Cold sore virus may contribute to cognitive and brain abnormalities in schizophrenia

ScienceDaily (May 28, 2010) — Exposure to the common virus that causes cold sores may be partially responsible for shrinking regions of the brain and the loss of concentration skills, memory, coordinated movement and dexterity widely seen in patients with schizophrenia, according to research led by Johns Hopkins scientists.

"We're finding that some portion of cognitive impairment usually blamed solely on the disease of schizophrenia might actually be a combination of schizophrenia and prior exposure to herpes simplex virus 1 infection, which reproduces in the brain," says study leader David J. Schretlen, Ph.D., an associate professor in the Department of Psychiatry at Johns Hopkins University School of Medicine.

The research, described in the May Schizophrenia Research, could lead to new ways to treat or prevent the cognitive impairment that typically accompanies this mental illness, including with antiviral drugs, the scientists say.

Doctors have long known that cognitive impairment, including problems with psychomotor speed, concentration, learning, and memory, are prevalent features of schizophrenia, which affects an estimated one percent of the U.S. population. Cognitive deficits often surface months to years before symptoms that are traditionally used to diagnose this disease, such as delusions or hallucinations.

Some previous studies have shown that schizophrenic patients with antibodies to herpes simplex virus 1 (HSV-1), the virus that causes cold sores, often have more severe cognitive deficits than patients without these antibodies. Other studies have shown that patients with HSV-1 antibodies have decreased brain volumes compared to patients without the antibodies. However, it has been unclear whether the cognitive deficits are directly related to the decreased brain volume.

To investigate, Schretlen and his colleagues recruited 40 schizophrenic patients from outpatient clinics at the Johns Hopkins and Sheppard Enoch Pratt hospitals in Baltimore, Md. Blood tests showed that 25 of the patients had antibodies for HSV-1 and 15 didn't. The researchers gave all of the patients tests to measure speed of coordination, organizational skills and verbal memory. The patients then underwent MRI brain scans to measure the volume of particular regions of their brains.

As in previous studies, results showed that patients with antibodies to HSV-1 performed significantly worse on the cognitive tests than patients without the antibodies. But expanding on those earlier studies, analysis of the brain scans showed that the same patients who performed poorly on the tests also had reduced brain volume in the anterior cingulate, which controls processing speed and the ability to switch tasks. There was also shrinkage in the cerebellum, which controls motor function.

These results suggest that HSV-1 might be directly causing the cognitive deficits by attacking these brain regions, Schretlen says.

Though the researchers aren't sure why schizophrenia might make brains more vulnerable to a viral assault, Schretlen says the results already suggest new ways of treating the disorder. Data from other studies has shown that antiviral medications can reduce psychiatric symptoms in some patients with schizophrenia. "If we can identify schizophrenic patients with HSV-1 antibodies early on, it might be possible to reduce the risk or the extent of cognitive deficits," he adds.

Other Johns Hopkins researchers who participated in this study include Tracy D. Vannorsdall, Ph.D., Jessica M. Winicki, B.A., Takatoshi Hikida, M.D., Akira Sawa, M.D., Ph.D., Robert H. Yolken, M.D., and Nicola G. Cascella, M.D.

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David J. Schretlen, Tracy D. Vannorsdall, Jessica M. Winicki, Yaser Mushtaq, Takatoshi Hikida, Akira Sawa, Robert H. Yolken, Faith B. Dickerson, Nicola G. Cascella. Neuroanatomic and cognitive abnormalities related to herpes simplex virus type 1 in schizophrenia. Schizophrenia Research, 2010; 118 (1-3): 224 DOI: 10.1016/j.schres.2010.01.008

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4/16 Herpes Life

Herpes Life Less herpes shame, more self love April 15, 2012 at 11:29 AM “Shame loves secrets. Shame cannot stand being spoken.” — Brene Brown The shame of having herpes tends to pull us into our own scary shadows (even though just a few feet away in the light are plenty of people telling you to quit the negative fantasy BS and hear that you’re worthy of a deluge of love.) Shame has us stay blind in the darkness of our own self-defeating mind-cage to try to deal with it on our own (like any strong person should be able to do, right?). But that has us telling ourselves the (false) story that we are alone. We are not alone. YOU are NOT alone! Squash the story! The more you can really allow yourself to get that, the less shame you will have, the more likely you will be to reach out when you need it, the more love will be available to let in, the more healing and growth happens. The more you free yourself of stigmatizing labels, the more free you are to be YOU. And what’s more lovable than that? (Rhetorical question.) "An addict needs shame like a man dying of thirst needs saltwater.” (Terrence Real) Brown (whose work also appears in this post) defines shame as “The intensely painful experience or belief that you’re flawed and unworthy of love and belonging.” And what better excuse to believe all those horrible things than herpes? Then somewhere along the line, some less-than-nice voice inside of us got the bright idea that if it shames us enough, we’ll somehow rewind time and be free of this virus. On some level, we believe that if we punish ourselves, the pain will go away. How ironic is that? Much of the pain is self-inflicted and in our own heads anyway. Why do we put ourselves through so much? What happens when we stop beating ourselves up? How is shame like saltwater to the thirsty? Brown says “A belief that we’re not worthy of love and belonging is what drives most of the destructive behavior we see.” So true. We seem to by default choose the stick to beat ourselves with instead of eating a healthy carrot. We somehow think that if we heap on enough shame, that will make things better, but it’s not quenching our thirst for love. Shame is just making things worse. So it’s not about avoiding the shame by trying to somehow prove our worthiness … You are worthy. Period. Know that. Own it. Once you get that you are worthy of love, you will start treating yourself differently, which will pave the way for the love from others to come charging in. We hear of the stigma of herpes and create a story about ourselves that doesn’t match with who we truly are. Are you stigmatizing yourself? Stop it! You don’t deserve it! Love yourself instead. Be compassionate with yourself instead. It will take you so much further. Sounds great, but how the heck do I move past the shame? Think about your process in stages of opening up yourself to more and more love and support. If shame is about closing down, self-love is about opening up. First thing I want you to notice: You’re here reading this article. That’s the first step to reaching out. You’re reading this because you care about yourself enough to feel better and to stop beating yourself up. Good job! Next steps: Connect with people who care. Reach out more when you need it. And the reaching out doesn’t necessarily have to have the whole herpes label attached to it; maybe it’s simply going out to lunch with a friend to catch up. Connecting with loved ones is a great way to prove that you’re not alone. Over-the-phone herpes support group. Attending our live virtual herpes support group might be the next step to start talking more openly about where you are with herpes; it’s over the phone, so you can have as much privacy as you’d like. Get an (h) buddy! We also have a herpes buddy system (contact me directly for that) where we’ll match you up one-on-one with someone else who has herpes so you two can talk about whatever you’d like. In-person herpes support groups. And there are plenty of in-person herpes support groups out there, too. When it comes down to it, there are plenty of opportunities to let go of the shame and move into your life. You get to make the decision. Less herpes shame, more self love April 15, 2012 at 11:29 AM “Shame loves secrets. Shame cannot stand being spoken.” — Brene Brown The shame of having herpes tends to have us pull away from sharing what we are going through. It has us stay in the darkness and try to deal with it on our own. But that has us telling ourselves the (false) story that we are alone. We are not alone. YOU are NOT alone! The more you can really allow yourself to get that, the less shame you will have, the more likely you will be to reach out when you need it, the more love will be available to let in, the more healing and growth happens. The more you free yourself of stigmatizing labels, the more free you are to be you. And what’s more lovable than that? "An addict needs shame like a man dying of thirst needs saltwater.” (Terrence Real) Some less-than-nice voice inside of us believes that if we beat ourselves up enough, we’ll eventually learn from our mistakes and nothing bad will ever happen again. If we punish ourselves enough, the pain will go away. But much of the pain is self-inflicted. Why do we put ourselves through so much? “A belief that we’re not worthy of love and belonging is what drives most of the destructive behavior we see.” So it’s not about avoiding the shame by trying to somehow prove our worthiness … you’re worthy. Period. Know that. Own it. Once you get that you are worthy of love, you will start treating yourself differently first, which will pave the way for the love of others to come on in, too. We hear of the stigma of herpes and create a story about ourselves that doesn’t match with who we truly are. Are you stigmatizing yourself? Stop it! You don’t deserve it! Love yourself instead. Be compassionate with yourself instead. It will take you so much further.

Discovery Of Protein That Reactivates Herpes Simplex Virus Helps Solve Medical Mystery

ScienceDaily (Mar. 26, 2009) — Research in PLoS Pathogens appears to solve a long standing medical mystery by identifying a viral protein, VP16, as the molecular key that prompts herpes simplex virus (HSV) to exit latency and cause recurrent disease.

Led by researchers at Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, the landmark study points to a molecular target for designing improved HSV vaccines and treatments. It also could direct refined engineering of HSV viruses used in cancer therapy, the investigators said.

The study was conducted in collaboration with the Medical Research Council Virology Unit of Glasgow, Scotland.

The two distinct lifestyles of HSV – active and latent – were first proposed 80 years ago. The virus replicates itself at the body surface, producing thousands of copies that can be transmitted to other people. In neurons, however, the virus can enter a silent state, where the viral genetic code can be maintained for the lifetime of the infected person.

"Our current findings show that, in elegant simplicity, the herpes simplex virus regulates this complex lifecycle through the expression of VP16," said Nancy Sawtell, Ph.D., author and researcher in the Division of Infectious Diseases at Cincinnati Children's Hospital Medical Center.

The study points to what causes the virus to periodically reactivate in latently infected neurons, prompting new rounds of virus replication at the body surface. By understanding how HSV achieves this complex interaction inside the human nervous system, researchers can gain crucial insight into how to control the spread of the virus. At present, there is no way to eliminate latent virus or prevent the virus from exiting latency. There also are no effective vaccines to protect people who are uninfected and transmission rates remain high, the researchers said.

In the study, the research team simulated high fever in a mouse model of HSV infection, demonstrating that VP16 must be produced before the virus can exit the latent state in neurons. Fever has long been known to induce HSV reactivation, and recurrent lesions are often called cold sores or fever blisters because of this association. In the vast majority of neurons, the virus remains latent. In a few neurons, however, the scientists observed that fever in the mice led to a stochastic, or random de-repression of VP16, causing the virus to exit latency and reactivate.

"This completely changes our thinking about how this virus reactivates from latency," said Richard Thompson, Ph.D., co-author and researcher in the Department of Molecular Genetics, Biochemistry and Microbiology at UC. "Instead of a simple positive switch that turns the virus on following stress, it appears instead to be a random de-repression of the VP16 gene that results in reactivation."

The leading infectious cause of blindness and acute sporadic encephalitis in the United States, HSV-1 is usually acquired during childhood. Both HSV-1 and HSV-2 can be sexually transmitted diseases that when passed to newborns during birth causes a severe and often fatal infection. As many as 80 percent or more of people are infected with HSV. Most of the time, people carrying the virus do not have symptoms, although they can still transmit the virus.

The researchers hypothesize that HSV usually remains latent because VP16, which normally enters the cell with the virus particle, does not make the long trip the virus takes through the nervous system and isn't transported efficiently to the nerve cell nucleus.

Future studies will use this new information to develop strategies to prevent or control herpetic disease, said Dr. Sawtell, who also is an associate professor of Pediatrics at UC.

Funding support for the study came from National Institutes of Health.

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Patients with COPD have higher risk of shingles, study finds

ScienceDaily (Feb. 22, 2011) — Patients with chronic obstructive pulmonary disease (COPD) are at greater risk of shingles compared with the general population, according to a study published in CMAJ (Canadian Medical Association Journal). The risk is greatest for patients taking oral steroids to treat COPD.

Shingles, or herpes zoster, is a reactivation of the chicken pox virus resulting in a painful rash with lesions.

People with a compromised immune system are at greater risk of developing shingles although it has not been previously studied in patients with COPD.

There is increasing evidence that COPD is an autoimmune disease. "Given that various immune-mediated diseases, such as rheumatoid arthritis and inflammatory bowel disease, have been reported to be associated with an increased risk of herpes zoster, it is reasonable to hypothesize that immune dysregulation found in COPD may put patients at higher risk of developing herpes zoster," writes Dr. Hui-Wen Lin, Taipei Medical University, Taiwan with coauthors.

This study, using data from the Taiwan Longitudinal Health Insurance Database, included 8486 patients with COPD and 33 944 subjects from the comparison cohort. Of the total sample of 42 430 patients, 1080 had incident of herpes zoster during the follow-up period. There were 321 cases of shingles identified in the COPD cohort, 16.4 per 1000 person years, and 759 cases in the comparison cohort, 8.8 per 1000 person years.

"Our cohort study demonstrated that patients with COPD are at an increased risk of developing herpes zoster compared with the general population, after controlling for other herpes zoster risk factors," write the authors. "The risk of herpes zoster associated with COPD is greater for patients with inhaled or oral corticosteroids therapy than patients without."

The authors conclude it is possible that "increased disease severity further contributes to the increased risk of herpes zoster associated with COPD."

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Yang, Ya-Wen, Chen, Yi-Hua, Wang, Kuo-Hsien, Wang, Chen-Yi, Lin, Hui-Wen. Risk of herpes zoster among patients with chronic obstructive pulmonary disease: a population-based study. Canadian Medical Association Journal, 2011; DOI: 10.1503/cmaj.101137

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New study alters long-held beliefs about shingles

ScienceDaily (Feb. 1, 2011) — For decades, medical wisdom about shingles has been that it's a once-in-a-lifetime experience. The commonly-held belief is that patients are protected from a recurrence of the herpes zoster virus, which causes shingles, after one episode. But according to a study published in the February issue of Mayo Clinic Proceedings, recurrences of shingles may be significantly more common than doctors have suspected.

"It's been thought that recurrences were limited to people with compromised immune systems, for instance from chemotherapy or bloodborne malignancies, but this is not the case," says lead author Barbara Yawn, M.D., director of research at Olmsted Medical Center in Rochester. "Recurrence was prevalent in the immunocompetent population. We were very surprised by the results."

The research team examined medical records, dating from 1996 to 2001, of nearly 1,700 patients over age 22 who had a documented episode of shingles. The condition causes a specific type of skin rash and severe pain. They then searched area medical records to determine whether those patients had been treated for a second episode at any point, following them up to 12 years (the average follow-up was eight years). The data showed the recurrence rate was over 5 percent, the same rate an age-matched cohort would be expected to experience a first case of shingles. Some patients had experienced as many as three recurrences. "And that's only within eight years," Dr. Yawn notes. "As you continue to follow these patients throughout their lives, it's likely the recurrence rate will be much higher than 5 percent."

The study found that women, who are more likely than men to have shingles, also were more likely to experience a recurrence of the disease. Although the team had suspected that recurrence rates would be higher in older patients, age did not appear to make individuals more susceptible to another round of the disease. Instead, researchers found the most striking determinant for recurrence was patients' pain during the initial episode. Those who had experienced pain lasting more than 30 days after the initial onset of shingles were more likely to face a recurrence, particularly in the first three to four years after the initial episode. This, too, surprised the research team. "We'd thought that suffering a worse case would possibly give patients more resistance to a second occurrence, but our data presented the exact opposite," says Dr. Yawn.

The results suggest that the herpes zoster vaccine, which is known to reduce first-time occurrences of shingles by 50 percent, may help patients avoid a second episode. "Until now, we haven't been able to tell patients their risks of getting zoster a second time," Dr. Yawn says. "This study offers another piece of information for patients and doctors who are discussing the likelihood of recurrence and considering a prevention strategy."

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B. P. Yawn, P. C. Wollan, M. J. Kurland, J. L. St. Sauver, P. Saddier. Herpes Zoster Recurrences More Frequent Than Previously Reported. Mayo Clinic Proceedings, 2011; 86 (2): 88 DOI: 10.4065/mcp.2010.0618

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Antiviral drugs may slow Alzheimer's progression

ScienceDaily (Oct. 17, 2011) — Antiviral drugs used to target the herpes virus could be effective at slowing the progression of Alzheimer's disease (AD), a new study shows.

The University of Manchester scientists have previously shown that the herpes simplex virus type 1 (HSV1) is a risk factor for Alzheimer's when it is present in the brains of people who have a specific genetic risk to the disease.

AD is an incurable neurodegenerative condition affecting about 18 million people worldwide. The causes of the disease or of the abnormal protein structures seen in AD brains -- amyloid plaques and neurofibrillary tangles -- are completely unknown.

The Manchester team has established that the herpes virus causes accumulation of two key AD proteins -- ß-amyloid (Aß) and abnormally phosphorylated tau (P-tau) -- known to be the main components of plaques and tangles respectively. Both proteins are thought by many scientists to be involved in the development of the disease.

"We have found that the viral DNA in AD brains is very specifically located within amyloid plaques," said Professor Ruth Itzhaki, who led the team in the University's Faculty of Life Sciences. "This, together with the production of amyloid that the virus induces, suggests that HSV1 is a cause of toxic amyloid products and of plaques.

"Our results suggest that HSV1, together with the host genetic factor, is a major risk for AD, and that antiviral agents might be used for treating patients to slow disease progression."

Currently available antiviral agents act by targeting replication of HSV1 DNA, and so the researchers considered that they might be successful in treating AD only if the accumulation of ß-amyloid and P-tau accumulation caused by the virus occurs at or after the stage at which viral DNA replication occurs.

"If these proteins are produced independently of HSV1 replication, antivirals might not be effective," said Professor Itzhaki. "We investigated this and found that treatment of HSV1-infected cells with acyclovir, the most commonly used antiviral agent, and also with two other antivirals, did indeed decrease the accumulation of ß-amyloid and P-tau, as well as decreasing HSV1 replication as we would expect.

"This is the first study investigating antiviral effects on AD-like changes and we conclude that since antiviral agents reduce greatly ß-amyloid and P-tau levels in HSV1-infected cells, they would be suitable for treating Alzheimer's disease. The great advantage over current AD therapies is that acyclovir would target only the virus, not the host cell or normal uninfected cells. Further, these agents are very safe and are relatively inexpensive.

"Also, by targeting a cause of Alzheimer's disease, other viral damage, besides ß-amyloid and P-tau, which might be involved in the disease's pathogenesis, would also be inhibited.

"The next stage of our research -- subject to funding -- will focus on finding the most suitable antiviral agent -- or combination of two agents that operate via different mechanisms -- for use as treatment. We then need to investigate the way in which the virus and the genetic risk factor interact to cause the disease, as that might lead to further novel treatments.

"Eventually, we hope to begin clinical trials in humans but this is still some way off yet and again will require new funding."

The study, carried out with Dr Matthew Wozniak and other colleagues in the Faculty of Life Sciences, is published in the Public Library of Science (PLoS) One journal.

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Matthew A. Wozniak, Alison L. Frost, Chris M. Preston, Ruth F. Itzhaki. Antivirals Reduce the Formation of Key Alzheimer's Disease Molecules in Cell Cultures Acutely Infected with Herpes Simplex Virus Type 1. PLoS ONE, 2011; 6 (10): e25152 DOI: 10.1371/journal.pone.0025152

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To drive infections, a hijacking virus mimics a cell's signaling system

ScienceDaily (Mar. 26, 2012) — New biological research reveals how an invading virus hijacks a cell's workings by imitating a signaling marker to defeat the body's defenses. By manipulating cell signals, the virus destroys a defensive protein designed to inhibit it. This finding, from studies in human cell cultures, may represent a broader targeting strategy used by other viruses, and may lay the scientific groundwork for developing more effective treatments for infectious diseases.

"Learning details of how cells respond to viruses helps us to understand key cellular machinery better," said study leader Matthew D. Weitzman, Ph.D., of the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia. "This study tells us how a virus overcomes intrinsic host defenses. In this case the virus mimics signals used during normal DNA repair mechanisms."

The study team, formerly based at the Salk Institute for Biological Studies in La Jolla, Calif., published their current findings online March 8 in Molecular Cell.

Biologists have long known that viruses hijack cellular processes to replicate themselves, while host cells have evolved intrinsic defense systems to resist viral invasion. To replicate, viruses must deliver their own DNA into a cell's nucleus, so a viral infection entails a conflict between two genomes -- the DNA of the host cell versus the foreign DNA of the virus.

Viruses mount their attack by interacting with specific cell proteins as a way of penetrating the cell's defenses. "In this study, we asked how the herpes simplex virus finds the specific proteins that it interacts with," said Weitzman. "By describing the mechanism of this particular interaction between a virus and a cell protein, we have pinpointed key regulators of a cell's processes, and shed light on how a cell regulates its defenses."

This laboratory study focused on herpes simplex virus type-1 (HSV-1), a common human virus that results in recurrent infections alternating with inactive periods. Like other viruses, HSV-1 is known to manipulate cellular processes in order to infect cells, but the specific mechanisms by which it acts on the DNA repair pathway were previously unknown.

Weitzman's study team was studying a viral protein called ICP0 that overcomes host defenses by targeting cellular proteins for destruction. They found that ICP0 exploits phosphorylation, a chemical mark that is often used in cells to promote interactions between proteins, especially as part of the cellular signaling response to DNA damage. In HSV-1 infection, the phosphorylation signal on ICP0 attracts a cellular DNA damage response protein, RNF8, which binds to the false signaling marker and is then degraded. Because RNF8 normally inhibits viral replication, its destruction leaves the cell vulnerable to HSV-1 infection, as the virus takes over the cell's machinery.

The researchers also found that ICP0 exploits the same phosphorylation signal to bind to other cellular proteins in addition to RNF8, a hint that it may play a broader role in defeating antiviral defenses and manipulating cellular machinery. Weitzman will continue to investigate HSV-1 infection in neurons and in animal models. He also plans to extend his research into other viruses, which may act on different pathways than HSV-1 does. "Ultimately," he added, "better knowledge of molecular mechanisms in infection may suggest strategies to interrupt the viral life cycle and treat infections."

The National Institutes of Health, the Salk Institute, the American Cancer Society and the Howard Hughes Medical Institute were among the funders of this research.

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Mira S. Chaurushiya, Caroline E. Lilley, Aaron Aslanian, Jill Meisenhelder, Daniel C. Scott, Sébastien Landry, Simina Ticau, Chris Boutell, John R. Yates, Brenda A. Schulman, Tony Hunter, Matthew D. Weitzman. Viral E3 Ubiquitin Ligase-Mediated Degradation of a Cellular E3: Viral Mimicry of a Cellular Phosphorylation Mark Targets the RNF8 FHA Domain. Molecular Cell, 2012; DOI: 10.1016/j.molcel.2012.02.004

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Why Even Treated Genital Herpes Sores Boost The Risk Of HIV Infection

ScienceDaily (Aug. 2, 2009) — New research helps explain why infection with herpes simplex virus-2 (HSV-2), which causes genital herpes, increases the risk for HIV infection even after successful treatment heals the genital skin sores and breaks that often result from HSV-2.

Scientists have uncovered details of an immune-cell environment conducive to HIV infection that persists at the location of HSV-2 genital skin lesions long after they have been treated with oral doses of the drug acyclovir and have healed and the skin appears normal. These findings are published in the advance online edition of Nature Medicine on Aug. 2.

Led by Lawrence Corey, M.D., and Jia Zhu, Ph.D., of the Fred Hutchinson Cancer Research Center and Anna Wald, M.D., M.P.H., of the University of Washington, both in Seattle, the study was funded mainly by the National Institute of Allergy and Infectious Diseases (NIAID) with support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, both part of the National Institutes of Health.

"The findings of this study mark an important step toward understanding why HSV-2 infection increases the risk of acquiring HIV and why acyclovir treatment does not reduce that risk," says NIAID Director Anthony S. Fauci, M.D. "Understanding that even treated HSV-2 infections provide a cellular environment conducive to HIV infection suggests new directions for HIV prevention research, including more powerful anti-HSV therapies and ideally an HSV-2 vaccine."

One of the most common sexually transmitted infections worldwide, HSV-2 is associated with a two- to three-fold increased risk for HIV infection. Some HSV-2-infected people have recurring sores and breaks in genital skin, and it has been hypothesized that these lesions account for the higher risk of HIV acquisition. However, recent clinical trials, including an NIAID-funded study completed last year, demonstrated that successful treatment of such genital herpes lesions with the drug acyclovir does not reduce the risk of HIV infection posed by HSV-2 . The current study sought to understand why this is so and to test an alternative theory.

"We hypothesized that sores and breaks in the skin from HSV-2 are associated with a long-lasting immune response at those locations, and that the response consists of an influx of cells that are a perfect storm for HIV infection," says Dr. Corey, co-director of the Vaccine and Infectious Diseases Institute at The Hutchinson Center and head of the Virology Division in the Department of Laboratory Medicine at the University of Washington. "We believe HIV gains access to these cells mainly through microscopic breaks in the skin that occur during sex."

The research team took biopsies of genital skin tissue from eight HIV-negative men and women who were infected with HSV-2. These biopsies were taken at multiple time points: when the patients had genital herpes sores and breaks in the skin, when these lesions had healed, and at two, four and eight weeks after healing. The researchers also took biopsies from four of the patients when herpes lesions reappeared and the patients underwent treatment with oral acyclovir. The scientists continued to take biopsies at regular intervals for 20 weeks after the lesions had healed. For comparison, the investigators also took biopsies from genital tissue that did not have herpes lesions from the same patients.

Previous research has demonstrated that immune cells involved in the body's response to infection remain at the site of genital herpes lesions even after they have healed. The scientists conducting the current study made several important findings about the nature of these immune cells. First, they found that CD4+ T cells—the cells that HIV primarily infects—populate tissue at the sites of healed genital HSV-2 lesions at concentrations 2 to 37 times greater than in unaffected genital skin. Treatment with acyclovir did not reduce this long-lasting, high concentration of HSV-2-specific CD4+ T cells at the sites of healed herpes lesions.

Second, the scientists discovered that a significant proportion of these CD4+ T cells carried CCR5 or CXCR4, the cell-surface proteins that HIV uses (in addition to CD4) to enter cells. The percentage of CD4+ T cells expressing CCR5 during acute HSV-2 infection and after healing of genital sores was twice as high in biopsies from the sites of these sores as from unaffected control skin. Moreover, the level of CCR5 expression in CD4+ T cells at the sites of healed genital herpes lesions was similar for patients who had been treated with acyclovir as for those who had not.

Third, the scientists found a significantly higher concentration of immune cells called dendritic cells with the surface protein called DC-SIGN at the sites of healed genital herpes lesions than in control tissue, whether or not the patient was treated with acyclovir. Dendritic cells with DC-SIGN ferry HIV particles to CD4+ T cells, which the virus infects. The DC-SIGN cells often were near CD4+ T cells at the sites of healed lesions—an ideal scenario for the rapid spread of HIV infection.

Finally, using biopsies from two study participants, the scientists found laboratory evidence that HIV replicates three to five times as quickly in cultured tissue from the sites of healed HSV-2 lesions than in cultured tissue from control sites.

All four of these findings help explain why people infected with HSV-2 are at greater risk of acquiring HIV than people who are not infected with HSV-2, even after successful acyclovir treatment of genital lesions.

"HSV-2 infection provides a wide surface area and long duration of time for allowing HIV access to more target cells, providing a greater chance for the initial 'spark' of infection," the authors write. This spark likely ignites once HIV penetrates tiny breaks in genital skin that commonly occur during sex. "Additionally," the authors continue, "the close proximity to DC-SIGN-expressing DCs [dendritic cells] is likely to fuel these embers and provide a mechanism for more efficient localized spread of initial infection." The investigators conclude that reducing the HSV-2-associated risk of HIV infection will require diminishing or eliminating the long-lived immune-cell environment created by HSV-2 infection in the genital tract, ideally through an HSV vaccine. Further, they hypothesize that other sexually transmitted infections (STIs) may create similar cellular environments conducive to HIV infection, explaining why STIs in general are a risk factor for acquiring HIV.

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J Zhu et al. Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nature Medicine, DOI: 10.1038/nm2006 (2009)Celum et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. The Lancet, 2008; 371 (9630): 2109 DOI: 10.1016/S0140-6736(08)60920-4

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Zoster vaccine associated with lower risk of shingles in older adults

ScienceDaily (Jan. 11, 2011) — Vaccination for herpes zoster, a painful rash commonly known as shingles, among a large group of older adults was associated with a reduced risk of this condition, regardless of age, race or the presence of chronic diseases, according to a study in the January 12 issue of JAMA.

"The pain of herpes zoster is often disabling and can last for months or even years, a complication termed postherpetic neuralgia. Approximately 1 million episodes of herpes zoster occur in the United States annually, but aside from age and immunosuppression, risk factors for this condition are not known," the authors write. Although prelicensure data provided evidence that herpes zoster vaccine works in a select study population under idealized circumstances, the vaccine needs to be evaluated in field conditions to show whether benefits of the vaccine can be generalized to conditions of clinical practice, according to background information in the article. The researchers note that this is particularly important for the herpes zoster vaccine, given the medical and physiological diversity in the elderly population for whom the vaccine is indicated.

Hung Fu Tseng, Ph.D., M.P.H., of Southern California Kaiser Permanente, Pasadena, Calif., and colleagues evaluated the risk of herpes zoster after receipt of herpes zoster vaccine among individuals in general practice settings. The study included community-dwelling adults, age 60 years or older, who were members of a managed care organization. There were 75,761 members in the vaccinated cohort, who were age matched (1:3) to 227,283 unvaccinated members.

Compared with the unvaccinated cohort, individuals in the vaccinated cohort were more likely to be white, women, and to have had more outpatient visits, and a lower prevalence of chronic diseases. There were 5,434 herpes zoster cases identified in the study (6.4 cases per 1,000 persons per year among vaccinated individuals and 13.0 cases per 1,000 persons per year among unvaccinated individuals). In the fully adjusted analysis, vaccination was associated with reduced risk of herpes zoster. The reduction in risk did not vary by age at vaccination, sex, race, or with presence of chronic diseases. Herpes zoster vaccine recipients had reduced risks of ophthalmic herpes zoster and hospitalizations coded as herpes zoster. Overall, the vaccine was associated with a 55 percent reduction in incidence of herpes zoster.

"Herpes zoster vaccine was licensed recently, which means the durability of its protection needs to be assessed in future studies. Meanwhile, however, this vaccine has the potential to annually prevent tens of thousands of cases of herpes zoster and postherpetic neuralgia nationally. To date, herpes zoster vaccine uptake has been poor due to weaknesses in the adult vaccine infrastructure and also due to serious barriers to the vaccine among clinicians and patients. Solutions to these challenges need to be found so that individuals seeking to receive herpes zoster vaccine will be able to reduce their risk of experiencing this serious condition," the authors conclude.

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H. F. Tseng, N. Smith, R. Harpaz, S. R. Bialek, L. S. Sy, S. J. Jacobsen. Herpes Zoster Vaccine in Older Adults and the Risk of Subsequent Herpes Zoster Disease. JAMA: The Journal of the American Medical Association, 2011; 305 (2): 160 DOI: 10.1001/jama.2010.1983

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Antiviral therapy associated with fewer recurring eye problems from herpes simplex virus

ScienceDaily (Sep. 13, 2010) — Taking oral antiviral medications following infection with the herpes simplex virus may be associated with a reduced risk of recurring eye-related manifestations of the disease, according to a report in the September issue of Archives of Ophthalmology, one of the JAMA/Archives journals.

"Herpes simplex virus (HSV) is a common cause of corneal disease and is the leading infectious cause of corneal blindness among developed nations," the authors write as background information in the article. After the initial exposure to the virus and the resulting systemic infection, herpes simplex establishes a latent infection in sensory nerve structures. Reactivation of this latent infection could lead to initial or recurrent disease in one or both eyes, including inflammation or infection of the cornea, eyelid, membrane inside the eye (conjunctivitis, or pink eye) or middle layer of the eye (uveitis).

Ryan C. Young, B.A., of Mayo Clinic, Rochester, Minn., and colleagues estimated the incidence of HSV eye disease in a community-based cohort, in Olmstead County, Minnesota, from 1976 through 2007. During this time period, 394 patients with ocular HSV were identified, for an annual incidence of 11.8 per 100,000 individuals.

Oral antiviral therapy was prescribed in 175 (44 percent) of these patients, who underwent therapy for an average of 2.8 years (36 percent of the average 7.7 years of follow-up). Patients not taking this prophylactic therapy were 9.4 times more likely to have a recurrence of epithelial keratitis (infection of the top layer of the cornea), 8.4 times more likely to have a recurrence of stromal keratitis (infection of deeper layers of the cornea) and 34.5 times more likely to have a recurrence of blepharitis (eyelid infection) or conjunctivitis than those taking antiviral medications.

A total of 20 patients experienced adverse outcomes, including visual loss and perforation of the cornea; of these, 17 (85 percent) were not taking oral antiviral prophylaxis.

"Overall, this community-based retrospective study demonstrated a stable incidence of HSV eye disease during a recent 32-year period," the authors write. "We found a more dramatic protective effect of oral antiviral prophylaxis on recurrences of ocular HSV than had been described previously."

"The results of this study suggest that oral antiviral prophylaxis should be considered for patients with frequent recurrences of corneal disease," they conclude. "Additionally, we recommend an evaluation of the possible barriers preventing compliance with antiviral prophylaxis and a reassessment of the cost-effectiveness of long-term oral antiviral therapy."

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Ryan C. Young; David O. Hodge; Thomas J. Liesegang; Keith H. Baratz. Incidence, Recurrence, and Outcomes of Herpes Simplex Virus Eye Disease in Olmsted County, Minnesota, 1976-2007: The Effect of Oral Antiviral Prophylaxis. Arch Ophthalmol, 2010; 128 (9): 1178-1183 [link]

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Cellular protein hobbles HIV-1

ScienceDaily (Nov. 16, 2010) — A cellular protein called BST-2 had already been known to interfere with the spread of human immunodeficiency virus type 1 (HIV-1), by inhibiting the release of its progeny particles from infected cells. Now a team from McGill University, Montreal, shows that in addition, each progeny virion's ability to cause infection is severely impaired.

"BST-2 may exert a more potent inhibition effect on HIV-1 transmission than previously thought," says coauthor Chen Liang. The research is published in the December Journal of Virology.

BST-2 appears to attenuate infectivity of progeny particles by interfering with their maturation. Normally, during synthesis of new virus particles, a protein called PR55Gag is cleaved into three major structural proteins of HIV. "This cleavage process transforms HIV-1 from an immature and non-infectious virion into a mature and infectious virion," says Chen. The protease inhibitors, drugs given to AIDS patients to contain the disease, block this step. Similarly, BST-2 seems to interfere with this step, because in the study, its presence was associated with accumulation of uncleaved Gag precursor and intermediate products. The mechanism of that interference has yet to be elucidated.

BST-2 (bone marrow stromal cell antigen-2), also known as tetherin, is a cellular protein which has been shown to restrict production of enveloped viruses besides HIV-1, including HIV-2, simian immunodeficiency virus, Kaposi's sarcoma herpes virus, Lassa virus, Marburg virus, and Ebola virus. It interferes with release of new virus particles by anchoring one end of itself in the plasma membrane of the infected cell while the other end becomes inserted into the viral envelope.

Different viruses have evolved various countermeasures. For example, in the case of HIV-1, the viral protein Vpu downregulates BST-2 from the cell surface, removing it from virus budding sites.

"The antiviral function of BST-2 has been extensively studied by a number of groups besides ours," says Chen. "Our hope is that the results of all of these studies can eventually be used to develop a BST-2 based anti-HIV-1 therapy."

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J. Zhang, C. Liang. BST-2 Diminishes HIV-1 Infectivity. Journal of Virology, 2010; 84 (23): 12336 DOI: 10.1128/JVI.01228-10

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Punching Holes Into Herpes Viruses

ScienceDaily (June 11, 2009) — A joint international research effort by Dr. Wouter Roos and Dr. Gijs Wuite from the VU University Amsterdam and Dr. Kerstin Radtke and Dr. Beate Sodeik from the Medizinische Hochschule Hannover has led to the first description of the mechanics of so-called nuclear herpes virus capsids.

These viral particles are complex icosahedral protein shells covering and shielding the genetic material of herpes viruses, and are purified from the nuclei of infected cells. The results of this research were published online on June 1st, 2009 in the journal Proceedings of the National Academy of Sciences USA.

Nuclear Herpes Simplex Virus particles measure only 125 nanometers (approximately one ten-thousandth of a millimeter), therefore, the structure and surface of individual particles can only be studied with methods that have a resolution that is higher than that of a light microscope. With the help of an Atomic Force Microscope, one can now "feel" the particles and image them by scanning systematically over the surface, like the needle on a record player. From these measurements, researchers can assemble a detailed topographic relief of individual viral structures. This can be done in liquid under conditions mimicking living cells. Most importantly, this system allows the mechanical manipulation of particles, as one really touches them.

The researchers used this approach to gain new insights into the mechanics of these viral particles: they punched holes into them, one by one. The force needed to do this gave information about the elastic and mechanical properties of the herpes virus particles. They showed that they are strengthened during the assembly by packaging of the viral DNA into the shell. This reinforcement of the virus probably occurs at the twelve corner points of its icosahedral shell. The unravelling of this viral stabilisation mechanism could open new possibilities to fight herpes infections but could also provide new ways to employ viral particles as nano-containers for delivering drugs or genetic material.

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Genital herpes virus reactivates widely throughout genital tract

ScienceDaily (Jan. 22, 2010) — Genital herpes caused by a reactivation of herpes simplex virus type 2 (HSV-2) is generally treated as a lesion in one specific area of the genital region. A new study, however, finds that the virus can frequently reactivate throughout the genital tract, an important new concept that could help guide both HSV-2 treatment and prevention. Now available online, the study appears in the Feb. 15 issue of The Journal of Infectious Diseases.

In the study, Christine Johnston, MD, MPH, and colleagues at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle collected daily samples during a 30-day period from seven separate genital sites in four women infected with HSV-2. HSV-2 was detected from more than one anatomic site on 56 percent of days when there was viral shedding -- and on genital surfaces on both sides of the participants' bodies on most days when virus was detected at more than one site.

Using a detailed sampling method and a sensitive assay, the authors showed that both symptomatic and asymptomatic HSV-2 reactivations often occurred at widely spaced regions throughout the genital tract. These reactivations were often on both sides of the body, even though clinical lesions typically emanate from one anatomic spot. The study's findings illustrate an important new concept in HSV-2 pathogenesis, the authors wrote, and may help in developing comprehensive treatment that both suppresses and limits the transmission of HSV-2 infection.

The authors also noted limitations of their study, including a small sample size and the unique features of the study's subjects. For example, all participants had a history of symptomatic genital herpes, and three of the four had acquired HSV-2 infection within the past year, increasing the chances of high viral reactivation and lesion rates. Additionally, although there were a high proportion of days with lesions during the study period, two of the participants who had recently acquired genital herpes contributed the majority of lesion days.

In an accompanying editorial, Edward W. Hook III, MD, of the University of Alabama at Birmingham, called the study's findings "of great potential importance, as they further challenge widely held beliefs regarding genital herpes and, by extension, its management." Many clinicians treat patients with newly diagnosed herpes episodically, managing the signs and symptoms of periodic symptomatic recurrences, Dr. Hook wrote. "From a personal and public health perspective, the biology of the infection suggests that a national campaign for serological testing of those at risk would provide the foundation for more effective efforts to control HSV transmission to others, and that for most sexually active persons with HSV-2 whose sex partners are not known to also be infected, suppressive therapy should be the preferred approach."

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Microbicide gel: Reduced risk of HIV and herpes infections in women, study shows

ScienceDaily (July 19, 2010) — Researchers have achieved an important scientific breakthrough in the fight against HIV and genital herpes with a vaginal gel that significantly reduces a woman's risk of being infected with these viruses. The results of the ground-breaking safety and effectiveness study of an antiretroviral microbicide gel study were reported by the Centre for the AIDS Programme of Research in South Africa (CAPRISA) at the XVIII International AIDS Conference in Vienna, Austria.

The microbicide containing 1% tenofovir -- an antiretroviral drug widely used in the treatment of HIV -- was found to be 39% effective in reducing a woman's risk of becoming infected with HIV during sex and 51% effective in preventing genital herpes infections in the women participating in the trial. Should other studies of tenofovir gel confirm these results, widespread use of the gel, at this level of protection, could prevent over half a million new HIV infections in South Africa alone over the next decade.

"Tenofovir gel could fill an important HIV prevention gap by empowering women who are unable to successfully negotiate mutual faithfulness or condom use with their male partners," said study co- principal investigator, Dr. Quarraisha Abdool Karim, Associate Director of CAPRISA and Associate Professor of Epidemiology at Columbia University. "This new technology has the potential to alter the course of the HIV epidemic, especially in southern Africa where young women bear the brunt of this devastating disease."

Tenofovir works by preventing HIV from growing inside human cells. Taken in pill form, tenofovir is a common component of various three-drug cocktails that are used to treat HIV infections. The new results now indicate that tenofovir formulated as a topical gel and inserted into the female genital tract also has great promise for use in HIV and herpes simplex virus type-2 (HSV-2) prevention.

The CAPRISA 004 trial of tenofovir gel involved 889 women at high risk of HIV infection at an urban and a rural site in KwaZulu-Natal, South Africa. Overall, 98 women out of the 889 became HIV positive during the trial -- with 38 in the tenofovir gel group and 60 in the placebo gel group. Out of the 434 women who tested negative for herpes at the start of the trial, 29 became infected in the tenofovir group and 58 became infected in the placebo group. The reduced rates of HIV and herpes infections among the women who used the tenofovir gel are statistically significant.

"Tenofovir gel has a potential dual effect in preventing HIV. Since women with genital herpes are much more likely to become infected with HIV, the additional protection of tenofovir gel against herpes creates a second mechanism whereby the gel may have a bigger impact in preventing HIV," said study co-principal investigator, Dr Salim S. Abdool Karim, Director of CAPRISA and Pro Vice-Chancellor (Research) of the University of KwaZulu-Natal, South Africa. "The trial results are a significant first step toward establishing the effectiveness of antiretroviral drugs for HIV and genital herpes prevention; confirmatory studies are now urgently needed."

During monthly visits, all participants were provided with HIV risk-reduction counseling, condoms and treatment for sexually transmitted infections, and each was clinically examined for potential side effects and tested for HIV infection. The study was double-blinded and neither the researchers nor the participating women knew whether a woman in the study received tenofovir gel or placebo gel. Women in the study were advised to use the gel up to 12 hours before sex and soon after having sex for a maximum of two doses in 24 hours -- a dosing strategy referred to as BAT24. Participants used the gel for a minimum of one year and a maximum of two and a half years. The trial team observed no substantive safety concerns from use of the gel. Further, no increase in risky behavior was observed in the women.

The CAPRISA researchers also found that the protective effect against HIV and genital herpes increased as use of the tenofovir gel increased. Women who used the gel in more than 80% of their sex acts had a 54% reduction in HIV infections, whereas those who used the gel in less than half of their sex acts had a 28% reduction in HIV infections. Among those women who became infected, tenofovir gel had no effect on the amount of HIV in their bloodstream at the time of infection. Also, none of the women who became infected with HIV showed resistance to tenofovir.

All volunteers to the study who tested HIV positive were provided care including ARV treatment at the CAPRISA clinics and women who became infected during the study were enrolled into CAPRISA studies and/or the CAPRISA AIDS treatment program at their respective sites for ongoing care and support.

This study was jointly funded by the Governments of South Africa and the United States, through the Technology Innovation Agency (TIA) and the US Agency for International Development (USAID), respectively. USAID provided $16.5M and TIA provided $1.1 for the study. "USAID is proud to be the major donor of this first-ever proof of concept that a vaginal microbicide can effectively and safely reduce the risk of HIV transmission from men to vulnerable women. The success of the CAPRISA 004 trial perfectly complements the Global Health Initiative and our focus on women's health, both in prevention and sustainable health delivery systems," stated USAID Administrator Raj Shah.

The promising findings of the CAPRISA 004 study is only a first step in determining if tenofovir gel is effective in preventing HIV and herpes infection; additional studies are urgently needed to confirm and extend the findings of the CAPRISA study. Important information is expected from current studies such as the Microbicide Trials Network's VOICE study, which is currently assessing daily tenofovir gel as well as daily tenofovir and Truvada tablets in women in several African countries. Studies of daily Truvada tablets are underway in intravenous drug users, young high-risk women and men who have sex with men.

"We are proud to have partnered with CAPRISA and CONRAD on this important study. We see it as a major victory in the field of HIV prevention research. This is the first evidence that an antiretroviral drug in a gel form -- a microbicide -- can reduce HIV and genital herpes infection in women," said Ward Cates, President of FHI. "The next step is to see whether other studies underway confirm these exciting results."

Only after drug regulatory authorities determine that tenofovir gel is safe and effective for HIV prevention, can the gel be made available to the public for HIV prevention. Since this process can take several years, TIA and U.S.-based CONRAD are working together to address the challenges to making the gel available first to women in South Africa.

"CONRAD has given the rights to manufacture this gel to the government of South Africa to get this much needed product to women in South Africa as rapidly as possible," said Dr. Henry Gabelnick, Executive Director of CONRAD, who provided the gel for the study. "The Technology Innovation Agency (TIA) is working closely with the South African government, CAPRISA and CONRAD to ensure that this important innovation makes an impact in preventing the spread of HIV/AIDS," said Dr. Mamphela Ramphele, Chairperson of TIA.

Ambassador Eric Goosby, U.S. Global AIDS Coordinator said, "The results of the CAPRISA trial provide new hope and direction for not only HIV prevention, but also broader efforts under the Global Health Initiative. We recognize that microbicides will be a great asset to HIV prevention efforts, and the U.S. Government is pleased to support this important research."

Professor Malegapuru Makgoba, Vice-Chancellor of the University of KwaZulu-Natal stated, "This piece of research is a significant milestone for women in the thirty year history of the HIV/AIDs epidemic, microbicides and antiretroviral research. The research represents that which is best in science with direct translation into prevention policy, bringing a message of hope and empowerment to women, policymakers and scientists. These research findings will not only significantly alter the shape and form but also the future direction of this devastating epidemic."

"The trial's findings create a new vision for the opportunity for prevention of HIV and re-define the public health approach to HIV control," added Dr Linda Fried, Dean of the Mailman School of Public Health of Columbia University, New York.

The trial was conducted by CAPRISA in partnership with the U.S.-based organizations FHI and CONRAD with funding from USAID. Gilead Sciences donated the active ingredient for the manufacture of the tenofovir gel.

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Map of herpes virus protein suggests a new drug therapy

ScienceDaily (July 6, 2010) — The mechanism by which a herpes virus invades cells has remained a mystery to scientists seeking to thwart this family of viruses. New research funded by the National Institutes of Health and published online in advance of print in Nature Structural & Molecular Biology reveals the unusual structure of the protein complex that allows a herpes virus to invade cells. This detailed map of a key piece of the herpes virus "cell-entry machinery" gives scientists a new target for antiviral drugs.

"Most viruses need cell-entry proteins called fusogens in order to invade cells. We have known that the herpes virus fusogen does not act alone and that a complex of two other viral cell-entry proteins is always required. We expected that this complex was also a fusogen, but after determining the structure of this key protein complex, we found that it does not resemble other known fusogens," said senior author Ekaterina Heldwein, PhD, assistant professor in the molecular biology and microbiology department at Tufts University School of Medicine.

"This unexpected result leads us to believe that this protein complex is not a fusogen itself but that it regulates the fusogen. We also found that certain antibodies interfere with the ability of this protein complex to bind to the fusogen, evidence that antiviral drugs that target this interaction could prevent viral infection," Heldwein continued. Heldwein is also a member of the biochemistry and molecular microbiology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

"Katya Heldwein's work has resulted in a map of the protein complex needed to trigger herpes virus infection. The NIH Director's New Innovator Awards are designed to support such breakthroughs. This research not only adds to what we know about how herpes viruses infect mammalian cells, but also sets the stage for new therapeutics that restrict herpes virus's access to the cell," said Jeremy M. Berg, PhD, director of the National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health.

"We hope that determining the structure of this essential piece of the herpes virus cell-entry machinery will help us answer some of the many questions about how herpes virus initiates infection. Knowing the structures of cell-entry proteins will help us find the best strategy for interfering with this pervasive family of viruses," said first author Tirumala K. Chowdary, PhD, a postdoctoral associate in the department of molecular biology and microbiology at TUSM and member of Heldwein's lab.

Currently, there is no cure for herpes viruses. Upon infection, the viruses remain in the body for life and can stay inactive for long periods of time. When active, however, different herpes viruses can cause cold sores, blindness, encephalitis, or cancers. More than half of Americans are infected with herpes simplex virus type 1 (HSV-1), which causes cold sores, by the time they reach their 20s. Currently, about one in six Americans is infected with herpes simplex virus type 2 (HSV-2), the virus responsible for genital herpes. Complications of HSV-2, a sexually-transmitted disease, include recurrent painful genital sores, psychological distress, and, if transmitted from mother to child, potentially fatal infections in newborn infants.

Heldwein teamed up with colleagues at University of Pennsylvania and used x-ray crystallography along with cell microscopy techniques to study the structure and function of this cell-entry protein complex in HSV-2. Heldwein is currently developing a molecular movie that illustrates how herpes virus enters the cell.

Additional authors are Tina Cairns, PhD, a research specialist; Doina Atanasiu, a research associate; and Gary Cohen, PhD, professor and chair, all in the department of microbiology at the University of Pennsylvania School of Dental Medicine; and Roselyn Eisenberg, PhD, professor in the department of microbiology at the University of Pennsylvania School of Veterinary Medicine.

This work was funded by the Office of the Director of the National Institutes of Health, through a New Innovator Award in 2007 to Ekaterina Heldwein. The New Innovator Awards, part of the NIH Roadmap for Medical Research initiative, are awarded to support early-career scientists who take innovative -- and potentially transformative -- approaches to major challenges in biomedical research. The work was also funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Pew Scholar Program in Biomedical Sciences.

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Tirumala K Chowdary, Tina M Cairns, Doina Atanasiu, Gary H Cohen, Roselyn J Eisenberg, Ekaterina E Heldwein. Crystal structure of the conserved herpesvirus fusion regulator complex gH-gL. Nature Structural & Molecular Biology, 2010; DOI: 10.1038/nsmb.1837

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Tansy may be used to treat herpes, study suggests

ScienceDaily (Apr. 14, 2011) — A folk remedy may be an effective treatment for the sexually transmitted disease herpes according to Dr Solomon Habtemariam from the University of Greenwich's School of Science and Professor Francisco Parra at the Universidad de Oviedo in Spain.

Tansy, Tanacetum Vulgare, is a flowering plant found across mainland Europe and Asia. From the Middle Ages onwards the plant, whose folk names include Golden Buttons and Mugwort, has been used as a remedy for various conditions, from fevers to rheumatism. However, its supposed medical benefits have always been questioned.

Joint work between research groups led by Dr Habtemariam from the School of Science at the University of Greenwich at Medway and Professor Francisco Parra at the Universidad de Oviedo in Spain, published in Phytotherapy Research, has revealed the clear potential of tansy as a treatment for herpes.

Dr Solomon Habtemariam says: "We have identified several compounds in the plant with strong antioxidant potential. Antioxidants are important for healing wounds and can be used to treat the skin eruptions and blister-like lesions or cold sores that are the symptoms of herpes. The drugs currently available to treat the disease are becoming less effective as the virus is developing resistance to them. Diseases such as genital herpes are also increasing due to immunosuppressive illnesses such as AIDS.

"Our studies have proved the scientific basis for many traditional medicinal plants. We are now able to identify even more structurally complex natural products and those that are present in plants in minute concentrations with our state-of-the-art analytical facilities. In collaboration with our international partners, we are searching for novel antidiabetic, antimicrobial, anticancer, anti-inflammatory and neuroprotective agents from natural sources."

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Ángel L. Álvarez, Solomon Habtemariam, Malindra Juan-Badaturuge, Caroline Jackson, Francisco Parra. In vitro anti HSV-1 and HSV-2 activity of Tanacetum vulgare extracts and isolated compounds: An approach to their mechanisms of action. Phytotherapy Research, 2010; DOI: 10.1002/ptr.3382

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Specific gene linked to cold sore susceptibility, study finds

ScienceDaily (Oct. 28, 2011) — Investigators have identified a human chromosome containing a specific gene associated with susceptibility to herpes simplex labialis (HSL), the common cold sore. Published in The Journal of Infectious Diseases and now available online, the study looks at how several genes may affect the severity of symptoms and frequency of this common infection. The findings, if confirmed, could have implications for the development of new drugs to treat outbreaks.

HSL outbreaks, or cold sores, are skin infections that appear with the reactivation of herpes simplex virus, a virus that infects 70 percent of the U.S. population. Cold sore outbreaks vary in frequency and severity; some people may experience symptoms rarely, only once every 5 to 10 years, while others may experience them once a month or even more frequently. In addition to investigating environmental activating factors (e.g., sunlight) that may play a role in outbreaks, researchers for some time have been looking at the possible role of genetic factors in virus susceptibility and activation.

This study, led by John D. Kriesel, MD, and colleagues from the University of Utah School of Medicine in Salt Lake City and the University of Massachusetts Medical School in Worcester, follows previous studies identifying a region of chromosome 21 as a base for genes possibly linked to cold sore outbreaks. To identify which of six possible genes in this region were associated with the frequency of outbreaks, this latest study used single nucleotide polymorphism genotyping in genome-wide, family-based linkage studies of 618 people from 43 large families. The investigators found a positive link between the frequency of outbreaks, hereditability, and the presence of a specific gene, C21orf91, on chromosome 21.

"While these findings await confirmation in a larger, unrelated population," the study authors note, "these findings could have important implications for the development of new drugs that affect determinants of the cold sore phenotype."

In an accompanying editorial, Anthony L. Cunningham, MD, and David Booth, MD, of the Centre for Virus Research and the Institute of Immunology and Allergy Research at Westmead Millennium Institute and the University of Sydney in Australia, note that if the findings regarding the C21orf91 gene are confirmed, additional research may then begin to determine possible therapeutic applications and whether the same gene also plays a role in recurring genital herpes.

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J. D. Kriesel, B. B. Jones, N. Matsunami, M. K. Patel, C. A. St. Pierre, E. A. Kurt-Jones, R. W. Finberg, M. Leppert, M. R. Hobbs. C21orf91 Genotypes Correlate With Herpes Simplex Labialis (Cold Sore) Frequency: Description of a Cold Sore Susceptibility Gene. Journal of Infectious Diseases, 2011; 204 (11): 1654 DOI: 10.1093/infdis/jir633A. L. Cunningham, D. Booth. The First Common Cold Sore Susceptibility Gene. Journal of Infectious Diseases, 2011; 204 (11): 1645 DOI: 10.1093/infdis/jir635

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Condoms Associated With Moderate Protection Against Herpes Simplex Virus 2

ScienceDaily (July 13, 2009) — Condom use is associated with a reduced risk of contracting herpes simplex virus 2, according to a report based on pooled analysis of data from previous studies.

Herpes simplex virus 2 (HSV-2) typically causes genital herpes, a chronic, life-long, viral infection. Although studies indicate that consistent condom use reduces the spread of HIV and other sexually transmitted diseases such as chlamydia and gonorrhea, the effectiveness of preventing the transmission of HSV-2 through condom use is less certain, according to background information in the article.

Emily T. Martin, M.P.H., Ph.D., of Children's Hospital Research Institute and the University of Washington, Seattle, and colleagues analyzed data from six HSV-2 studies to assess the effectiveness of condom use in preventing the virus. The studies included three candidate HSV-2 vaccine studies, an HSV-2 drug study, an observational sexually transmitted infection (STI) incidence study and a behavioral STI intervention study. These yielded results from 5,384 HSV-2-negative individuals (average age 29) at baseline for a combined total of 2,040,894 follow-up days.

More than 66 percent of those who took part in the six studies were male, 60.4 percent were white, 94.1 percent were heterosexual and most reported no prior STIs.

A total of 415 of the individuals acquired HSV-2 during follow-up. "Consistent condom users [used 100 percent of the time] had a 30 percent lower risk of HSV-2 acquisition compared with those who never used condoms," the authors write. "Risk of HSV-2 acquisition decreased by 7 percent for every additional 25 percent of the time that condoms were used during anal or vaginal sex." The risk of acquiring the virus increased significantly with increasing frequency of unprotected sex acts. There were no significant differences found in condom effectiveness between men and women.

"Based on findings of this large analysis using all available prospective data, condom use should continue to be recommended to both men and women for reducing the risk of HSV-2 acquisition," the authors conclude. "Although the magnitude of the protective effect was not as large as has been observed with other STIs, a 30 percent reduction in HSV-2 incidence can have a substantial benefit for individuals as well as a public health impact at the population level."

Funding for this project was provided by grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases. 

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Emily T. Martin, MPH; Elizabeth Krantz, MS; Sami L. Gottlieb, MD, MSPH; Amalia S. Magaret, PhD; Andria Langenberg, MD; Lawrence Stanberry, MD, PhD; Mary Kamb, MD, MPH; Anna Wald, MD, MPH. A Pooled Analysis of the Effect of Condoms in Preventing HSV-2 Acquisition. Arch Intern Med, 2009;169(13):1233-1240 [link]

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Chicken pox vaccine reduces shingles risk in kids

ScienceDaily (Dec. 4, 2009) — Herpes zoster, also known as shingles, is very rare among children who have been vaccinated against chicken pox, according to a Kaiser Permanente study in the December issue of the Pediatric Infectious Diseases Journal.

The study, the largest of its kind, used electronic health records to identify more than 170,000 children vaccinated with the varicella (chicken pox) vaccine from 2002 to 2008 in Kaiser Permanente's Southern California region, then followed children for an average of two and a half years to identify the occurrence of herpes zoster.

Researchers found only 122 cases of herpes zoster among the 172,163 vaccinated children, for an estimated incidence of 1 case per 3,700 vaccinated children per year. This is a lower rate compared to what one would expect in the unvaccinated children based on previous experiences.

"The message to parents and pediatricians is: vaccinating your child against the chicken pox is also a good way to reduce their chances of getting herpes zoster," said the study's lead author, HungFu Tseng, Ph.D, MPH, a research scientist and epidemiologist at the Kaiser Permanente Department of Research and Evaluation in Pasadena, Calif. "More research is needed to identify the virus strains that cause herpes zoster."

This study did not look at side effects of the varicella vaccine.

Herpes zoster is an acute skin viral infection caused by reactivation of latent varicella-zoster virus, which remains in certain nerve cells of the body after an infection with either wild-type or the varicella vaccine virus. The wild-type virus is found in the natural infection, in contrast to the virus strain found in vaccine.

Since the vaccine's introduction in 1995, there have been few studies on the incidence of childhood herpes zoster among children vaccinated with the varicella vaccine.

Following licensure in 1995, 1-dose varicella vaccine was recommended for children 12 months to 12 years of age. In 2006, a routine second dose of varicella vaccine for previously vaccinated persons aged 4 years and older was recommended.

Other study authors included: Ning Smith, MS, Lina S. Sy, MPH, S Michael Marcy, MD, and Steven J. Jacobsen, MD, Ph.D., from the Kaiser Permanente Department of Research and Evaluation.

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The above story is reprinted from materials provided by Kaiser Permanente, via EurekAlert!, a service of AAAS.

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