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May 13, 2024

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Herpes cure with gene editing makes progress in laboratory studies

by Fred Hutchinson Cancer Center

Researchers at Fred Hutch Cancer Center have found in pre-clinical studies that an experimental gene therapy for genital and oral herpes removed 90% or more of the infection and suppressed how much virus can be released from an infected individual, which suggests that the therapy would also reduce the spread of the virus.

"Herpes is very sneaky. It hides out among nerve cells and then reawakens and causes painful skin blisters," said Keith Jerome, MD, Ph.D., professor in the Vaccine and Infectious Disease Division at Fred Hutch. "Our aim is to cure people of this infection, so that they don't have to live with the worry of outbreaks or of transmitting it to another person."

Published May 13 in Nature Communications , Jerome and his Fred Hutch team published an encouraging step toward a gene therapy for herpes.

The experimental gene therapy involves injecting into the blood a mixture of gene editing molecules that seek out where the herpes virus resides in the body. The mixture includes laboratory-modified viruses called a vector—commonly used in gene therapies—plus enzymes that work like molecular scissors. Once the vector reaches the clusters of nerves where the herpes virus hangs out, the molecular scissors snip away at the herpes virus's genes to damage them or remove the virus entirely.

"We are using a meganuclease enzyme that cuts in two different places in the herpes virus's DNA," said first author Martine Aubert, Ph.D., principal staff scientist at Fred Hutch. "These cuts damage the virus so much that it can't repair itself. Then the body's own repair systems recognize the damaged DNA as foreign and get rid of it."

Using mouse models of the infection, the experimental therapy eliminated 90% of herpes simplex virus 1 (HSV-1) after facial infection, also known as oral herpes, and 97% of herpes HSV-1 after genital infection. It took about a month for the treated mice to show these reductions, and the reduction of virus seemed to get more complete over time.

In addition, the researchers found that the HSV-1 gene therapy had a significant reduction in both the frequency and amount of viral shedding.

"If you talk to people living with herpes, many are worried about whether their infection will transmit to others," Jerome said. "Our new study shows that we can reduce both the amount of virus within the body and how much virus is shed."

The Fred Hutch team also simplified their gene editing treatment, making it safer and easier to make. In a 2020 study , they used three vectors and two different meganucleases. The latest study uses just one vector and one meganuclease capable of cutting the virus DNA in two places.

"Our streamlined gene editing approach is effective at eliminating the herpes virus and has less side effects to the liver and nerves," Jerome said. "This suggests that the therapy will be safer for people and easier to make, since it has fewer ingredients."

While the Fred Hutch scientists are encouraged by how well the gene therapy works in animal models and are eager to translate the findings to treatments for people, they are also careful about the steps needed to prepare for clinical trials . They also noted that though the current study examined HSV-1 infections, they are working on adapting the gene editing technology to target HSV-2 infections.

"We're collaborating with numerous partners as we approach clinical trials so we align with federal regulators to ensure safety and effectiveness of the gene therapy," Jerome said. "We deeply appreciate the support of herpes advocates as they share our vision for curing this infection."

Herpes simplex virus (HSV) is a common infection that lasts a lifetime once people are infected. Current therapies can only suppress but not completely eliminate symptoms, which include painful blisters. According to the World Health Organization , an estimated 3.7 billion people under the age of 50 (67%) have HSV-1, which causes oral herpes. An estimated 491 million people aged 15-49 (13%) worldwide have HSV-2, which causes genital herpes.

Herpes can create other harms to people's health. HSV-2 increases the risk of acquiring HIV infection. Other studies have linked dementia with HSV-1.

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Genital Herpes Treatments in the Pipeline

Researchers are hard at work on new treatments to fight genital herpes, otherwise known as herpes simplex virus 2.

Microbicides are one option scientists are exploring in the search for new genital herpes treatments . Microbicides are chemicals that protect against infection by killing microbes (small organisms such as bacteria and viruses) before they enter the body. Two products show some promise -- tenofovir gel and siRNA nanoparticles -- microbicides that are applied to the vagina . Studies show these may be able to kill herpes , as well as some other sexually transmitted viruses, and even reduce the spread of the herpes virus from person to person.

Pritelivir is a new class of drugs that targets the DNA of the virus and stops it from replicating.  It has received FDA approval and is taken orally each day.

Scientists also are working on other new drugs that keep the herpes virus from replicating. To replicate (make copies of itself), a virus has to duplicate its DNA exactly. Scientists hope these new drugs will prevent the virus from doing that.

Everyone would like a vaccine that protects against HSV-2, but experimental products have had mixed and somewhat discouraging results.

Clinical Trials: Key to Genital Herpes Research

Although these new genital herpes treatments are just on the horizon, it may be years before any are available to consumers.

The process of introducing a new treatment to the public can be a long one. Before the FDA approves a drug, it must go through rigorous clinical trials , which are divided into three phases. In phase I, researchers try to find out if the drug is safe for people to take. If the drug is deemed safe, it may go on to phase II, when researchers aim to determine if the drug works as it should. They also collect more safety data. In phase III trials, they expand their research to include more patients in more places.

To conduct a clinical trial, scientists need people to participate voluntarily. Clinical trials often involve thousands of patients who volunteer to take the experimental drug. The FDA and an independent review board carefully monitor every aspect of the trial. There are rules the researchers must follow to ensure that their work is scientifically correct and ethically sound. Study volunteers have clearly defined rights, such as the right to drop out of the trial at any time.

While there are risks involved in joining a clinical trial, there may be benefits, too. You might get a new "wonder drug" long before it hits the market. If you're interested, ask your doctor if you could benefit by joining one. Your doctor may know of a trial that is seeking volunteers in your area. The National Institutes of Health also has an online database that you can search. This web site provides detailed information on what's involved in joining a clinical trial.

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We thought herpes was untreatable. Now, that might change

“Herpes is very sneaky. It hides out among nerve cells and then reawakens and causes painful skin blisters,” said  Keith Jerome, MD, PhD , professor in the Vaccine and Infectious Disease Division at Fred Hutch. “Our aim is to cure people of this infection, so that they don’t have to live with the worry of outbreaks or of transmitting it to another person.”

Published May 13 in  Nature Communications , Jerome and his Fred Hutch team report an encouraging step toward a gene therapy for herpes.

The experimental gene therapy involves injecting into the blood a mixture of gene editing molecules that seek out where the herpes virus resides in the body. The mixture includes laboratory-modified viruses called a vector — commonly used in gene therapies — plus enzymes that work like molecular scissors. Once the vector reaches the clusters of nerves where the herpes virus hangs out, the molecular scissors snip away at the herpes virus’s genes to damage them or remove the virus entirely.

“We are using a meganuclease enzyme that cuts in two different places in the herpes virus’s DNA,” said first author  Martine Aubert, PhD , principal staff scientist at Fred Hutch. “These cuts damage the virus so much that it can’t repair itself. Then the body’s own repair systems recognize the damaged DNA as foreign and get rid of it.”

Using mouse models of the infection, the experimental therapy eliminated 90% of herpes simplex virus 1 (HSV-1) after facial infection, also known as oral herpes, and 97% of herpes HSV-1 after genital infection. It took about a month for the treated mice to show these reductions, and the reduction of virus seemed to get more complete over time.

In addition, the researchers found that the HSV-1 gene therapy had a significant reduction in both the frequency and amount of viral shedding.

“If you talk to people living with herpes, many are worried about whether their infection will transmit to others,” Jerome said. “Our new study shows that we can reduce both the amount of virus within the body and how much virus is shed.”

The Fred Hutch team also simplified their gene editing treatment, making it safer and easier to make. In a  2020 study , they used three vectors and two different meganucleases. The latest study uses just one vector and one meganuclease capable of cutting the virus DNA in two places.

“Our streamlined gene editing approach is effective at eliminating the herpes virus and has less side effects to the liver and nerves,” Jerome said. “This suggests that the therapy will be safer for people and easier to make, since it has fewer ingredients.”

While the Fred Hutch scientists are encouraged by how well the gene therapy works in animal models and are eager to translate the findings to treatments for people, they are also careful about the steps needed to prepare for clinical trials. They also noted that though the current study examined HSV-1 infections, they are working on adapting the gene editing technology to target HSV-2 infections.

“We’re collaborating with numerous partners as we approach clinical trials so we align with federal regulators to ensure safety and effectiveness of the gene therapy,” Jerome said. “We deeply appreciate the support of herpes advocates as they share our vision for curing this infection.”

Herpes simplex virus (HSV) is a common infection that lasts a lifetime once people are infected. Current therapies can only suppress but not completely eliminate symptoms, which include painful blisters. According to the  World Health Organization , an estimated 3.7 billion people under the age of 50 (67%) have HSV-1, which causes oral herpes. An estimated 491 million people aged 15-49 (13%) worldwide have HSV-2, which causes genital herpes.

Herpes can create other harms to people’s health. HSV-2 increases the risk of acquiring HIV infection. Other studies have linked dementia with HSV-1.

The work was funded by the National Institutes of Health, the Caladan Foundation and more than 2,000 individual donors. The meganucleases used in this research are derivatives of commercially-available meganucleases.

Note: Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future.

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New gene therapy approach eliminates at least 90% latent herpes simplex virus 1

SEATTLE — August 18, 2020 — Infectious disease researchers at Fred Hutchinson Cancer Research Center have used a gene editing approach to remove latent herpes simplex virus 1, or HSV-1, also known as oral herpes. In animal models, the findings show at least a 90 percent decrease in the latent virus, enough researchers expect that it will keep the infection from coming back.

The study, published August 18 in Nature Communications , used two sets of genetic scissors to damage the virus’s DNA, fine-tuned the delivery vehicle to the infected cells, and targeted the nerve pathways that connect the neck with the face and reach the tissue where the virus lies dormant in individuals with the infection.

“This is the first time that scientists have been able to go in and actually eliminate most of the herpes in a body,” said senior author Dr. Keith Jerome , professor in the Vaccine and Infectious Disease Division at Fred Hutch. “We are targeting the root cause of the infection: the infected cells where the virus lies dormant and are the seeds that give rise to repeat infections.”

Most research on herpes has focused on suppressing the recurrence of painful symptoms, and Jerome said that his team is taking a completely different approach by focusing on how to cure the disease.

“The big jump here is from doing this in test tubes to doing this in an animal,” said Jerome, who also leads the Virology Division at UW Medicine. “I hope this study changes the dialog around herpes research and opens up the idea that we can start thinking about cure, rather than just control of the virus.”

Two-thirds of the world population under the age of 50 have HSV-1, according to the World Health Organization. The infection primarily causes cold sores and is lifelong.

In the study, the researchers used two types of genetic scissors to cut the DNA of the herpes virus. They found that when using just one pair of the scissors the virus DNA can be repaired in the infected cell. But by combining two scissors – two sets of gene-cutting proteins called meganucleases that zero in on and cut a segment of herpes DNA – the virus fell apart.

“We use a dual meganuclease that targets two sites on the virus DNA,” said first author Martine Aubert , a senior staff scientist at Fred Hutch. “When there are two cuts, the cells seem to say that the virus DNA is too damaged to be repaired and other molecular players come in to remove it from the cell body.”

The dual genetic scissors are introduced into the target cells by delivering the gene coding for the gene-cutting proteins with a vector, which is a harmless deactivated virus that can slip into infected cells. The researchers injected the delivery vector into a mouse model of HSV-1 infection, and it finds its way to the target cells after entering the nerve pathways.

The researchers found a 92% reduction in the virus DNA present in the superior cervical ganglia, the nerve tissue where the virus lies dormant. The reductions remained for at least a month after the treatment and is enough the researchers say to keep the virus from reactivating.

The team did other comparisons to fine-tune the gene editing approach:

-       Gene cuts with meganucleases were more efficient that with CRISPR/Cas9.

-       Refining the vector delivery mechanism, they found the adeno-associated virus (AAV) vector that was the most efficient at getting the gene edits to cells infected with the virus.

The researchers are pursuing a similar strategy for herpes simplex 2, which causes genital herpes. They expect it to take at least 3 years to move toward clinical trials.

“This is a curative approach for both oral and genital HSV infection,” Aubert said. “I see it going into clinical trials in the near future.”

The National Institutes of Health (R21AI117519 and R01AI132599) and Caladan Foundation funded the study along resources from the Fred Hutch/University of Washington Cancer Consortium (P30 CA015704) and philanthropic donors to Fred Hutch.

Note: Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future.

Media Contact: Molly McElroy 206.667.2210 [email protected]   

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• v.117; 2022

Family Herpesviridae and neuroinfections: current status and research in progress

Vanessa salete de paula.

1 Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Virologia Molecular, Rio de Janeiro, RJ, Brasil

This article addresses the relationship between human herpesviruses (HHVs) and neuroinfections. Alphaherpesviruses, betaherpesviruses and gammaherpesviruses are neurotropic viruses that establish latency and exhibit reactivation capacity. Encephalitis and meningitis are common in cases of HHV. The condition promoted by HHV infection is a purported trigger for certain neurodegenerative diseases. Ongoing studies have identified an association between HSV-1 and the occurrence of Alzheimer’s disease, multiple sclerosis and infections by HHV-6 and Epstein-Barr virus. In this review, we highlight the importance of research investigating the role of herpesviruses in the pathogenesis of diseases that affect the nervous system and describe other studies in progress.

Neurological disorders are among the leading causes of global mortality. Although the aetiology of neuroinfections is unclear, recent studies have linked the onset of neurological disorders to herpesvirus infection, which can cause neurological symptoms or lead to immune responses that trigger pathological signs. Currently, this relationship is primarily based on epidemiological data regarding infections and the seroprevalence of patients with neurological disorders.

The Herpesviridae family comprises nine viruses that cause infections in humans and is divided into three subfamilies: Alphaherpesvirinae , Betaherpesvirinae and Gammaherpesvirinae [International Committee on Taxonomy of Viruses (ICTV 2021)]. These viruses are prevalent worldwide and cause various diseases, including cold sores, genital herpes, stromal keratitis, cancer, meningitis and encephalitis. All herpesviruses have two replication cycles: lytic and latent. Lytic replication produces particles to infect other cells and organisms, whereas latency has limited gene expression and absence of infectious particles. Herpesviruses establish latency at different sites ( Table ) and can cause disease during both primary infection and reactivation; however, the mechanisms leading to latency and reactivation and the viral and host factors controlling them remain unclear. Thus, we present the main clinical manifestations of each type of herpesvirus and demonstrate that, in addition to classical disorders such as encephalitis, other neurological manifestations have been associated with herpesviruses, such as multiple sclerosis (MS), epilepsy, schizophrenia and Alzheimer’s disease (AD).

EBV: Epstein-Barr virus; HCMV: human cytomegalovirus; HHV: human herpesvirus; HSV: herpes simplex virus; ICT: International Committee on Taxonomy of Viruses; VZV: varicella zoster virus.

Alphaherpesvirus Human alphaherpesvirus 1 and 2 Herpes simplex viruses (HSVs) 1 and 2

HSV, which belongs to the Alphaherpesvirinae subfamily, was first isolated in 1920 by Gruter; 1 however, HSV categorisation into herpes simplex 1 (HSV-1) and herpes simplex 2 (HSV-2), based on epidemiological, clinical and immunological differences, was done only in 1968. 2 ) HSV has a double-stranded DNA genome, approximately 152 kb in HSV-1 and 155 kb in HSV-2. 3 , 4 ) In general, HSV-1 causes skin lesions in the orolabial region; however, it can also cause serious complications such as herpetic keratitis. 5 ) HSV-1 can also cause genital herpes, although this is a characteristic symptom of HSV-2 infection, with genital or anal blisters or ulcers. 6

After infection and replication in epithelial cells, HSV migrates via retrograde axonal transport to the dorsal root ganglia, where it establishes latency in neurons and can cause neurological disorders. 5 , 7 ) After primary infection, immunological changes in the host organism can lead to HSV reactivation in which viral particles are transported to axon terminals in an anterograde fashion. 8 Released viral particles promote the infection of new epithelial cells and can infect neurons and reach the central nervous system (CNS), triggering inflammatory responses driven by microglia. This persistent activation has harmful effects on neurons and contributes to neurological diseases. 9

HSV is widely associated with neurological disorders, such as encephalitis, meningitis and meningoencephalitis, 10 ) where immunosuppression by other etiological agents during the course of infection is one of the triggers for the reactivation of HSV-1 and HSV-2, worsening the prognosis. 11 ) In fact, a recent study observed the occurrence of HSV encephalitis in post-coronavirus disease (COVID) syndrome patients, possibly caused by reactivation during immune dysregulation in SARS-CoV-2 infection. 12

Several studies have proposed an association between HSV-1 infection and neurodegenerative disease. 8 , 13 ) It is hypothesised that HSV-1 modulates neuronal apoptosis during acute and latent infection, which may be related to changes in neuronal processes, leading to neuronal damage and brain diseases. 8 ) An increasing number of studies support the involvement of HSV-1 in AD. Viral infection induces the accumulation of beta-amyloid proteins and phosphorylated tau protein, which are considered important components in AD progression. 14 - 16 ) Despite many questions that require clarification, these data indicate a strong link between HSV-1 and AD, warranting further investigation.

Human alphaherpesvirus 3 Varicella zoster virus (VZV)

VZV, isolated in 1952 by Thomas H. Weller in tissue culture, has a genome of 125 kb (17, 18) and infects epithelial cells of the upper respiratory mucosa, subsequently causing a vesicular eruption that is widely distributed throughout the body and varicella. 19 Similar to other alphaherpesviruses, it infects neurons during primary infection, reaching the ganglia by retrograde axonal transport where latency is established. 20 ) Decline in immunity can reactivate VZV, causing herpes zoster and triggering complications such as neuropathic pain called post-herpetic neuralgia, resulting from neuron damage caused by the inflammatory response to the reactivation and migration of VZV. 21 Thus, similar to other herpesviruses, VZV also causes meningoencephalitis as a consequence of viral reactivation. 22 In addition, VZV penetrates the walls of cerebral arteries after reactivation in nerve ganglia and can cause vasculopathy via productive infection by the virus in the cerebral arteries, leading to ischemic stroke, aneurysm and cerebral venous thrombosis. 22 , 23 ) Studies have indicated that neuroinflammation and immunological changes triggered by some neurotropic viruses play an important role in neurodegeneration. Researchers have also aimed to identify a link between VZV infection and neurodegenerative diseases. 24 , 25

Betaherpesviruses Human betaherpesvirus 5 Human cytomegalovirus (HCMV)

HCMV, first isolated in 1956, 26 ) has the largest genome of any known human virus. Its genome is 236 kb in size and contains a double-stranded DNA molecule comprising two unique regions, each flanked by inverted repeats. 27 HCMV is a β-herpesvirus found at a frequency of 40-100% in the adult population worldwide. 28 ) Being a herpesvirus, it establishes latency that can lead to periodic reactivation. Infections in healthy individuals are commonly asymptomatic; 29 ) however, immunocompromised individuals can develop serious illnesses and even die because of HCMV infection.

Although the primary infection in immunocompetent adults is asymptomatic, viremia can persist for weeks or even months. 30 ) HCMV can infect most cells in the human body, and infection of the renal epithelial cells and salivary glands allows viral transmission through saliva and urine for months, thereby transmitting it to new hosts. When the host immune response fails, the HCMV may access the CNS through the “Trojan horse” system by infecting endothelial cells, monocytes or macrophages. Some studies have also suggested its propagation through cerebrospinal fluid (CSF). 31

Tissue necrosis observed in the CNS is because of direct cytopathology mediated by HCMV as well as by cytotoxic cytokines, interleukins and tumour necrosis factor. 32 ) Most pre- or immediately post-natal infections are characterised by increased viral replication, greater risk of persistence and, consequently, more severe conditions than those associated with infections acquired at an older age. 33 ) HCMV is the leading cause of congenital viral infections, the most common non-genetic cause of hearing loss and a major cause of neurodevelopmental delay. It affects 0.2-2% of all newborns worldwide. 34 ) Approximately 10-15% of children with congenital HCMV are symptomatic at birth. The infection presents with various symptoms, such as intrauterine growth retardation, hepatosplenomegaly, jaundice and neurodevelopmental deficits. 35

In adults, HCMV encephalitis presents with several neurological symptoms, most of which occur in human immunodeficiency virus (HIV)-infected and immunosuppressed patients. 36 It has an observable affinity with the limbic system, an area known to be affected in schizophrenia, and is a chronic neuropsychiatric disorder characterised by abnormalities involving brain structure and function. 37

An immunocompetent patient who presented with auditory hallucinations, delusions, tangential thinking and flattened affect was initially diagnosed with schizophrenia until a post-mortem analysis based on neuropathological findings and CSF antibody levels indicated HCMV encephalitis. 38 ) An association with a sensorimotor control deficit has been identified in rodent models infected with HCMV, similar to that reported in individuals with schizophrenia. 39

Based on the literature, neuropathogenesis in individuals infected with HCMV is unclear because of the lack of an adequate experimental models and lack of dedicated research.

Human betaherpesvirus 6 Human herpesvirus 6 (HHV-6A/B)

HHV-6 was first isolated in 1986 by Salahuddin et al. ( 40 ) in patients with lymphoproliferative diseases or acquired immunodeficiency syndrome. Subsequent studies suggested the existence of two variants of HHV-6, variant A or HHV-6A, initially isolated by Salahuddin et al., 40 and variant B or HHV-6B, which was isolated from peripheral blood lymphocytes of patients with sudden rash by Yamanishi et al. 41 ) The IVTV has recognised HHV-6 variants as two distinct viruses: HHV-6A, having a higher level of virulence and considered the most cytolytic, and HHV-6B, the causative agent of exanthema subitum, present in infantile roseola (an acute childhood disease that characteristically presents with a high fever followed by a generalised rash). 42 However, the term HHV-6 remains in use to collectively refer to both species. Although the genomes of the two viruses share 90% global identity, the size of the HHV-6A genome is 159 kb, whereas that of HHV-6B is 162 kb. 43 , 44 ) HHV-6B was designated as a human B lymphotropic virus because it has tropism for B cells. 40 HHV-6 is pleiotropic, replicates well in CD4+ T lymphocytes and can proliferate in macrophages, fibroblasts and other cells. 45

HHV-6B infection is very common in children between the ages of 2 and 3 years. 46 ) It is transmitted horizontally via saliva, as the salivary glands function as a valuable reservoir for this virus. 47 ) However, the common latency site for HHV-6A and HHV-6B is the monocyte/macrophage cell population. 48 ) HHV-6A and HHV-6B can also infect the CNS and cause neurological disorders. 49

Studies have reported that 95% of adults are seropositive for HHV-6. Other manifestations related to primary HHV-6 infection have already been investigated, and current research is focused on its neurotropic properties, suggesting a possible link with encephalitis, seizure disorders, AD and MS. 45

Active or latent infection by HHV-6 in immune and glial cells can alter the sensitive balance between demyelination and remyelination, a process that defines the progression of MS. Although HHV-6 infection alone cannot trigger the onset of MS, it can worsen the inflammatory state of the CNS and exacerbate demyelination in these patients. 50 The possible role of latent HHV-6 infection has also been considered, for no studies have reported evidence of active replication of viral particles in demyelinating MS lesions. 51 ) Moreover, permeabilisation of the blood-brain barrier (BBB) may facilitate the entry of HHV-6 into the CNS, as it has high tropism for activated CD4+ T lymphocytes. 50

HHV-6 has also been associated with acute seizures and epilepsy in children. 52 , 53 ) Symptoms described in the context of primary infection and reactivation include febrile seizures, acute symptomatic seizures following encephalitis, status epilepticus and temporal lobe epilepsy. 54 A significant moderately positive correlation was identified between A delta and C nerve fibre damage severity and HHV-6 infection in fibromyalgia, which is a disease in which patients experience chronic pain. 55 ) Owing to the high frequency of HHV-6 infection in the population, further investigations are essential.

The high degree of homology between HHV-6A and HHV-6B hinders the investigation of these viruses separately. However, primary HHV-6B infection results in roseola, whereas information concerning the clinical manifestations of primary HHV-6A infection is limited. 56 ) Although both viruses are neurotropic and cause neurological disorders such as encephalitis, studies have reported that HHV-6A exhibits greater neurovirulence. 57 , 58 The roles of HHV-6A and HHV-6B have been investigated in the pathogenesis of MS; however, studies have reported a higher prevalence of HHV-6A in patients with MS. 59

Human betaherpesvirus 7 Human herpesvirus 7 (HHV-7)

HHV-7, first isolated in 1990, 60 ) is closely related to HHV-6 and also has a double-stranded DNA genome of approximately 144 kb. 61 ) On comparison, we observed that HHV-6 is the most described and investigated in the literature, which justifies the need for further investigations regarding HHV-7.

HHV-7 infects CD4+ T lymphocytes and, less frequently, CD8+ and immature T cells. 62 ) Similar to other herpesviruses, it becomes established in the host after primary infection for prolonged periods, alternating between latent and lytic phases. 63 However, the site of latency remains unclear. 60 HHV-7 is ubiquitous and primary infection occurs primarily during infancy between the ages of 1 and 3 years, slightly later than HHV-6. By the age of 5 years, approximately 90% of the population is infected with HHV-7. 64 ) HHV-7 infection has different clinical presentations in children, similar to HHV-6, such as exanthema subitum, fever without exanthema, febrile convulsions and status epilepticus 65 . Till date, available data support a possible association between HHV-7 and epilepsy. 66 ) Recent evidence has suggested that inflammation plays a role in epileptogenesis. 67

Information regarding how HHV-7 crosses the BBB and causes invasion of the CNS is scarce. 68 Recently, a small number cases of HHV-7-related encephalitis or encephalopathy have been described in children, adults and immunocompetent or immunocompromised patients. 69 The clinical presentation of CNS involvement may be excessively heterogeneous to distinguish it from other neurological disorders, including fever, seizures, encephalitis, meningoencephalitis, facial palsy, vestibular neuritis, severe headache, drowsiness, fatigue, nausea, vomiting, photosensitivity, ataxia and coma. 69

Gammaherpesviruses Human gammaherpesvirus 4 Epstein-Barr virus (EBV)

EBV is a gammaherpesvirus with a DNA genome of approximately 170 kb. 70 ) It was identified in 1964 by Michael Anthony Epstein in isolates from patients with Burkitt lymphoma. 71 EBV infection in adults leads to infectious mononucleosis; however, it can also be associated with other complications, in addition to being associated with malignancies. 72 ) EBV infects epithelial and memory B cells, where it establishes latency, 73 ) and can replicate in the CNS and disrupt the integrity of the BBB. 74 EBV infection is associated with neurological disorders, such as meningitis, encephalitis, myelitis, psychoses and ‘’Alice in Wonderland’’ syndrome, among others, which can affect even immunocompetent individuals both during primary infection and during reactivation. 72 , 75 , 76 ) Some studies have indicated an association between EBV infection and neurodegenerative diseases, and strong evidence suggests a role of EBV infection in the pathogenesis of MS. 74 ) MS is an immune-mediated disease characterised by permanent inflammation of the CNS, causing loss of neural tissue. Hence, viral infection may be a crucial factor in the development and progression of MS. Several researchers have theorised that EBV may contribute to the spread of inflammation and injury in the CNS, triggering an immune response that is important in the pathogenesis of MS. 77 ) A longitudinal study has revealed the risk of MS after EBV infection in addition to the increased concentrations of the neurofilament light chain, a biomarker of neurodegeneration, after EBV infection. 78 ) These data indicate the important role of EBV infection in the pathogenesis of MS.

Research in “long COVID” patients has identified EBV reactivation, suggesting that its symptoms, including neurological manifestations, may be the result of EBV reactivation induced by SARS-CoV-2 infection. 79 Studies such as this emphasise the importance of investigating herpesvirus infections in the context of COVID-19.

Human gammaherpesvirus 8 Human herpesvirus 8 (HHV-8)

HHV-8 was identified in 1994 by Yuan Chang 80 ) as the causative agent of Kaposi’s sarcoma in patients with acquired immunodeficiency syndrome. Subsequent studies have strongly associated this herpesvirus with other pathologies such as primary effusion lymphoma and multicentric Castleman disease in immunodeficient individuals; however, HHV-8 can also affect immunocompetent individuals. 81 ) HHV-8 contains a double-stranded DNA genome of approximately 140 kb. 82 ) It exhibits tropism for endothelial, epithelial and lymphocyte cells and establishes latency in B lymphocytes. 83 , 84 ) To date, knowledge regarding the ability of HHV-8 to infect neural cells and cause neurological disorders is limited. However, research has demonstrated the ability of HHV-8 to infect neural cells and act as a reservoir for latent infection. 83 , 85 ) Studies have investigated the association between neurological disorders and HHV-8 infection, including amyotrophic lateral sclerosis and MS. 86 , 87 Although the detection of HHV-8 DNA in brain tissues of MS patients indicates neurotropism, a possible association between HHV-8 infection and MS pathogenesis needs to be further investigated. 87 ) These findings provide novel insights into the association of HHV-8 with neuronal diseases and require further clarification.

Herpesvirus in the context of neuronal disorders

Herpesviruses have been strongly associated with neurological disorders, with meningitis and encephalitis being triggered by all HHVs except HHV-8. 10 , 49 , 69 ) HCMV is associated with neurodevelopmental deficits and schizophrenia. 38 , 39 VZV has been implicated in cases of vasculopathy leading to ischemic stroke, aneurysm and cerebral venous thrombosis. 22 , 23 EBV has been related to psychosis and distortion of perception, such as the Alice in Wonderland syndrome. 72 , 75 , 76 HHV-6 and HHV-7 are considered as possible causes of epilepsy. 53 , 54 , 66 ) Although HHV-8 is not known to be associated with neurological diseases, several studies have indicated such a relationship; future research may elucidate new findings regarding this association. 85 Ongoing studies surrounding the relationship between herpesvirus infection in neurodegenerative diseases are worth mentioning, such as the association between AD and HVS and the relationship between MS and EBV and HHV-6 infection ( Table ). 15 , 50 , 51 , 78 In recent years, some studies have investigated a possible association between alpha herpesvirus infections and Parkinson’s disease. 13 , 25

Nonetheless, several issues need to be clarified, ranging from stresses that can induce recurrent virus reactivation to viral particles produced after reactivation that can reach the CNS, causing diffuse acute infection and/or neurological manifestations. Recently, the reactivation viral has been correlated with the production and accumulation of neuropathological biomarkers of AD. 88 The different cellular and molecular mechanisms underlying the acute and long-term damage caused by herpesvirus infection in the CNS should be investigated to bridge these gaps in knowledge.

It is worth noting that although herpesviruses are highly prevalent and are latently present in all infected individuals, not everyone will experience reactivation or develop neurological manifestations. The fact that certain individuals are more likely than others to develop serious diseases and neurological manifestations after herpes infection can be partially explained by the existence of genetic polymorphisms in humans and the intrinsic, innate and adaptive immune responses that are fundamental for controlling diseases and infections caused by herpesviruses. 89

Although the number of studies exploring the mechanisms of action by which viral infections can directly or indirectly contribute to the development of neurological disorders has increased over the years, these studies remain insufficient. 90

With the advancement in technologies and tools for the investigation of virological, genetic and immunological factors, several knowledge gaps can be addressed.

To summarise, understanding the pathogenesis of these diseases and exploring new theories may facilitate the development of new diagnostic and therapeutic strategies. Reviewing and updating evidence regarding the relationship between viral infection and neurological disorders are essential to confirm the hypotheses and potential of herpesviruses as triggering agents of neurological disorders.

ACKNOWLEDGEMENTS

To Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundação Oswaldo Cruz and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).