viruses. Moreover, HIV-1 subtype C, now the most common subtype in sub-Saharan Africa, is mainly composed of R5 virus strains 55 , but causes AIDS with the same frequency as other subtypes. Consequently, although viruses of higher virulence often appear during intra-host viral evolution, this alone is not responsible for the development of AIDS.

Taken together, most studies of intra-host HIV evolution indicate that the extent and structure of viral genetic diversity is more a marker of the arms race between host and virus than the cause of AIDS itself. In particular, a strong host immune response generates a strong selective reply from the virus, as measured in d N / d S . Therefore, the greatest positive selection in HIV is generally seen in patients with longer asymptomatic phases 35 , 45 .

Evolution within and among hosts. The persistent nature of HIV infection means that evolution occurs both within and among hosts. Strikingly, intra-host and inter-host evolution seem to be very different processes, with positive selection dominating in the former but not the latter. This is evident in the structure of phylogenetic trees ( Fig. 4 ). Intra-host HIV phylogenies have a strong temporal structure, reflecting the successive fixation of advantageous mutations and the extinction of unfavourable lineages. By contrast, those trees that track viral evolution among hosts show little evidence for continual positive selection. Rather, they depict the (neutral) spatial and temporal diffusion of the virus, with viral lineages co-existing for extended time periods. Indeed, there is little evidence that fitness differences determine subtype structure and distribution. For example, experimental studies have revealed that subtype C viruses consistently have lower in vitro fitness than those assigned to subtype B (Ref. 56 ). Although caution should be shown when extrapolating from the laboratory to nature, this indicates that the high prevalence of subtype C in sub-Saharan Africa is the result of its chance entry into populations with high rates of partner exchange. However, it is unclear whether the success of HIV-1 group M, relative to groups N and O, is the result of some intrinsic property of the virus that enhances transmissibility, or because the founding virus from group M was fortunate enough to find itself in populations in which the epidemiological conditions were ideal for transmission.

The tree was constructed using the NEIGHBOUR-JOINING METHOD on envelope gene-sequence data that was taken from nine HIV-infected patients 48 (a total of 1,195 sequences, 822 base pairs in length), with those viruses sampled from each patient depicted by a different colour. In each case, intra-host HIV evolution is characterized by continual immune-driven selection, such that there is a successive selective replacement of strains through time, with relatively little genetic diversity at any time point. By contrast, there is little evidence for positive selection at the population level (bold lines connecting patients), so that multiple lineages are able to coexist at any time point. A major BOTTLENECK is also likely to occur when the virus is transmitted to new hosts.

Why is natural selection a less potent force among hosts than within them? The first factor is the bottleneck that accompanies inter-host transmission, which greatly reduces genetic diversity. Evidence for a strong bottleneck at transmission is the homogeneity of the virus during primary infection 57 , 58 , although this could depend on the mode of transmission 59 . The second important factor concerns the behavioural aspects of HIV transmission. HIV is predominantly a sexually transmitted disease, and so the extensive variation in rates of partner exchange will, in combination with the transmission bottleneck, generate strong genetic drift. As a result, strains with advantageous mutations could, by chance, find themselves in individuals with low rates of partner exchange and so will not be transmitted far in the population. Of more debate is whether a bottleneck has a selective component, so that strains that are better adapted to new hosts (such as R5 strains) competitively establish themselves in primary infection 60 , or whether it is entirely neutral 61 and thereby only magnifies the effects of genetic drift.

Finally, some advantageous mutations, such as those conferring CTL escape, might not appear until relatively late in infection 62 . If these late-escape mutants do not arise until after most individuals have transmitted the virus, natural selection will be less effective at the population level. As a consequence, HIV strains might not readily adapt to the HLA HAPLOTYPE distributions of their local populations 63 , because some CTL-escape mutants have little opportunity for further transmission. The data presented to support the adaptation of HIV to HLA haplotypes at the population level only considered within-host evolution, albeit in a large number of patients, and did not measure the effect of transmission. Indeed, the fact that repeated individual adaptation was observed in these patients indicates that the HIV population as a whole was not adapted to the host HLA distribution. Moreover, although certain CTL-escape mutants can be transmitted through the population 64 , it is possible that CTL-escape mutations that are passed to individuals with the 'wrong' HLA background will sometimes be deleterious and removed by purifying selection. In summary, inter-host HIV evolution is not merely intra-host evolution played out over a longer timescale, and the evolutionary process that occurs within hosts will not select for viruses with enhanced transmissibility.

Recombination and HIV diversity. Genetic recombination is an integral part of the HIV lifecycle, occurring when reverse transcriptase switches between alternative genomic templates during replication. As already mentioned, the recombination rate of HIV is one of the highest of all organisms, with an estimated three recombination events occurring per genome per replication cycle 65 , thereby exceeding the mutation rate per replication. The discovery that most infected cells harbour two or more different proviruses 66 , and the evidence for dual infection 67 , 68 , set the stage for recombination to have a central role in generating HIV diversity. Indeed, recombination has now been detected at all phylogenetic levels: among primate lentiviruses 7 , 8 , among HIV-1 groups 69 , among subtypes 70 and within subtypes 71 . Prevalent inter-subtype recombinants are denoted 'circulating recombinant forms' (CRFs). There are 15 currently recognized CRFs that show a broad range of complexity and are widely distributed. In some geographical regions, CRFs account for at least 25% of all HIV infections 72 . Probably because it is more difficult to detect, the role of intra-subtype recombination has traditionally been downplayed. However, recent population-genetic studies indicate that recombination is also a pervasive force within subtypes 71 , 73 .

As hinted at earlier, recombination has important implications for understanding the HIV epidemic. In particular, many evolutionary inferences about HIV are made after the reconstruction of phylogenies, which can be greatly affected by recombination. Therefore, analyses of phylogenetic relationships, the timing of events, demographic processes or natural selection, are all potentially affected by recombination 21 , 73 , 74 . For example, although the data set used for dating the origin of HIV-1 M group to the 1930s was 'cleaned' for known recombinants before analysis 17 , the presence of recombination still seems evident, raising concerns about the accuracy of this estimate 75 . Because recombination is so frequent, it cannot be factored out by simply identifying recombinants and excluding those from the analysis. Indeed, today's subtypes might comprise old and successful recombinant lineages that trace back to a shared ancestral population ( Fig. 3 ). HIV should therefore be studied with methods that are robust to the occurrence of recombination, or that explicitly take recombination into account. The development of such methods will doubtless prove difficult, but is necessary to make reliable inferences on many aspects of HIV-1 evolution. A simple way to start might be through the use of network approaches for phylogenetic inference, in which individual sequences are allowed to have many ancestors, and which provide a good alternative to traditional trees 76 , 77 .

Within individual hosts, recombination interacts with selection and drift to produce complex population dynamics, and perhaps provides an efficient mechanism for the virus to escape from the accumulation of deleterious mutations or to jump between ADAPTIVE PEAKS . Specifically, recombination might accelerate progression to AIDS 78 and provide an effective mechanism (coupled with mutation) to evade drug therapy, vaccine treatment 79 or immune pressure 80 , 81 . For example, vaccines without STERILIZING activity (such as CTL-inducing vaccines) or drug therapies with inconsistent application might offer the chance for SUPERINFECTION , in turn allowing recombination to produce viruses that carry many vaccine or drug escape mutations. Clearly, more studies are needed to quantify in vivo the role of recombination in generating important HIV diversity.

Consequences of HIV evolution

The evolution of drug resistance. The emergence of drug resistance in HIV has perhaps been the single largest setback in the treatment of AIDS. Once touted as a cure for HIV infection 82 , there is now less optimism that highly active antiretroviral therapy (HAART), involving combinations of drugs that act against different aspects of the viral life cycle, can rid the body of virus altogether. Mathematical models that predicted the eradication of virus from a patient within 2–3 years 83 failed to adequately take into account two key aspects of HIV biology: viral reservoirs and evolution. No doubt, the development of HAART has greatly extended life expectancy and quality of life for those suffering from AIDS who can access these expensive drugs. The failure of HAART as a cure has led to many important lessons concerning our understanding of HIV biology 84 .

The discovery of latent reservoirs of HIV-1 in patients on HAART 85 was one of the key components in understanding the ability of the virus to persist long after the initiation of therapy 86 . These reservoirs can serve to replenish the main pool of replicating virus and are now known from a variety of cell types, including CD4 + T lymphocytes, follicular dendritic cells 87 and macrophages 88 , and are housed in various tissues throughout the body 89 . However, key questions remain regarding when and how these reservoirs become stocked with virus, whether or not replication is ongoing in or near the reservoirs, and whether the reservoirs are restocked with virus from subsequent replication. Although drug therapy is efficient at controlling viral levels in the plasma, the viruses in reservoirs are protected from interaction with drugs and can be extremely long-lived. It is therefore crucial to gain a clearer picture of the role and function of reservoirs in HIV infection.

Although the importance of viral evolution in immune escape is well understood, the evolutionary potential of HIV was severely underestimated by those proposing HAART therapy as a cure for AIDS. This occurred for two reasons. First, whereas the evolution of drug resistance in single drug therapy (such as AZT) had been documented, conventional wisdom was that the new triple-drug combination therapy would prove too difficult to evolve a solution to, because mutations were believed to occur singly and to accumulate in an ordered fashion 90 . However, this ignored recombination, which allows the virus to accumulate and exchange drug-resistant mutations in a nonlinear fashion, leading to rapid evolution of drug-resistant mutants, even between different reservoirs 81 ( Fig. 5 ). Second, early studies from patients on HAART concluded that the virus was not undergoing evolution in those with 'undetectable' levels of viral load 85 , 91 . In fact, the data from these studies clearly indicated that the virus was evolving; sequences from different time points were separated by measurable branch lengths, indicating that mutational changes had accumulated. Evidently, it was only a matter of time before the virus hit the mutations that would confer drug resistance 92 , 93 . Thankfully, through computational and mathematical approaches, we are now gaining a better understanding of the evolutionary dynamics of HIV-1 and its reaction to drug therapy 94 .

Hypothetical example showing how recombination will be an important mechanism to generate drug resistance in HIV. In this figure, two different HIV strains that are resistant to drug A (in red) and drug B (in blue) recombine to produce a new strain that is resistant to both drugs.

There is now a growing database of HIV mutations that confer drug resistance (see HIV drug resistance database in online links box) and their implications for drug resistance are, of course, enormous. More worryingly, there is evidence that some drug-resistant mutants show a greater infectivity, and in some cases a higher replication rate, compared with viruses without drug-resistant mutations 95 . Drug-resistant mutations are now being seen in drug-naive patients 96 , perhaps indicative of adaptation of the virus to a changed environment in parts of the world where drug treatment is widespread. However, it is unclear how many of these cases are simply the result of contact with a drug-treated individual, as in most cases drug-resistance mutations have an overall fitness cost in the absence of drugs 97 .

Viral genetic diversity and vaccine design. The development of an HIV vaccine has been frustratingly slow. Most attention has been directed towards the viral envelope region and comprises a variety of approaches, including recombinant proteins, synthetic peptides, recombinant viral vectors, recombinant bacterial vectors, recombinant particles, and whole-killed and live-attenuated HIV. The latter two have not progressed to clinical trials owing to an unfavourable benefit/risk ratio, which is further supported by experimental evidence from humans and simian models 98 , 99 .

Not least of the hurdles in the development of an effective HIV vaccine is the clinical trial process to show efficacy against the virus. Phase I and II vaccine trials are performed on small numbers of volunteers at relatively low risk for HIV-1 infection and attempt to establish a record of safety and provide valuable immunogenicity data. Phase III trials, on the other hand, are large-scale natural experiments on populations with high incidence and high risk for HIV-1 infection. Although more than 60 Phase I and II trials have taken place for more than 30 candidate vaccines, only two, developed by VaxGen (see online links box), have progressed to Phase III trials. The results from the first US-based Phase III trial showed that the vaccine had no efficacy for the target population experiencing subtype B infection. However, there was evidence of some efficacy in certain minority subpopulations, although the sample size in these categories was limited 100 . A similar (no efficacy) result was recently announced from their Phase III trial in Thailand.

The other intriguing result from the US trial was that the sampling greatly increased the estimates of HIV genetic diversity across that country 100 . As such, these data make it clear that, despite attempts to characterize genetic diversity in the USA for HIV vaccine development 101 , our database of HIV variation is still woefully inadequate, even for understanding diversity in a single subtype. We have relied on the published HIV database to serve as the basis for population-genetic and diversity studies, even though these data have largely been collected for medical studies. Recently, it has been suggested that reconstructions of ancestral HIV sequences or simple consensus sequences could be used to develop vaccine strains 101 , 102 . The intent of these techniques is to obtain a strain that is, as best as possible, similar to all the strains of a given subtype and therefore will provide maximum possible coverage. Although these approaches are based on evolutionary reasoning, the long development and testing cycle of a new vaccine will mean that the genetic diversity of HIV might have changed considerably in the intervening time. It is therefore crucial, for the development of successful vaccines, to better understand the impact of drug resistance in HIV, and to accurately document the overall evolution of this virus and, especially, to continually monitor genetic diversity of HIV on a global perspective. The use of carefully designed sampling strategies, concomitant with our improving understanding and modelling of the molecular evolution and epidemiology of this virus, will allow us to begin to predict how this diversity will change.

Conclusions

As this review has shown, great progress has been made in our understanding of the origins and evolution of HIV. However, it is clear that there are a number of unanswered questions and areas for which future research will be highly beneficial. Perhaps the issue of greatest importance is to fully determine the extent of the difference between viral evolution within and among hosts. With this knowledge, we will be better able to predict the long-term spread of drug resistance and CTL-escape mutations, as well as the likely impact of vaccination.

Box 1 | HIV/AIDS: History and diversity

AIDS was first recognized in the United States in 1981, following an increase in the incidence of usually rare opportunistic infections (such as the pneumonia caused by Pneumocystis carinii ) in homosexual men that were caused by a general immune deficiency. Human immunodeficiency virus (HIV) was first isolated in 1983 (Ref. 103 ) and by the mid-1980s it was evident that two types of HIV, with slightly different genome structures — were circulating in human populations. Both viruses are characterized by extensive genetic diversity; HIV-1 is phylogenetically divided into three groups (see Fig. 2 ) — 'M', 'N' and 'O', with the M group further split into 9 subtypes and 15 circulating recombinant forms. Today, group M has a near global distribution, whereas groups N and O are restricted to individuals of West African origin. HIV-2 is also most common in individuals from West Africa and is composed of seven subtypes. Despite its initial association with homosexual men, it is clear that HIV-1 and HIV-2 are now primarily transmitted by heterosexual intercourse 104 and from mother to infant.

Box 2 | Analysing rates of nucleotide substitution in HIV

Numerous methods have been described for estimating the rate of genetic change in viruses 105 . The common feature of these techniques is the use of viral sequences sampled over time to directly observe evolutionary change. This is possible owing to the exceptional rate of nucleotide substitution of RNA viruses, such as the human immunodeficiency virus (HIV). One of the most straightforward methods — a linear regression of genetic divergence against the time of isolation of the viruses — was used to estimate the date of the most recent common ancestor of HIV-1 group M to the 1930s (Ref. 17 ). Although this study has been criticized for not adequately accounting for recombination, which could affect its accuracy 75 , and for flaws in the statistical methods, which could affect its precision 105 , it remains our best estimate so far. Reassuringly, the inferred regression slope (shown in the figure) almost exactly predicts the position of the oldest HIV sequence, a 1959 sample from the Democratic Republic of Congo (DRC). Figure modified with permission from Ref. 17 © (2000) American Association for the Advancement of Science.

UNAIDS. AIDS Epidemic Update 2002, < http://www.unaids.org/worldaidsday/2002/press/Epiupdate.HtmlReport > (2002).

Hahn, B. H., Shaw, G. M., de Cock, K. M. & Sharp, P. M. AIDS as a zoonosis: scientific and public health implications. Science 287 , 607–614 (2000). Important review of the origin of HIV-1 and HIV-2. Clearly shows that AIDS is a zoonotic disease with its origins in the primate lentiviruses.

Article CAS PubMed Google Scholar

Gao, F. et al. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes . Nature 397 , 436–441 (1999).

CAS PubMed Google Scholar

Santiago, M. L. et al. SIVcpz in wild chimpanzees. Science 295 , 465–465 (2002).

Gao, F. et al. Human infection by genetically diverse SIVsm-related HIV-2 in West Africa. Nature 358 , 495–499 (1992).

Sharp, P. M. et al. The origins of acquired immune deficiency syndrome viruses: where and when. Phil. Trans. Roy. Lond. B 356 , 867–876 (2001).

CAS Google Scholar

Salemi, M. et al. Mosaic genomes of the six major primate lentiviruses lineages revealed by phylogenetic analysis. J. Virol. 77 , 7202–7213 (2003).

CAS PubMed PubMed Central Google Scholar

Bailes, E. et al. Hybrid origin of SIV in chimpanzees. Science 300 , 1713 (2003). Recent sequence analysis paper showing that chimpanzee SIVcpz has a hybrid origin, with two monkey SIVs acting as 'parental' strains.

Allan, J. S. et al. Species-specific diversity among simian immunodeficiency viruses from African green monkeys. J. Virol. 65 , 2816–2828 (1991).

Beer, B. E. et al. Simian immunodefiency virus (SIV) from sun-tailed monkeys ( Ceropithecus solatus ): evidence for host-dependent evolution of SIV within the C. lhoesti superspecies. J. Virol. 73 , 7734–7744 (1999).

Bibollet-Ruche, F. et al. Simian immunodeficiency virus infection in a patas monkey ( Erythrocebus patas ): evidence for cross-species transmission from African green monkeys ( Cercopithecus aethiops sabaeus ) in the wild. J. Virol. 77 , 773–781 (1996).

Courgnaud, V. et al. Partial molecular characterization of two simian immunodeficiency virus (SIV) from African colobids: SIVwrc from western red colobus ( Piliocolobus badius ) and SIVolc from olive colobus ( Procolobus verus ). J. Virol. 77 , 744–748 (2003).

Charleston, M. A. & Robertson, D. L. Preferential host switching by primate lentiviruses can account for phylogenetic similarity with the primate phylogeny. Syst. Biol. 51 , 528–535 (2002).

Sharp, P. M. et al. Origins and evolution of AIDS viruses: estimating the timescale. Biochem. Soc. Trans. 28 , 275–282 (2000).

Müller-Trutwin, M. C. et al. The evolutionary rate of nonpathogenic simian immunodeficiency virus (SIVagm) is in agreement with a rapid and continuous replication in vivo . Virology 223 , 89–102 (1996).

PubMed Google Scholar

Rey-Cuillé, M. A. et al. Simian immunodeficiency virus replicates to high levels in sooty mangabeys without inducing disease. J. Virol. 72 , 3872–3886 (1998).

PubMed PubMed Central Google Scholar

Korber, B. et al. Timing the ancestor of the HIV-1 pandemic strains. Science 288 , 1789–1796 (2000). High-profile paper that provides a timescale for the origin and evolution of HIV-1.

Salemi, M. et al. Dating the radiation of HIV-1 group M in 1930s using a new method to uncover clock-like molecular evolution. FASEB J. 15 , 276–278 (2000).

Yusim, K. et al. Using human immunodeficiency virus type 1 sequences to infer historical features of the acquired immune deficiency syndrome epidemic and human immunodeficiency virus evolution. Phil. Trans. R. Soc. Lond. B 356 , 855–866 (2001).

Lemey, P. et al. Tracing the origin and history of the HIV-2 epidemic. Proc. Natl Acad. Sci. USA 100 , 6588–6592 (2003).

Schierup, M. H. & Hein, J. Recombination and the molecular clock. Mol. Biol. Evol. 17 , 1578–1579 (2000).

Worobey, M. A novel approach to detecting and measuring recombination: new insights into evolution in viruses, bacteria, and mitochondria. Mol. Biol. Evol. 18 , 1425–1434 (2001).

Zhu, T. F. et al. An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Nature 391 , 594–597 (1998).

Peeters, M. et al. Risk to human health from a plethora of Simian immunodeficiency viruses in primate bushmeat. Emerg. Infect. Dis. 8 , 451–457 (2002).

Vidal, N. et al. Unprecedented degree of HIV-1 group M genetic diversity in the Democratic Republic of Congo suggests that the HIV-1 pandemic originated in Central Africa. J. Virol. 74 , 10498–10507 (2000).

Rambaut, A., Robertson, D. L., Pybus, O. G., Peeters, M. & Holmes, E. C. Phylogeny and the origin of HIV-1. Nature 410 , 1047–1048 (2001). Shows how the subtype structure of the tree for the HIV-1 M group is produced by a combination of incomplete sampling and local founder effects.

Robbins, K. E. et al. US human immunodeficiency virus type 1 epidemic: date of origin, population history, and characterization of early strains. J. Virol. 77 , 6359–6366 (2003).

Smith, U. R., Kuiken, C. & Korber, B. T. Recent evolutionary history of human immunodeficiency type 1 subtype B–response. J. Mol. Evol. 56 , 643–644 (2003).

Holmes, E. C., Zhang, L. Q., Simmonds, P., Ludlam, C. A. & Leigh Brown, A. J. Convergent and divergent sequence evolution in the surface envelope glycoprotein of human immunodeficiency virus type 1 within a single infected patient. Proc. Natl Acad. Sci. USA 89 , 4835–4839 (1992).

Preston, B. D., Poiesz, B. J. & Loeb, L. A. Fidelity of HIV-1 reverse transcriptase. Science 242 , 1169–1171 (1988).

Google Scholar

Perelson, A. S., Neumann, A. U., Markowitz, M., Leonard, J. M. & Ho, D. D. HIV-1 dynamics in vivo : virion clearance rate, infected cell life-span, and viral generation time. Science 271 , 1582–1586 (1996). Presents an analysis that shows the remarkable replicatory dynamics of HIV.

Frost, S. D. W., Dumaurier, M. J., Wain-Hobson, S. & Leigh Brown, A. J. Genetic drift and within-host metapopulation dynamics of HIV-1 infection. Proc. Natl Acad. Sci. USA 98 , 6975–6980 (2001).

Richman, D. D., Wrin, T., Little, S. J. & Petropoulos, C. J. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc. Natl Acad. Sci. USA 100 , 4144–4149 (2003).

Wei, X. et al. Antibody neutralization and escape by HIV-1. Nature 422 , 307–312 (2003).

Ross, H. A. & Rodrigo, A. G. Immune-mediated positive selection drives human immunodeficiency virus type 1 molecular variation and predicts disease duration. J. Virol. 76 , 11715–11720 (2002).

Kelleher, A. D. et al. Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27 restricted CTL responses. J. Exp. Med. 193 , 375–385 (2001).

Ogg, G. S. et al. Quantitation of HIV-1 specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279 , 2103–2106 (1998).

Phillips, R. E. et al. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature 354 , 453–459 (1991).

Yusim, K. et al. Clustering patterns of cytotoxic T-lymphocyte epitopes in human immunodeficiency virus type 1 (HIV-1) proteins reveal imprints of immune evasion on HIV-1 global variation. J. Virol. 76 , 8757–8768 (2002).

Allen, T. M. et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 407 , 386–390 (2000).

O'Connor, D. H. et al. Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nature Med. 8 , 493–499 (2002).

Barouch, D. H. et al. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415 , 335–339 (2002).

Bonhoeffer, S., Holmes, E. C. & Nowak, M. A. Causes of HIV diversity. Nature 376 , 125 (1995).

Zanotto, P. M. D. A., Kallas, E. G., de Souza, R. F. & Holmes, E. C. Genealogical evidence for positive selection in the nef gene of HIV-1. Genetics 153 , 1077–1089 (1999).

Williamson, S. Adaptation in the env gene of HIV-1 and evolutionary theories of disease progression. Mol. Biol. Evol. 20 , 1318–1325 (2003). Important paper that presents an analysis of the rate of adaptive evolution in a large number of HIV patients and how this relates to disease progression.

Nowak, M. A. et al. Antigenic diversity threshold and the development of AIDS. Science 254 , 963–969 (1991).

Markham, R. B. et al. Patterns of HIV-1 evolution in individuals with differing rates of CD4 T cell decline. Proc. Natl Acad. Sci. USA 95 , 12568–12573 (1998).

Shankarappa, R. et al. Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection. J. Virol. 73 , 10489–10502 (1999). An extensive analysis of the dynamics of intra-host HIV evolution in a multi-patient study.

Wolinksy, S. M. et al. Adaptive evolution of human immunodeficiency virus-type 1 during the natural course of infection. Science 272 , 537–542 (1996).

Anisimova, M., Nielsen, R. & Yang, Z. Effect of recombination on the accuracy of the likelihood ratio method for detecting positive selection at amino acid sites. Genetics 164 1229–1236 (2003).

Shriner, D., Nickle, D. C., Jensen, M. A. & Mullins, J. I. Potential impact of recombination on sitewise approaches for detecting positive natural selection. Genet. Res. 81 , 115–121 (2003).

Cheng-Mayer, C., Seto, D., Tateno, M. & Levy, J. A. Biological features of HIV-1 that correlate with virulence in the host. Science 240 , 80–82 (1988).

Bjorndal, A. et al. Coreceptor usage of primary human immunodeficiency virus type 1 isolates varies according to biological phenotype. J. Virol. 71 , 7478–7487 (1997).

Zhang, L. Q. et al. Chemokine coreceptor usage by diverse primary isolates of human immunodeficiency virus type 1. J. Virol. 72 , 9301–9312 (1998).

Peeters, M. et al. Evidence for differences in MT2 cell tropism according to genetic subtypes of HIV-1: syncytium-inducing variants seem rare among subtype C HIV-1 viruses. J. Acq. Imm. Def. Syn. Human Retro. 20 , 115–121 (1999).

Ball, S. C. et al. Comparing the ex vivo fitness of CCR5-tropic human immunodeficiency virus type 1 isolates of subtypes B and C. J. Virol. 77 , 1021–1038 (2003).

Delwart, E. et al. Homogeneous quasispecies in 16 out of 17 individuals during very early HIV-1 primary infection. AIDS 16 , 189–195 (2002).

Zhu, T. F. et al. Genotypic and phenotypic characterization of HIV-1 in patients with primary infection. Science 261 , 1179–1181 (1993).

Dickover, R. E., Garratty, E. M., Plaeger, S. & Bryson, Y. J. Perinatal transmission of major, minor, and multiple maternal human immunodeficiency virus type 1 variants in utero and intrapartum. J. Virol. 75 , 2194–2203 (2001).

Wolinksy, S. M. et al. Selective transmission of human immunodeficiency virus type-1 variants from mothers to infants. Science 255 , 1134–1137 (1992).

Verhofstede, C. et al. Diversity of the human immunodeficiency virus type 1 (HIV-1) env sequence after vertical transmission in mother-child pairs infected with HIV-1 subtype A. J. Virol. 77 , 3050–3057 (2003).

Goulder, P. J. R. et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nature Med. 3 , 212–217 (1997).

Moore, C. B. et al. Evidence for HIV-1 adaptation to HLA-restricted immune responses at the population level. Science 296 , 1439–1443 (2002). Extensive study that shows how HIV-1 adapts to HLA haplotypes at the intra-host level. However, the paper does not consider whether intra-host 'escape' mutants are transmitted among hosts.

Goulder, P. J. R. et al. Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412 , 334–337 (2001).

Zhuang, J. et al. Human immunodeficiency virus type 1 recombination: rate, fidelity, and putative hot spots. J. Virol. 76 , 11273–11282 (2002). Recent paper that shows the extremely high rate of recombination in HIV.

Jung, A. et al. Multiply infected spleen cells in HIV patients. Nature 418 , 144 (2002).

Jost, S. et al. A patient with HIV-1 superinfection. N. Engl. J. Med. 347 , 731–736 (2002).

Koelsch, K. K. et al. Clade B HIV-1 superinfection with wild-type virus after primary infection with drug-resistant clade B virus. AIDS 17 , F11–6 (2003).

Takehisa, J. et al. Human immunodeficiency virus type 1 intergroup (M/O) recombination in cameroon. J. Virol. 73 , 6810–6820 (1999).

Robertson, D. L., Sharp, P. M., McCutchan, F. E. & Hahn, B. H. Recombination in HIV-1. Nature 374 , 124–126 (1995).

Crandall, K. A. & Templeton, A. R. in The Evolution of HIV (ed. Crandall, K. A.) 153–176 (The Johns Hopkins University Press, Baltimore, 1999).

Pandrea, I. et al. Analysis of partial pol and env sequences indicates a high prevalence of HIV type 1 recombinant strains circulating in Gabon. AIDS Res. Hum. Retroviruses 18 , 1103–1116 (2002).

McVean, G., Awadalla, P. & Fearnhead, P. A coalescent-based method for detecting and estimating recombination from gene sequences. Genetics 160 , 1231–1241 (2002).

Posada, D. & Crandall, K. A. The effect of recombination on the accuracy of phylogeny estimation. J. Mol. Evol. 54 , 396–402 (2002).

Schierup, M. H. & Forsberg, R. in Proceedings of the conference: Origin of HIV and emerging persistent viruses (Accademia Nazionale dei Lincei, Rome, 2003).

Posada, D. & Crandall, K. A. Intraspecific gene genealogies: trees grafting into networks. Trends Ecol. Evol. 16 , 37–45 (2001).

Wain-Hobson, S., Renoux-Elbe, C., Vartanian, J. P. & Meyerhans, A. Network analysis of human and simian immunodeficiency virus sequence sets reveals massive recombination resulting in shorter pathways. J. Gen. Virol. 84 , 885–895 (2003).

Liu, S. L. et al. Selection for human immunodeficiency virus type 1 recombinants in a patient with rapid progression to AIDS. J. Virol. 76 , 10674–10684 (2002).

Nájera, R., Delgado, E., Pérez-Alvarez, L. & Thomson, M. M. Genetic recombination and its role in the development of the HIV-1 pandemic. AIDS 16 , S3–16 (2002).

Kellam, P. & Larder, B. A. Retroviral recombination can lead to linkage of reverse transcriptase mutations that confer increased zidovudine resistance. J. Virol. 69 , 669–674 (1995).

Morris, A. et al. Mosaic structure of the human immunodeficiency virus type 1 genome infecting lymphoid cells and the brain: evidence for frequent in vivo recombination events in the evolution of regional populations. J. Virol. 73 , 8720–8731 (1999).

Wain-Hobson, S. Down or out in blood and lymph? Nature 387 , 123–124 (1997).

Perelson, A. S. et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387 , 188–191 (1997).

Cohen, O. J. & Fauci, A. S. Transmission of multidrug-resistant human immunodeficiency virus — the wake-up call. N. Engl. J. Med. 339 , 341–343 (1998).

Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278 , 1295–1300 (1997).

Blankson, J. N., Persaud, D. & Siliciano, R. F. The challenge of viral reservoirs in HIV-1 infection. Ann. Rev. Med. 53 , 557–593 (2002).

Smith, B. A. et al. Persistence of infectious HIV on follicular dendritic cells. J. Immunol. 166 , 690–696 (2001).

Igarashi, T. et al. Macrophage are the principal reservoir and sustain high virus loads in rhesus macaques after the depletion of CD4+ T cells by a highly pathogenic simian immunodeficiency virus/HIV type 1 chimera (SHIV): implications for HIV-1 infections of humans. Proc. Natl Acad. Sci. USA 98 , 658–663 (2001).

Clements, J. et al. The central nervous system as a reservoir for simian immunodeficiency virus (SIV): steady-state levels of SIV DNA in brain from acute through asymptomatic infection. J. Infect. Dis. 186 , 905–913 (2002).

Molla, A. et al. Ordered accumulation of mutations in HIV protease confer resistance to ritonavir. Nature Med. 2 , 760–766 (1996).

Wong, J. K. et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278 , 1291–1295 (1997).

Chun, T. -W., Davey, R. T., Engel, D., Lane, H. C. & Fauci, A. S. AIDS: re-emergence of HIV after stopping therapy. Nature 401 , 874–875 (1999). Important paper that explores the development of drug resistance in HIV.

Martinez-Picado, J. et al. Antiretroviral resistance during successful therapy of HIV type 1 infection. Proc. Natl Acad. Sci. USA 97 , 10948–10953 (2000).

Ribeiro, R. M. & Bonhoeffer, S. Production of resistant HIV mutants during antiretroviral therapy. Proc. Natl Acad. Sci. USA 97 , 7681–7686 (2000).

Simon, V. et al. Infectivity and replication capacity of drug-resistant human immunodeficiency virus type 1 variants isolated during primary infection. J. Virol. 77 , 7736–7745 (2003).

Pitisuttithum, P. et al. Safety and immunogenicity of combinations of recombinant subtype E and B human immunodeficiency virus type 1 envelope glycoprotein 120 vaccines in healthy Thai adults. J. Infect. Dis. 188 , 219–227 (2003).

Back, N. K. et al. Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme. EMBO J. 15 , 4040–4049 (1996).

Baba, T. W. et al. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nature Med. 6 , 200–206 (2000).

Greenough, T. C., Sullivan, J. L. & Desrosiers, R. C. Declining CD4 T-cell counts in a person infected with nef-deleted HIV-1. N. Engl. J. Med. 340 , 236–237 (1999).

Berman, P. Preliminary results of VAX004: The first large scale field trial of an HIV vaccine. in Keystone Conference: HIV Vaccine (Banf, CA, 2003).

Gaschen, B. et al. Diversity considerations in HIV-1 vaccine selection. Science 296 , 2354–2360 (2003).

Nickle, D. C. et al. Consensus and Ancestral State HIV Vaccines. Science 299 , 1515–1518 (2003).

Barré-Sinoussi, F. et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220 , 868–871 (1983). Ground-breaking paper that reports the isolation of HIV for the first time.

Walker, P. R., Worobey, M., Rambaut, A., Holmes, E. C. & Pybus, O. G. Sexual transmission of HIV in Africa. Nature 422 , 679 (2003).

Drummond, A. J., Pybus, O. G. & Rambaut, A. Inference of viral evolutionary rates from molecular sequences. Adv. Parasit. 54 , 331–358 (2003). Review that describes the methods for estimating rates of evolution from virus sequences that have been sampled over time.

Download references

Acknowledgements

We thank O. Pybus and D. Robertson for some useful discussion, and A. Rodrigo and two anonymous referees for constructive comments on the draft of this manuscript. Support in the form of a research fellowship from the Royal Society (to A.R.), from the 'Ramón y Cajal' programme of the Spanish government (to D.P.), and from a National Institutes of Health grant (to K.A.C and D.P.) is gratefully acknowledged.

Author information

Authors and affiliations.

Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK

Andrew Rambaut & Edward C. Holmes

Departamento de Bioquímica, Genética e Inmunología, Facultad de Ciencias, Universidad de Vigo, Vigo, 36200, Spain

David Posada

Department of Microbiology and Molecular Biology, Brigham Young University, Provo, 84602, Utah, USA

Keith A. Crandall

You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward C. Holmes .

Ethics declarations

Competing interests.

Andrew Rambaut, David Posada and Keith A. Crandall have undertaken consultancy work for VaxGen, which involved genetic analysis of HIV sequences after the completion of the Phase III trials. Edward C. Holmes has no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article.

Rambaut, A., Posada, D., Crandall, K. et al. The causes and consequences of HIV evolution. Nat Rev Genet 5 , 52–61 (2004). https://doi.org/10.1038/nrg1246

Download citation

Issue Date : 01 January 2004

DOI : https://doi.org/10.1038/nrg1246

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Hiv infection.

Linda-Gail Bekker
Chris Beyrer
Jeffrey V. Lazarus

Nature Reviews Disease Primers (2023)

A large population sample of African HIV genomes from the 1980s reveals a reduction in subtype D over time associated with propensity for CXCR4 tropism

Heather E. Grant
Sunando Roy
Andrew J. Leigh Brown

Retrovirology (2022)

Immunoescape of HIV-1 in Env-EL9 CD8 + T cell response restricted by HLA-B*14:02 in a Non progressor who lost twenty-seven years of HIV-1 control

Oscar Blanch-Lombarte
María Pernas

Fc receptors and the diversity of antibody responses to HIV infection and vaccination

Raphael Carapito
Christiane Moog

Genes & Immunity (2022)

Epidemic spreading under mutually independent intra- and inter-host pathogen evolution

Xiyun Zhang
Zhongyuan Ruan
Baruch Barzel

Nature Communications (2022)

Quick links

Explore articles by subject
Guide to authors
Editorial policies

Update your browser for the best possible experience

As of January 1st, 2020, Internet Explorer (versions 11 and below) is no longer supported by Evolve. To get the best possible experience using Evolve, we recommend that you use another web browser. See the browsers we support. .

Personalize Your Experience

Already have an account? Log In

Free standard shipping is valid on orders of $45 or more (after promotions and discounts are applied, regular shipping rates do not qualify as part of the $45 or more) shipped to US addresses only. Not valid on previous purchases or when combined with any other promotional offers.

Register for an enhanced, personalized experience.

Receive free access to exclusive content, a personalized homepage based on your interests, and a weekly newsletter with topics of your choice.

Home / Innovation & Research / The innovative research behind HIV/AIDS treatment

The innovative research behind HIV/AIDS treatment

Please login to bookmark.

Username or Email Address

Remember Me

It’s been 40 years since the release of the first scientific report describing acquired immune deficiency syndrome (AIDS). Thanks to innovative research, scientists learned how the HIV virus that causes AIDS replicates and how the immune system responds to the virus. Today, many people with HIV take just one pill a day to suppress the virus, and treatment is continuing to evolve.

In this video, Dr. Stacey Rizza , Mayo Clinic infectious disease physician and HIV researcher, explains how dedicated innovative science contributed to where we are today and what scientists are working on for the future.

What did the early research find?

Because of truly dedicated innovative science, within a few years, the scientific community figured out that AIDS was due to HIV. It then took a few years to figure out how to test for that virus. Several years later, the scientific community was able to quantitate how much virus was in a person’s blood. During all this time, truly innovative research into how the virus replicates and how the immune system responds to the virus allowed bio pharmacy companies to develop what we call anti-retroviral drugs or medications to slow down the viral replication. How has medication to treat HIV evolved?

The first drug approved for HIV was in 1987, which was AZT (now known as zidovudine). At that time, it was the fastest drug ever approved by the FDA (Food and Drug Administration) and started the fast-track mechanism through the FDA.

Then several other drugs within that same class were approved in the early 1990s. In late 1995, very early 1996, the first HIV protease inhibitors were approved. At that point, it was possible to combine three different medications from two different classes and completely suppress the HIV replication.

In the last 20 years, we’ve gone from people taking multiple medicines with lots of side effects to many of my patients with HIV now take a single pill a day. That’s a combination of medicines coformulated into one pill a day that’s extremely well-tolerated and completely suppresses their virus. We know it does not eliminate the virus. If they were to stop taking that medicine, the virus would come back. But we now have a handful of people in the world who have been what we called functionally cured of HIV, meaning they’ve gone through some research protocols that eliminated the reservoir of HIV in their body.

The new drugs are so effective in people who have fully suppressed virus that many only need to use two medications to maintain HIV treatment and control. New research is investigating ways to deliver the medications differently, such as a shot that lasts several months, or maybe someday even implantable medication delivery mechanisms so that people don’t have to take the pill every day. It is very exciting that HIV therapy is moving that direction.

Why isn’t there a cure for HIV?

The reason why it is so difficult to cure HIV is that once HIV infects a person’s body, it integrates into the host genome of several cell types. Those cells then hide in any of the lymphoid tissue, such as the lymph nodes, the liver and the spleen. And they lay there as what we call “latent” or “hiding”, as long as the person is on HIV therapy. Anytime a virus does leave a cell, it gets taken care of by HIV therapy. But if the infected individual stops the HIV therapy, that latent virus will come back. To cure HIV, you have to eliminate those hiding viruses in the cells or that latent viral reservoir, which is the term. There are many ways you can approach eliminating the reservoir.

Where is the research now?

One of the more popular ways that have been investigated is something called — and there are many different terms for it — “prime, shock, and kill” or “kick, and kill”, which is essentially giving medications that first wake the virus up from latency and then find ways to make the cells that have the virus susceptible to dying. When the virus is awake, and the cell is susceptible to dying, it kills itself but does not kill any other cells in the body.

Essentially, it specifically targets the HIV-infected cells and eliminates them without hurting anything else. This new science is exciting. It’s getting closer and closer to understanding how to do this effectively. And if you can do that with oral medications rather than fancy therapies like gene therapy or bone marrow transplant, it’s scalable to large parts of the world, and you can touch millions of people that way. That’s where the area of research is on how to make those hiding cells wake up, how to make them sensitive to die, and how to target just the HIV-infected cell.

Will we see a vaccine for HIV?

HIV has been a very hard vaccine to develop. In the world of viruses, vaccines fall into one of three buckets. They fall into the bucket where they respond to antibodies induced by the vaccine, and the vaccines are outstanding. Such viruses include polio, mumps, and lucky for us, SARS-CoV-2. Then we have the second category, like the influenza vaccine, which is about 60% effective. It certainly saves lives and makes a difference, but it’s not perfect. And then we have the third bucket, which quite frankly is the vast majority of viruses that infect humans. And HIV is in that category, where simply forming an antibody to the virus is not adequate to prevent infection. You have to do very sophisticated engineering to induce T cell effects, as well as innate effects and antibody effects. Even then, sometimes it’s very hard to decide what is the part of the virus to target. After decades, and billions of dollars of research, we’re still not there for HIV. There have been many approaches of how to do this science. Many different scientific delivery mechanisms, many different areas of the viruses targeted, many different parts of the immune system targeted, and so far, none of them have been effective at preventing HIV infection.

What needs to happen next?

We still need to slow down the number of people getting infected through good public health measures and good education to stop the HIV epidemic. We still need to get more people who are infected on therapy.

We know we can do it with public health measures. But we also need to find out more about how we eliminate that reservoir and get people cured of the virus in a simple and effective way so that we can cure more people. And the last major hurdle we have is to develop an effective vaccine. We still don’t have a vaccine that can prevent infection, a preventive vaccine, or a therapeutic vaccine where you give it to people who already have the virus that can help them control the infection. A huge amount of research has happened, but we’re still not there yet.

This article originally appeared on Mayo Clinic News Network.

Relevant reading

The Doctors Mayo

The classic biography of a family of physicians and the medical center that bears their name. This book has been acclaimed as the authoritative biography of Dr. William Worrall Mayo and his physician sons since it first was published in 1941. Page count: 437

Discover more Innovation & Research content from articles, podcasts, to videos.

You May Also Enjoy

by Jag Singh, M.D.

by Monica Gandhi, M.D.

by Sister Mary Brigh Cassidy

Privacy Policy

We've made some updates to our Privacy Policy. Please take a moment to review.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Publications
Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

Advanced Search
Journal List
MedEdPORTAL

HIV: A Socioecological Case Study

Jarrett sell.

1 Assistant Professor, Department of Family and Community Medicine, Pennsylvania State University College of Medicine

Daniel George

2 Associate Professor, Humanities Department, Pennsylvania State University College of Medicine

Martha P. Levine

3 Associate Professor of Pediatrics, Psychiatry, and Humanities, Pennsylvania State University College of Medicine

Associated Data

B. SE Case Small-Group Facilitator's Guide.docx

C. SE Case Small-Group Student Guide.docx

D. SE Case Presentation.pptx

All appendices are peer reviewed as integral parts of the Original Publication.

Introduction

New strategies are needed to lower health care costs and address the health care needs of communities, especially for marginalized persons and subpopulations. Improved education in health systems, which encompasses population, community, preventive, and public health, is one way to better train the future physician workforce to meet national and local health care needs. This resource was created as part of an 18-month science of health systems and navigation curriculum.

The purpose of this resource is to use the socioecological model lens to analyze health disparities for marginalized persons and subpopulations. A medically and socially complex patient with HIV is presented as the initial case study that leads to identification of barriers and needs on individual, community, and public policy levels. This is an active-learning resource that includes both small- and large-group discussion driven by self-directed learners using the provided resources.

This resource was successfully implemented as a required session for 150 medical students beginning the second year of medical school. A cohort of 21 students randomly selected to complete a standard online course evaluation for the session, rated their agreement (1 = strong disagreement , 5 = strong agreement ) to the statement “Rate the extent to which the lecture supported your mastery of the learning objectives,” as 4.4, on average.

This curriculum has been implemented and evaluated for medical students, but it is broadly applicable to residents and interprofessional students in health-related fields. It is designed to give learners a practical medical context for the application of principles that may be taught within a health systems or population health course.

Educational Objectives

By the end of the session, learners will be able to:

1. Apply the socioecological model to persons with HIV/AIDS.
2. Analyze causes of health disparities for marginalized patient populations (e.g., LGBT persons).
3. Identify approaches at the clinical, community, and policy levels that clinicians can use to help care and advocate for their patients.

In the Institute of Medicine's 2012 report on primary care and public health, the committee specifically recognized the need “to develop the workforce needed to support the integration of primary care and public health” 1 through “curriculum development and clinical experiences that favor the integration of primary care and public health.” 1 This call for integration is based on several factors, including (1) the unsustainability of our current health care delivery model, (2) the impact of social and environmental determinants of health, (3) the accessibility of population-based data available to guide interventions, and (4) the importance of primary prevention to improve health outcomes and lower costs. New strategies are needed to lower health care costs and address the health care needs of communities, especially for marginalized persons and subpopulations. Improved education in health systems, which encompasses population, community, preventive, and public health, is one way to better train the future physician workforce to meet national and local health care needs.

This resource was created as part of an 18-month science of health systems and navigation curriculum (SyNC) for medical students during their first 2 years of medical school. In addition to undergoing didactic learning with regard to public and population health and the socioecological model, students in the course concurrently visit several regional clinics to participate in patient navigation, which is an experience that informs classroom discussions. Opportunities such as these that bridge didactic and clinical-experiential learning were developed in response to repeated requests for applying these teaching principles during just-in-time feedback sessions.

Students engage with this case during the socioecological medicine module (the fifth of seven modules) at our institution; the case can be easily incorporated into other courses that teach principles of population health, public health, community health, or health systems for a variety of learners. The goal is to apply basic health systems concepts in a real-world setting and highlight the role of physicians in addressing complex health care needs using a systems approach (nursing and public health students could also find this resource useful).

This resource adds to the field of health disparity education by using a case-based approach to analyze a medically complex patient with poor health outcomes and encouraging students to identify multilevel solutions to achieve health equity through a discussion of current health disparities for LGBT individuals, racial minorities, and those affected by HIV. Through this process, learners determine preventative strategies to improve health. There are a growing number of MedEdPORTAL resources that look at health disparities from the lens of cultural competency, 2 communication, 3 – 5 and medical ethics, 6 utilizing didactic, 7 standardized patient, 3 , 4 and team-based 6 , 8 teaching styles. This resource looks at health disparities within the context of the HIV epidemic in the United States with an emphasis on the socioecological model.

Using the lens of the socioecological model, students are able to analyze health disparities for marginalized persons and subpopulations. The socioecological model is

an ecological model for health promotion which focuses attention on both individual and social environmental factors as targets for health promotion HIV interventions. It addresses the importance of interventions directed at changing interpersonal, organizational, community, and public policy, factors which support and maintain unhealthy behaviors. 9

A medically and socially complex patient with HIV is presented as the initial case study that leads to gradual identification of barriers and needs on individual, community, and public policy levels. Background knowledge of HIV for students and facilitators is not required for the session, although the PowerPoint presentation may best be led by someone with experience in caring for patients with HIV. Students are encouraged to move beyond the basic medical aspects of care and to incorporate their experience and knowledge of health systems to identify barriers to health equality and optimal care. During the session, students are actively prompted to propose questions and seek answers in small groups and teams.

Lecture-based courses are under increasing scrutiny as medical pedagogy transitions to a greater focus on learning approaches that are more active, such as case-, problem-, and team-based learning. 10 These emerging modalities enable students to progress beyond acquiring factual knowledge and achieve a depth of understanding through solving complex problems amongst peers as part of a team or group. Whereas learners in lecture-based modes of instruction tend to be motivated to attend class and study lecture notes in order to acquire information, active learning guides students to access this information outside of class and incentivizes their active participation in applied group discussions. These approaches are putting systemic pressure on lecture-based courses—long the hallmark of medical education—to better integrate active learning.

In a course teaching health systems science to 150 second-year medical students, we have found it most effective to anchor student learning in real-world cases that evoke core learning content (e.g., social determinants of health, barriers to health, epidemiology, etc.). In addition to empowering students to explore complex systems-level issues with their peers in an open-ended fashion, such approaches also invite students to apply and synthesize the experiences they have as patient navigators working with underserved patients in the area.

In advance of the 2-hour session, learners ( N = 150) are provided with the presession overview ( Appendix A ) so that they can prepare and begin to think about issues that will be discussed in the case.

During the first hour of the session, learners are divided into small groups of approximately six to 12 students, with one facilitator for each small group. Approximately 14 small-group rooms are needed for this activity, and each group requires printed materials but no electronic equipment. The time line for the 1-hour small-group activity is as follows:

• Check-in (5 minutes).
○ Hand out pages 1 and 2 to the group (10 minutes).
○ Hand out page 3 to the group (10 minutes).
○ Hand out page 4 to the group (15 minutes).
○ Hand out page 5 to the group (15 minutes).
• Checkout (5 minutes).

For the activity, each facilitator should have the small-group facilitator's guide ( Appendix B ) with key points for guiding the discussion. Facilitators need not be content experts, since key learning points are provided, but should be skilled at fostering conversation and group dynamics and at using the Socratic method to spark critical thought in students. Therefore, facilitators can be chosen from a variety of disciplines based solely on interest in facilitating group discussion and the presence of solid facilitation skills. At our institution, facilitators have included physicians, nurses, and administrators, all of whom have had varied expertise and interest in teaching students about health systems. Facilitators may use answers in the small-group facilitator's guide to help students answer the questions as a group. It is important that the facilitator not read the answers verbatim as they are provided as a guide to keep the group discussion on task and to make sure students are examining the case at acceptable levels of complexity. The facilitator should hand out individual pages from the small-group student guide ( Appendix C ) to the small groups at the appropriate time intervals. It is important to designate a timekeeper to limit each activity to its suggested time.

During the second hour of the session, learners join together in a lecture hall for the PowerPoint presentation ( Appendix D ). Approximately 5 minutes is allocated for student travel time between small-group rooms and the lecture hall. Small groups should sit next to each other so that they can collectively respond to questions during the large-group presentation. Ideally, the leader of the large-group session would have some background expertise in the national HIV epidemic and/or public health. The large-group session focuses on broader themes initially identified in the small-group case presentation. The PowerPoint presentation is divided into four sections: (1) HIV in the US, (2) HIV Detection, (3) Engagement in Care, and (4) HIV Prevention.

Three breaks for small-group discussion are included in the presentation. These are opportunities for each small group to reflect on the issues and actively develop solutions to the problems presented. Students may use their computers to research information. There are many answers to these broad questions that may vary regionally. The leader has the choice of assigning different prompting questions to different small groups. After 5–10 minutes of discussion, the small groups should then report their findings to the larger group. The time line for the large-group sessions is as follows:

○ Small-group discussion—Slide 16 (10 minutes).
○ Small-group discussion—Slide 28 (10 minutes).
○ Small-group discussion—Slide 42 (10 minutes).
• Conclusion (5–10 minutes).

This resource was successfully implemented as a required session for 150 medical students beginning the second year of medical school as part of their SyNC course. Facilitators were able to provide feedback on the activities in an open-ended reflection meeting held by course directors after each session. The facilitators noted that providing background information for the small-group session allowed for rich student-led discussion that did not require facilitators to have expertise in HIV, which enabled facilitators instead to focus on highlighting the realistic challenges in medical care that may benefit from a systems-based approach to improve care.

A cohort of 21 students selected randomly by the Office of Medical Education completed standard online course evaluations for the session, rating their agreement using a 5-point Likert scale (1 = strong disagreement, 5 = strong agreement ) and providing open-ended comments about the session. Student mean ratings are as follows:

• Rate the extent to which the lecture supported your mastery of the learning objectives: M = 4.4.
• Rate the learning resource: M = 4.1.
• Rate your perceptions of the lecture overall: M = 4.3.

Students’ open-ended comments included the following statements:

• “Lecture was very well structured and provided both clinical and systems based learning with time for discussion in groups. Really well put-together.”
• “This was one of the best SyNC sessions we have had by far. There was good integration of the case from the first hour and the lecture had solid information as well as practical considerations for future physicians.”
• “It was definitely one of the most engaging and directly applicable sessions we have had. I appreciated the mix of lecture and group activities because it helped keep people engaged and thinking about realistic aspects of care that are not covered in our other courses.”

This resource was a pleasure to create and execute, since it engaged learners in using their creativity and knowledge to critically apply a health systems approach to address current medical needs in the region and nationally. During the session, emphasis was placed not on content delivery but on raising questions, highlighting barriers to care, and allowing learners to formulate plans to improve care. These are skills that are necessary for addressing the current and future health care needs of the nation. Student feedback suggests that the session was well structured, conveyed useful/realistic information, and effectively balanced lecture-based and active-learning approaches.

The case was chosen to highlight a patient with complex medical and social issues and challenge learners, who might not have HIV-specific medical knowledge, to identify gaps in care and potential solutions within the socioecological model. Starting with a realistic patient case introduces issues that are then broadened to larger populations. Strengths of this approach include the ability to connect real-world scenarios with more abstract health systems concepts in a way that challenges learners to integrate knowledge from different disciplines. Students’ feedback demonstrates that they appreciated the realistic case and the balance of small- and large-group activities.

On the other hand, a significant limitation of the session is the broad nature of the topics discussed in only 2 hours. Learners who have little experience in being presented with new information that requires on-the-spot discussion may have more difficulty with the small-group sessions. Many topics, such as LGBT health disparities, touched on during the session could be developed in much greater detail. The session is intended for learners who have some background in health systems education in order to enable them to apply their clinical experience to core principles in health systems. Although it has not been designed for learners with a strong foundation in HIV knowledge, some learners or facilitators without experience or in-depth knowledge of HIV care may have more difficulty during the discussions. Based on facilitator and student feedback, the PowerPoint presentation has been revised to be more concise with regard to the information presented, as well as to allow more time for student discussion.

Because of the variety of topics touched on during the session, there is potential for variable learning, particularly during the small-group sessions. The key points provided in the facilitator's guide and the information presented in the large-group session are intended to reduce learner variability. Having a large-group presenter who is familiar with the information being presented and small-group facilitators who can make sure all the key points are touched on during the session can also help reduce variability.

This session was originally designed for medical students in their second year of medical school, but with additional effort and design, it can likely be adapted for a variety of other learners. It has already been condensed and redesigned for an hour-long teaching session with 15 family medicine residents. That version included a deeper focus on some of the medical aspects while still retaining the emphasis on identifying gaps in care and addressing solutions through a socioecological lens. Further adaptations could be considered for learners within other residency disciplines, as well as social work, public health, or nursing education.

A. SE Case Presession Overview.docx

Disclosures

None to report.

Funding/Support

Ethical approval.

Reported as not applicable.

Publications
Conferences & Events
Professional Learning
Science Standards
Awards & Competitions
Instructional Materials
Free Resources
American Rescue Plan
For Preservice Teachers
NCCSTS Case Collection
Science and STEM Education Jobs
Interactive eBooks+
Digital Catalog
Regional Product Representatives
e-Newsletters
Bestselling Books
Latest Books
Popular Book Series
Submit Book Proposal
Web Seminars
National Conference • New Orleans 24
Leaders Institute • New Orleans 24
Exhibits & Sponsorship
Submit a Proposal
Conference Reviewers
Past Conferences
Latest Resources
Professional Learning Units & Courses
For Districts
Online Course Providers
Schools & Districts
College Professors & Students
The Standards
Teachers and Admin
eCYBERMISSION
Toshiba/NSTA ExploraVision
Junior Science & Humanities Symposium
Teaching Awards
Climate Change
Earth & Space Science
New Science Teachers
Early Childhood
Middle School
High School
Postsecondary
Informal Education
Journal Articles
Lesson Plans
e-newsletters
Science & Children
Science Scope
The Science Teacher
Journal of College Sci. Teaching
Connected Science Learning
NSTA Reports
Next-Gen Navigator
Science Update
Teacher Tip Tuesday
Trans. Sci. Learning

MyNSTA Community

My Collections

Murder by HIV? Grades 9-12 Edition

By Laura B. Regassa, Naowarat (Ann) Cheeptham, Michèle I. Shuster

Share Start a Discussion

This case study gives students an opportunity to draw a conclusion about an actual crime that was prosecuted in Louisiana. A physician was accused of intentionally infecting his ex-girlfriend with HIV-tainted blood drawn from a patient in his practice. The scientific investigation uses bioinformatics tools and relies on the ability to interpret phylogenetic trees. Students develop hypotheses about the crime, then use sequences and online tools to generate a phylogenetic tree to test the hypotheses and render a verdict. The authors have designed and implemented three parallel cases - one for Grades 5-8, one for Grades 9-12, and one for upper-division undergraduates, specifically for a course in molecular evolution. This is the Grades 9-12 version.

Download Case

Date Posted

Identify and isolate DNA sequences from a public database.
Construct a phylogenetic tree.
Describe the basic properties of a phylogenetic tree.
Interpret data from several sources to draw conclusions.

Phylogenetic tree; nucleotide sequences; human immunodeficiency virus; HIV; viral life cycles; mutation rates; reverse transcriptase sequences; murder; crime; criminal investigation; forensics; Louisiana

Subject Headings

EDUCATIONAL LEVEL

High school

TOPICAL AREAS

Ethics, Science and the media, Social issues

TYPE/METHODS

Teaching Notes & Answer Key

Teaching notes.

Case teaching notes are protected and access to them is limited to paid subscribed instructors. To become a paid subscriber, purchase a subscription here .

Teaching notes are intended to help teachers select and adopt a case. They typically include a summary of the case, teaching objectives, information about the intended audience, details about how the case may be taught, and a list of references and resources.

Download Notes

Answer Keys are protected and access to them is limited to paid subscribed instructors. To become a paid subscriber, purchase a subscription here .

Download Answer Key

Materials & Media

Supplemental materials, you may also like.

Web Seminar

Join us on Monday, October 28, from 7:00 PM to 8:15 PM ET, to learn about how to safely use lithium-ion batteries in instructional spaces....

Allergy & Immunology
Anesthesiology
Critical Care
Dermatology
Diabetes & Endocrinology
Emergency Medicine
Family Medicine
Gastroenterology
General Surgery
Hematology - Oncology
Hospital Medicine
Infectious Diseases
Internal Medicine
Multispecialty
Ob/Gyn & Women's Health
Ophthalmology
Orthopedics
Pathology & Lab Medicine
Plastic Surgery
Public Health
Pulmonary Medicine
Rheumatology
Transplantation
Today on Medscape
Business of Medicine
Medical Lifestyle
Science & Technology
Medical Students
Pharmacists

Latest HIV Cure Case Comes With a Twist

Richard Mark Kirkner

July 29, 2024

The first HIV cure case in which the stem cell donor had a single — rather than double — gene mutation is opening the donor pool in renewed cure efforts to make stem cell transplants more widely available.

The anonymous patient is the first to achieve long-term HIV remission — in this case approaching 6 years — after receiving a single CCR5 delta 32 mutation. Specifically, the patient received a CCR5 wild-type, delta 32 transplant, known as a heterozygous transplant, for acute myeloid leukemia , investigators reported at the International AIDS Conference 2024 in Munich, Germany.

Other cures have involved donors with two copies of the CCR5 delta 32 mutation, known as homozygous.

Researchers are calling the anonymous patient "the next Berlin patient," an homage to Timothy Ray Brown, the first, now renowned, American patient living at the time in Germany who was cured of HIV.

Brown — dubbed an ambassador of hope — would never test positive for HIV again, but at age 54, it would be the leukemia that led to his HIV cure that would take Brown's life after spreading to his brain and spinal cord.

Expanding the Donor Pool

Since then, four others who received the dual-copy mutation in a homozygous stem cell transplant have experienced long-term HIV remission.

Another case, known as the "Geneva patient," received a stem cell transplant from a wild-type CCR5 donor. Researchers from Geneva, Switzerland, reported that case last year at the conference.

Using donors with single mutations in addition to those with double mutations could meaningfully expand the pool of donors and the availability of allogeneic stem cell transplantation, said Christian Gaebler, MD, coleader of the personalized infectious medicine program at the Berlin Institute of Health and associate professor at Charité – Universitätsmedizin Berlin, who presented the case at the conference.

"When we don't find a donor with these delta 32 mutations — and it's hard to find them, especially in geographical regions outside western or northern countries where it's almost impossible to find a homozygous delta 32 donor — it may be beneficial to take a heterozygous donor," Gaebler said during an interview. "They're easier to find."

"This case is giving us hope that there is still a cure and underlying mechanisms that we're currently not understanding," said Christoph Spinner, MD, MBA, an infectious disease specialist at the University Hospital of the Technical University of Munich, and AIDS 2024 conference co-chair.

"Research is needed to understand and translate the findings of this case for the cure research around the globe," he said.

Reducing the HIV Reservoir

The key mechanism in a cure is depletion of the HIV reservoir, Gaebler said, but more work is needed to better understand its role.

The most recent cured patient had the stem cell transplant to treat acute myeloid leukemia initially, Gaebler explained, and more than 5 years after the stem cell transplant and after discontinuing antiretroviral therapy, the patient has undetectable levels of HIV DNA and HIV RNA as well as higher levels of CD4+ and CD8+ T cells, he said.

"When we see this next Berlin patient and that we're coming close to 6 years of HIV remission, I think we can quite confidently say we can have HIV reservoir reduction, HIV remission, and potentially HIV cure independent of the CCR5 status," Gaebler said.

"These initial cases of HIV cure have triggered a lot of studies looking at CCR5 and basically modulating CCR5 expression, gene-edited cells, [and] CCR5 blockage," he pointed out after his presentation. "This is all very valid and it will likely play a role, but it probably comes down to a combination of these things," he said.

Send comments and news tips to [email protected] .

TOP PICKS FOR YOU

Perspective
Drugs & Diseases
Global Coverage
Additional Resources
Why Some of the Most Capable Nations Won't Hit UNAIDS Targets
US Urges Court to Preserve Obamacare Mandate to Cover Cancer Screenings, HIV Drugs
GSK Gives Few Clues on Plans to Replenish Medicine Cabinet
Drugs bictegravir/emtricitabine/tenofovir AF
Diseases & Conditions Cutaneous Manifestations of HIV
Tables & Protocols HIV Treatment Regimens CDC Guidelines, Adult/Adolescent
Diseases & Conditions Laboratory Assays for Diagnosis and Monitoring of HIV Infection
Laboratory Assays for Diagnosis and Monitoring of HIV Infection
HIV Infection and AIDS
Early Symptomatic HIV Infection
Pediatric HIV Infection
HIV Treatment Regimens CDC Guidelines, Adult/Adolescent
Ocular Manifestations of HIV Infection
Sexual Abuse: The 'Hidden Pediatric Problem'
US, Mexican Border Restrictions Did Not Reduce HIV Infection
Rituximab Tied to Increased Infection Risk in RRMS
Could a Fungal Infection Cause a Future Pandemic?

IMAGES

PPT
Overview of HIV/AIDS case studies
(PDF) The impact of HIV and AIDS research: a case study from Swaziland
Case Study
Hiv Case Study Presentation
Case study: Progression of HIV to AIDS

VIDEO

Tripura HIV case| Increase HIV Annually in Tripua #aids #tripura #students
HIV Case Study
Case Discussion || HIV || CNS Infection
Tripura HIV case,intoxication #tripura #HIV #AIDS
Study: Anti-retroviral therapy eliminates transmission risk
Tripura HIV Case#tranding #news #tripura #viral #hospital #biggboss #tripuranews

COMMENTS

HIV & TB HESI CASE STUDY Flashcards
After 3 days, the nurse receives the results from Raymond's TB skin test that was administered at his HCP's office. Even though Raymond's reaction to the TB skin test measures only 5mm, the HCP documents a positive test result. A new graduate nurse finds this confusing. The new graduate nurse thought that a 10mm induration was the minimum size ...
HESI Case Study: HIV & TB Flashcards
What statement shows that Jeff understands why he is at risk for TB? My T-helper cells are diminished from HIV and those cells are needed to fight HIV. How should the nurse preceptor respond? This is not always true. 5mm induration is considered positive in an HIV positive client. How should the nurse respond?
Case 9-2018: A 55-Year-Old Man with HIV Infection and a Mass on the
Dr. Robert H. Goldstein (Medicine): A 55-year-old man with Crohn's disease and a new diagnosis of human immunodeficiency virus type 1 (HIV-1) infection was seen in the infectious diseases clinic ...
Case 27-2021: A 16-Year-Old Boy Seeking Human Immunodeficiency Virus
Dr. Anne M. Neilan: This 16-year-old, sexually active male adolescent was referred for an evaluation for HIV PrEP. An estimated 1 in 2 Black men who have sex with men in the United States will ...
New study: HIV can evolve to be more severe
"Let this study stand in stark contrast to the claim that all viruses will inevitably evolve to be benign." A contagious new discovery The discovery of the HIV variant was sparked by a curious set ...
Journey from victim to a victor—a case study of people living with HIV
This case study is about Anamika (name changed), a 35-year-old female who is an empowered HIV-positive and presently works as Community Co-ordinator at an anti-retroviral treatment (ART) centre. Her transformation from a victim of social stigma and discrimination due to her HIV-positive status to her present role has been possible due to her ...
NU372 Week 2 HESI Case Study: Human Immunodeficiency Virus (HIV) and
UMB NU372 NURS32 NU 372 Concepts of Health and Illness I (UMB UMass Boston, Fall 2021) HESI Human Immunodeficiency Virus (HIV) and Tuberculosis (TB)
Understanding HIV's evolutionary past
HIV today. More than 30 years after scientists discovered HIV as the cause of the then-unfolding AIDS pandemic, there's much we still don't understand about the virus. Emerman and his research team study how HIV evolved to adapt to the human immune system, but much of their work is focused on the human and other primate genes that produce proteins that defend — or fail to defend ...
The causes and consequences of HIV evolution
The present genetic diversity of HIV is the result of multiple cross-species transfers to humans from African non-human primates. HIV-1 has its origin in chimpanzees and is the result of three ...
PDF Murder by HIV? Grades 9-12 Edition
NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE Introduction HIV-1 mutates very rapidly. Because of its high mutation rate, the virus will continue to change (evolve) after a person is infected. Thus, within an infected individual, there may be multiple variants of the virus, all of which diverged from the same strain since the time of ...
HESI: Case Studies:
On Demand Training • Classic HESI: Case Studies: 1. Introduction 2. Functionality 3. Submissions and Settings 4. Visibility 5. Delivery Options
PDF TEACHER'S GUIDE Case Study
When did HIV evolve? When the first cases of AIDS were reported in the early 1980s, the cause of ... One of the case studies in the book is the (now discredited) Oral Polio Vaccine (CHAT) theory ...
HESI Case Studies: Complete RN Collection (1 Year Version ...
Use your knowledge and apply key concepts to realistic patient care scenarios. HESI Case Studies provide real-world patient care scenarios accompanied by application-based questions and rationales that will help you learn how to manage complex patient conditions and make sound clinical judgments. Questions cover nursing care for patients with a wide variety physiological and psychosocial ...
Recent advances in understanding HIV evolution
Recent advances in understanding HIV evolution. The human immunodeficiency virus (HIV) evolves rapidly owing to the combined activity of error-prone reverse transcriptase, recombination, and short generation times, leading to extensive viral diversity both within and between hosts. This diversity is a major contributing factor in the failure of ...
HESI RN Case Study: HIV/TB Flashcards
2.5 (6 reviews) Raymond Malone, age 45 years admitted from his healthcare provider's office (HCP) to the acute care facility. Jeff was diagnosed HIV positive 2 years ago. His history includes fatigue, a productive cough, and weight loss. A tuberculosis (TB) test was administered in the healthcare provider's office.
The innovative research behind HIV/AIDS treatment
Thanks to innovative research, scientists learned how the HIV virus that causes AIDS replicates and how the immune system responds to the virus. Today, many people with HIV take just one pill a day to suppress the virus, and treatment is continuing to evolve. In this video, Dr. Stacey Rizza, Mayo Clinic infectious disease physician and HIV ...
Origins of HIV and the AIDS Pandemic
Ever since HIV-1 was first discovered, the reasons for its sudden emergence, epidemic spread, and unique pathogenicity have been a subject of intense study. A first clue came in 1986 when a morphologically similar but antigenically distinct virus was found to cause AIDS in patients in western Africa (Clavel et al. 1986).
History of HIV/AIDS
The doctors who worked on his case at the time suspected he was a prostitute or the victim of sexual abuse, though the patient did not discuss his sexual history with them in detail. 1973: Ugandan children ... The study "HIV-1 Infection Among Intravenous Drug Users in Manhattan, New York City, from 1977 through 1987", ...
PN Human Immunodeficiency Virus (HIV) and Tuberculosis (TB) HESI Case Study
B. Liver function should be routinely monitored. In revising the plan of care, the PN and RN first discuss the client's positive tuberculin skin test. Which understanding by the PN would be correct? D. A 5 mm induration is considered positive if a client is immunosuppressed.
HIV: A Socioecological Case Study
Methods. The purpose of this resource is to use the socioecological model lens to analyze health disparities for marginalized persons and subpopulations. A medically and socially complex patient with HIV is presented as the initial case study that leads to identification of barriers and needs on individual, community, and public policy levels.
Murder by HIV? Grades 9-12 Edition
Abstract. This case study gives students an opportunity to draw a conclusion about an actual crime that was prosecuted in Louisiana. A physician was accused of intentionally infecting his ex-girlfriend with HIV-tainted blood drawn from a patient in his practice. The scientific investigation uses bioinformatics tools and relies on the ability to ...
Latest HIV Cure Case Comes With a Twist
The first HIV cure case in which the stem cell donor had a single — rather than double ... "These initial cases of HIV cure have triggered a lot of studies looking at CCR5 and basically ...
Study shows promise for a universal flu vaccine
The study, published today in ... This approach harnesses a vaccine platform previously developed by scientists at OHSU to fight HIV and tuberculosis, and in fact is already being used in a clinical trial against HIV. ... The spike proteins on the virus exterior surface evolve to elude antibodies. In the case of flu, vaccines are updated ...
Chapter 1
1. HIV integrates its genome into a host cells genome and can lie dormant there where it cannot be destroyed by medication. 2. HIV strains can spread easily and mutation rate is fast - or it is hard to interrupt the viruses lifecycle without interrupting the host cells lifecycle - can only target a few enzymes that are specific to HIV - idk.