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 (http://www3.niaid.nih.gov/news/newsreleases/2008/hptn039.htm). 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 cellsthe cells that HIV primarily infectspopulate 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 lesionsan 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.

For more information about HIV/AIDS research, go to http://www3.niaid.nih.gov/topics/HIVAIDS/, and for more information about HSV-2 research, go to http://www3.niaid.nih.gov/topics/genitalHerpes/default.htm.

NIAID conducts and supports researchat NIH, throughout the United States, and worldwideto study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH)The Nation’s Medical Research Agencyincludes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

References: 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).

C 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. Lancet DOI: 10.1016/S0140-6736(08)60920-4 (2008).

A new technique that detects the HIV virus early and monitors its development without requiring refrigeration may make AIDS testing more accessible in sub-Saharan Africa.

According to UNAIDS, sub-Saharan Africa accounts for almost a third of all new HIV infections and AIDS-related deaths globally. Yet there may be many people who do not get tested due to the high cost of treatment and minimal access to health care.

Duke Physician John Crump and a team of researchers recently completed a 10-month experiment at two remote sites in Tanzania. They examined Tanzanian infants born to HIV-infected parents and people with known HIV infections who needed monitoring of their viral loads. Viral load is a measurement used to diagnose HIV infection or determine the severity of HIV infection.

In the largest field study of its kind, researchers compared viral load measurements by using the current standard of frozen plasma and the alternative method of dried blood spots (DBS). The samples were measured at a central lab at the Kilimanjaro Christian Medical Centre in Moshi, some 250 and 350 kilometers away from the two study sites.

The Duke study found a strong correlation between viral load values in plasma and DBS, making the two testing approaches comparable. This finding could lay the foundation for a new way of testing for and monitoring patients with HIV in the future, according to Dr. John Bartlett, Duke Global Health Institute Associate Director for Research.

The sooner infants are diagnosed with HIV, the sooner they can receive life-prolonging medications to treat the disease. The infection cannot be detected in newborns using the typical HIV antibody test, and must be detected with other techniques, including viral load testing.

Viral load testing is also the optimal way for monitoring HIV infection in patients with known infections, especially for those receiving treatment.

But few labs in Tanzania perform the viral load procedure, and blood samples must be transported long distances to specialized medical facilities for testing. Plasma requires continuous cold storage during shipment, which can be challenging or impossible in resource-limited settings. This may prevent people from getting tested or result in inaccurate tests.

“Dried blood spots offer the advantage of not requiring cold storage,” says Bartlett, who also points out that this method may result in lower total health care costs. “Before using it for care and treatment programs, it will need further evaluation. But, this is the largest field study of DBS’s done to date, and the results appear promising.”

The study findings were presented on Monday, July 20th in Cape Town, South Africa at the fifth HIV Pathogenesis, Treatment and Prevention conference. The event, hosted by the International AIDS Society, is the world’s largest open scientific conference on HIV/AIDS with more than 5,000 attendees. The study’s lead author Sarah Lofgren is a third year medical student at Duke. This study was selected for distinction by the Conference Scientific Program Committee.

Additional information about the conference can be found at www.ias2009.org.

Duke University

PROVIDENCE, R.I. [Brown University] Brazil’s nearly two-decade effort to treat people living with HIV and AIDS shows that developing countries can successfully combat the epidemic. Inexpensive generic medicines are a large part of the solution, say researchers from Brown University and the Harvard School of Public Health.

Brazil did this, researchers said, largely by pursuing controversial policies that prompted pharmaceutical companies with exclusive drugs to lower their prices dramatically and generic companies to develop lower-cost alternatives for use in emerging markets.

“Brazil has proved it is possible to treat people with AIDS in developing countries,” said lead author Amy Nunn, assistant professor of medicine (research) at The Warren Alpert Medical School of Brown University. She added that the country saved more than $1 billion as a result of bargaining with multinational pharmaceutical companies, resulting in significant changes in global AIDS policy.

That effort, Nunn said, has had a wide impact.

“Before Brazil’s efforts, as recently as the year 2000,” she said, “most people living with HIV/AIDS in developing countries died without receiving treatment.”

Details of their findings will be published in the July/August issue of Health Affairs. Francisco Bastos, a well-known AIDS epidemiologist at the Oswaldo Cruz Foundation in Rio de Janiero, and Elize da Fonseca at the University of Edinburgh in Scotland also participated in the research. Senior author Sofia Gruskin is an associate professor of health and human rights at the Harvard School of Public Health in Boston, where the initial research began.

One of the biggest advances in Brazil’s push to address the advance of HIV and AIDS came in the 1990s, when the country passed a law guaranteeing free, universal access to drugs for AIDS treatment. The country also began producing generic AIDS medicines in public factories. Brazilian authorities also pressured drug companies to reduce their prices drastically for patented medicines by threatening to produce generic versions of those drugs.

Brazil was working to contain the virus years before taking that step. Researchers noted that Brazil began its HIV education and prevention campaigns early in the 1980s, focusing on condom distribution and HIV testing. Health officials also targeted prevention campaigns to those vulnerable to contracting HIV, including sex workers, injecting drug users and men who have sex with men.

The results were enormously beneficial. Researchers said the countrys treatment initiatives also helped minimize the spread of the virus in Brazil. In doing so, health officials proved AIDS treatment was possible in a developing country. The example helped prompt sweeping changes in global public health policy and foreign aid relating to global health, with Brazils actions as an example of how to make HIV/AIDS policies more effective.

Gruskin said that Brazil also spearheaded important changes in global health, trade policies, and international human rights protections related to medicines, and the country forced greater transparency about global drug prices.

An example of the change: Since 2003, the United States and other developed countries once opposed to Brazils policies have invested billions of dollars annually to provide generic AIDS medicines to people in developing countries.

At home, Brazil kept its HIV/AIDS epidemic confined to .5 percent of the population. Today, about 660,000 Brazilians live with the disease.

Nunn said the study’s findings show that developing countries around the world can dramatically reduce AIDS-related deaths by treating patients. She added that the research highlights the value of strategic global political engagement by developing countries.

Still, there are challenges ahead. The study shows that the cost of treating HIV/AIDS patients in Brazil has risen in recent years. The long-term costs of treating people living with HIV/AIDS will continue to rise in other countries as more people receive treatment, life expectancy is extended, and patients require more costly and often patented medicines.

A number of organizations funded the research: The U.S. Departments of State and Education, the National Institute on Drug Abuse and the National Institute of Allergy and infectious Diseases.

Brown University

A discovery by a team of Canadian and American researchers could provide new ways to fight HIV-AIDS. According to a new study published in Nature Medicine, HIV-AIDS could be treated through a combination of targeted chemotherapy and current Highly Active Retroviral (HAART) treatments. This radical new therapy would make it possible to destroy both the viruses circulating in the body as well as those playing hide-and-seek in immune system cells.

The study was led by Dr. Rafick-Pierre Skaly, of the Universit de Montral. Dr. Jean-Pierre Routy of the Research Institute of the McGill University Health Centre (RI-MUHC) and scientists from the National Institutes of Health (NIH) and the University of Minnesota in the United States also collaborated on the investigation.

To date, anti-AIDS treatments have been stymied by “HIV reservoirs” immune system cells where the virus hides and where existing HAART treatments cannot reach. The researchers successfully identified the cells where HIV hides and the “stealth” mechanisms that allow the virus to escape existing treatments. This breakthrough opens the way towards innovative therapies that are completely different from current approaches.

“Our results argue in favour of a strategy similar to the one used against leukemia, which is targeted chemotherapy, associated with a targeted immune treatment. This would make it possible to destroy the cells containing a virus, while giving the immune system time to regenerate with healthy cells,” says Dr. Rafick-Pierre Skaly, a professor at the Universit de Montral, researcher at the Centre Hospitalier de Universit de Montral (CHUM), director of INSERM 743 and scientific director of the Vaccine and Gene Therapy Institute of Florida.

“For the first time, this study proves that the HIV reservoirs are not due to a lack of potency of the antiretroviral drugs, but to the virus hiding inside two different types of long life CD4 memory immune cells,” explains Dr. Jean-Pierre Routy, a hematologist with the MUHC, researcher in infection and immunity at the RI-MUHC and professor of hematology at McGill University. “There are several types of HIV reservoirs, each necessitating a different treatment to eliminate them.”

Indeed, once the virus is hidden in these reservoir cells, it becomes dependent on them: if the cell lives, the virus lives, but if the cell dies, so does the virus. As such, destroying these immune cells will allow for the elimination of the resilient or hidden parts of the virus. Existing HAART treatments destroy the viruses circulating in the body, yet cannot reach those hidden in reservoir cells.

“We now have brand-new options to fight HIV,” concludes Nicolas Chomont, a postdoctoral intern at the Universit de Montral’s Department of Microbiology and Immunology and one of the co-authors of this study. “The combination of fundamental and clinical approaches led to amazing results that allow us to elucidate another mystery of this virus of a thousand faces.”

These new therapeutic options will require many more years of research before they are validated and become a reality for patients. However, this study represents an invaluable work plan that will provide a map for many laboratories around the world.

Funding

This study was funded by the American Foundation for AIDS Research (amfAR), the National Institutes of Health, the Canadian Institutes of Health Research and the FRSQ-AIDS and Infectious Diseases Network.

Partners

The study, “HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation,” published in Nature Medicine, was coauthored by Rafick-Pierre Skaly, Elias K. Haddad, Nicolas Chomont, Mohamed El Far, Petronela Ancuta, Lydie Trautmann, Francesco A. Procopio, Bader Yassine-Diab and Genevive Boucher of the Universit de Montral and Centre Hospitalier de Universit de Montral (CHUM), Jean-Pierre Routy, Mohamed-Rachid Boulassel and Georges Ghattas of the McGill University Health Centre (MUHC) and McGill University, Brenna J. Hill, Daniel C. Douek and Jason M. Brenchley of the National Institutes of Health, U.S.A., and Timothy W. Schacker of the University of Minnesota, U.S.A.

McGill University Health Centre

University of Montreal

WHAT: Most vaccines that protect against viruses generate infection-fighting proteins called antibodies that either block infection or help eliminate the virus before it can cause disease. Attempts to create a vaccine that induces antibodies that prevent HIV infection or disease, however, have so far been unsuccessful. But several recent studies suggest promising new research directions for the development of an antibody-based HIV vaccine, according to John R. Mascola, M.D., deputy director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, and colleagues.

These studies demonstrate that, contrary to widespread belief, it is not uncommon for people infected with HIV to naturally make antibodies that can neutralize a variety of HIV strains. These antibodies do not protect people from the virus because they arise years after HIV infection is established. However, if a vaccine could prime the body to make these broadly neutralizing antibodies before exposure to HIV, they could potentially prevent infection or hold the virus at bay until an army of immune cells assembles to limit viral replication.

Based on these findings, Dr. Mascola and colleagues recommend a research strategy that uses naturally occurring, broadly neutralizing anti-HIV antibodies for the ultimate design of an antibody-based HIV vaccine.

Key aspects of this strategy include

• Obtaining new broadly neutralizing antibodies to HIV to expand the pool available for scientists to study
• Identifying regions on the surface of HIV that are vulnerable to broadly neutralizing antibodies and determining the atomic-level crystal structure of those regions
• Understanding how broadly neutralizing antibodies to HIV evolve and persist
• Clarifying the structural differences between anti-HIV antibodies that do and do not have neutralizing properties
• Determining what quantity of broadly neutralizing antibodies an HIV vaccine must elicit to be effective
• Learning how anti-HIV neutralizing antibodies and HIV surface proteins evolve in response to one another in people who eventually produce a powerful neutralizing antibody response to the virus
• Clarifying how HIV surface proteins are presented to the immune cells that produce broadly neutralizing antibodies to HIV
• Determining what immune-system conditions promote the production of broadly neutralizing anti-HIV antibodies

ARTICLE: L Stamatatos et al. Neutralizing antibodies generated during natural HIV-1 infection: good news for an HIV-1 vaccine? Nature Medicine DOI 10.1038/nm.1949 (2009).

WHO: John R. Mascola, M.D., deputy director of NIAID’s Vaccine Research Center, is available for comment.

CONTACT: To schedule interviews, please contact Laura Sivitz, 301-402-1663, sivitzl@niaid.nih.gov.

NIAID conducts and supports researchat NIH, throughout the United States, and worldwideto study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH)The Nation’s Medical Research Agencyincludes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

Latent HIV genes can be ’smoked out’ of human cells. The so-called ’shock and kill’ technique, described in a preclinical study in BioMed Central’s open access journal Retrovirology, might represent a new milestone along the way to the discovery of a cure for HIV/AIDS.

Dr. Enrico Garaci, president of the Istituto Superiore di Sanit (the Italian Institute of Health) and Dr. Andrea Savarino, a retrovirologist working at the institution, worked with a team of researchers to study the so-called “barrier of latency” which has been the main obstacle to HIV eradication from the body.

Cells harbouring a quiescent HIV genome are responsible for HIV persistence during therapy. In other words, HIV-1 genes become pieces of the human organism, and many scientists have simply thought there is nothing we can do. Dr Savarino’s team aimed to ’smoke out’ the virus in order to render the latently infected cells targetable by the immune system or artificial means. They write, “This can be achieved using inhibitors of histone deacetylases (HDACs), which are a class of enzymes that maintain HIV latency. However, their effects on HIV are evident only when used in toxic quantities”.

To overcome this problem, the Italian researchers tested a collection of HDAC inhibitors, some of which specifically target only certain enzyme isoforms (class I HDACs) that are involved in HIV latency. The toxicity of this approach, however, was not markedly decreased, although it compromises a more limited number of cellular pathways. Moreover, at non-toxic quantities, class I HDAC inhibitors were able to induce the ‘awakening’ of a portion of cells within a latently infected cell population. The researchers then repeated the experiment adding a drug inducing oxidative stress, buthionine sulfoximine (BSO). The results showed that BSO recruited cells non-responsive to the HDAC inhibitors into the responding cell population. An important result was that the infected cells’ ‘awakening’ was followed by cell death, whereas the non-infected cells were left intact by the drug combination.

“I really hope this study may open new avenues to the development of weapons able to eliminate the HIV-infected cells from the body”, says Dr. Andrea Savarino, “Such weapons, in combination with antiretroviral therapies, could hopefully allow people living with HIV/AIDS to get rid of the virus and return to a normal life. Of note, there are testable drug combinations composed of molecules that have passed phase I clinical trials for safety in humans”. This type of approach has been dubbed ’shock and kill’. “Although this type of approach is largely accepted by the scientific community”, adds Dr. Savarino, “to be honest, we have to take into consideration that some scientists are skeptical about this approach, and others even think that a cure for HIV/AIDS will never be found. Experiments using animal models will shed a new light on this difficult problem.”

Source: BioMed Central

New research in the FASEB Journal describes a one-two punch in the battle against HIV

In what could be a major pharmaceutical breakthrough, research published online in The FASEB Journal (http://www.fasebj.org) describes how scientists from St George’s, University of London have devised a one-two punch to stop HIV. First the report describes a new protein that can kill the virus when used as a microbicide. Then the report shows how it might be possible to manufacture this protein in quantities large enough to make it affordable for people in developing countries.

“We desperately need to control the spread of HIV, particularly in developing countries,” said Julian Ma of the Department of Cellular and Molecular Medicine at St. George’s and the senior researcher involved in the work. “A vaccine is still some way off, but microbicides could provide a more immediate solution, provided we can overcome major hurdles of high efficacy, low cost, and wide availabilityall of which we address in this study.”

In the research paper, Ma and colleagues describe how they combined two protein microbicides (b12 monoclonal antibody and cyanovirin-N) into a single “fusion” molecule and showed that this molecule is more active against HIV than either of its individual components. They designed synthetic DNA for producing this molecule and introduced this DNA into plant cells. After regenerating transgenic plants that produce the fusion molecule, they prepared the microbicide from a plant extract made by grinding the leaves.

“This study is nothing short of a breakthroughnot only does it yield a new drug to fight the spread of HIV, but it also shows us how we can produce it on the scale necessary to get it into the hands of those who need it most,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “Unlike their unregulated counterparts in the dietary supplement industry, these scientists are using the engines of nature to manufacture pharmaceuticals that must undergo extensive safety and efficacy testing long before the first gel or cream is administered.”

Receive monthly highlights from The FASEB Journal by e-mail. Sign up at http://www.faseb.org/fasebjournalreaders.htm. The FASEB Journal (http://www.fasebj.org) is published by the Federation of the American Societies for Experimental Biology (FASEB). The journal has been recognized by the Special Libraries Association as one of the top 100 most influential biomedical journals of the past century and is the most cited biology journal worldwide according to the Institute for Scientific Information. FASEB comprises 22 nonprofit societies with more than 80,000 members, making it the largest coalition of biomedical research associations in the United States. FASEB advances biological science through collaborative advocacy for research policies that promote scientific progress and education and lead to improvements in human health.

Details: Amy Sexton, Sarah Harman, Robin J. Shattock, and Julian K.-C. Ma
Design, expression, and characterization of a multivalent, combination HIV microbicide. doi:10.1096/fj.09-131995. http://www.fasebj.org/cgi/content/abstract/fj.09-131995v1

Federation of American Societies for Experimental Biology

Gene transfer technology may lead to an HIV vaccine

A research team may have broken the stubborn impasse that has frustrated the invention of an effective HIV vaccine, by using an approach that bypasses the usual path followed by vaccine developers. By using gene transfer technology that produces molecules that block infection, the scientists protected monkeys from infection by a virus closely related to HIVthe simian immunodeficiency virus, or SIVthat causes AIDS in rhesus monkeys.

“We used a leapfrog strategy, bypassing the natural immune system response that was the target of all previous HIV and SIV vaccine candidates,” said study leader Philip R. Johnson, M.D., chief scientific officer at The Children’s Hospital of Philadelphia. Johnson developed the novel approach over a ten-year period, collaborating with K. Reed Clark, Ph.D., a molecular virologist at Nationwide Children’s Hospital in Columbus, Ohio.

The study appeared today in the online version of Nature Medicine.

Johnson cautioned that many hurdles remain before the technique used in this animal study might be translated into an HIV vaccine for humans. If the technique leads to an effective HIV vaccine, such a vaccine may be years away from realization.

Most attempts at developing an HIV vaccine have used substances aimed at stimulating the body’s immune system to produce antibodies or killer cells that would eliminate the virus before or after it infected cells in the body. However, clinical trials have been disappointing. HIV vaccines have not elicited protective immune responses, just as the body fails on its own to produce an effective response against HIV during natural HIV infection.

The approach taken in the current study was divided into two phases. In the first phase, the research team created antibody-like proteins (called immunoadhesins) that were specifically designed to bind to SIV and block it from infecting cells. Once proven to work against SIV in the laboratory, DNA representing SIV-specific immunoadhesins was engineered into a carrier virus designed to deliver the DNA to monkeys. The researchers chose adeno-associated virus (AAV) as the carrier virus because it is a very effective way to insert DNA into the cells of a monkey or human.

In the second part of the study, the team injected AAV carriers into the muscles of monkeys, where the imported DNA produced immunoadhesins that entered the blood circulation. One month after administration of the AAV carriers, the immunized monkeys were injected with live, AIDS-causing SIV. The majority of the immunized monkeys were completely protected from SIV infection, and all were protected from AIDS. In contrast, a group of unimmunized monkeys were all infected by SIV, and two-thirds died of AIDS complications. High concentrations of the SIV-specific immunoadhesins remained in the blood for over a year.

Further studies need to be conducted if this technique is to become an actual preventive measure against HIV infection in people, Johnson said. “To ultimately succeed, more and better molecules that work against HIV, including human monoclonal antibodies, will be needed,” he and his co-authors conclude. Finally, added Johnson, their approach may also have potential use in preventing other infectious diseases, such as malaria.

Grants from the National Institute of Allergic and Infectious Diseases of the National Institutes of Health supported this study. Johnson’s collaborators, in addition to Clark, were Jianchao Zhang, of Nationwide Children’s Hospital, Columbus, Ohio; Eloisa Yuste and Ronald C. Desrosiers of the New England Primate Research Center and Harvard Medical School; and Bruce C. Schnepp, Mary J. Connell, and Sean M. Greene, of Children’s Hospital and the University of Pennsylvania School of Medicine. Johnson also is on the University of Pennsylvania faculty.

Johnson et al, “Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys,” Nature Medicine, published online May 17, 2009. (http://dx.doi.org/10.1038/nm.1967)

About The Children’s Hospital of Philadelphia

The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

Children’s Hospital of Philadelphia

A natural approach for HIV vaccine

Research suggests scientists should follow the body’s lead to prevent HIV from taking root

For 25 years, researchers have tried and failed to develop an HIV vaccine, primarily by focusing on a small number of engineered “super antibodies” to fend off the virus before it takes hold. So far, these magic bullet antibodies have proved impossible to produce in people. Now, in research to be published March 15 online by Nature, scientists at The A natural approach for HIV vaccineRockefeller University have laid out a new approach. They have identified a diverse team of antibodies in “slow-progressing” HIV patients whose coordinated pack hunting knocks down the virus just as well as their super-antibody cousins fighting solo.

By showcasing the dynamic, natural immune response in these exceptional patients, the research, led by Michel C. Nussenzweig, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology, suggests that an effective HIV vaccine may come from a shotgun approach using of a wide range of natural antibodies rather than an engineered magic bullet.

“We wanted to try something different, so we tried to reproduce what’s in the patient. And what’s in the patient is many different antibodies that individually have limited neutralizing abilities but together are quite powerful,” says Nussenzweig, who also is a Howard Hughes Medical Institute investigator. “This should make people think about what an effective vaccine should look like.”

HIV strains mutate rapidly, making them especially wily adversaries of the immune system. But one element is shared almost universally among the diverging strains a protein on the envelope of the virus called gp140 that HIV needs to infect immune cells. Prior research has shown that four randomly engineered antibodies that block the activity of that protein prevent the virus from infecting immune cells in culture, but all attempts to coax the human body into producing those four have failed.

So Johannes Scheid, a visiting student in Nussenzweig’s lab who is now a doctoral candidate, turned his attention to the antibodies produced by six people infected with HIV whose immune systems put up an exceptionally strong fight. The patients represent the roughly 10 to 20 percent of HIV patients who are able to control the virus and are very slow to progress to disease. Their immune systems’ memory B cells produce high levels of antivirus antibodies, but until now, researchers have known little about the antibodies or how effective they are.

With help from Rockefeller’s Center for Clinical and Translational Science and Rockefeller scientists David D. Ho and Jeffrey V. Ravetch, Scheid and colleagues isolated 433 antibodies from these individuals’ blood serum that specifically targeted the envelope protein the chink in HIV’s protean armor. He cloned the antibodies and produced them in bulk, mapped which part of the envelope protein each targeted, and gauged how effective each was in neutralizing the virus. In the process, he identified a new structure within the envelope protein called the gp120 core that had never been recognized as a potential target for antibodies. “It’s the first time that anyone has defined what is really happening in the B cell response in these patients,” says Scheid.

Scheid’s work shows that it’s common for these antibodies to have neutralizing activity, says Nussenzweig. But each antibody alone has limited ability to fight the virus. “Individually, they’re not as strong as the Famous Four,” says Nussenzweig, referring to the high-profile super antibodies on which several vaccine attempts have been based. But in high concentrations, a combination of the sets of antibodies cloned from the individual patients seemed to act as teams to knock down the virus in cell culture as well as any single antibody studied to date. These natural antibodies were also able to recognize a range of HIV strains, indicating that their diversity may be an advantage over a single super antibody that focuses on only one part of the virus, which can mutate. The findings suggest that research into vaccines that mimic this natural antibody response could pay off.

A cheap ingredient used in ice cream and cosmetics could be used as a gel to protect women against Aids, researchers reported today.

The compound, called glycerol monolaurate, or GML, is found in breast milk. Tests found it appeared to protect monkeys against infection with a similar virus.

It stopped inflammation and protected the cells the Aids virus usually infects.

While the compound did not provide 100 per cent protection, it could greatly reduce a woman’s risk of being infected, the researchers wrote in the journal Nature. They added that a dose cost just pennies to produce.

If it can be shown to work safely in women, GML could be applied as a vaginal gel or cream.

HIV infects 33 million people globally and has killed 25 million. It is transmitted sexually, in blood and breast milk. In Africa, it is most commonly passed during heterosexual contact.

AIDS experts say many victims are married women whose husbands will not use condoms and are often trying to have children. The gel would provide a safe and private way to protect themselves.

HIV is particularly hard to fight because it infects the very immune cells the body uses to attack a virus. When HIV infects an area such as the vagina, the CD4 T-cells rush to defend against it. The body sends out signaling chemicals called cytokines to call in more T-cells.

HIV can then infect them all and spread through the body.

GML appears to stop the cytokine call for help and stops so many T-cells from rushing to the area, Ashley Haase and Pat Schlievert of the University of Minnesota said. This in turn reduces the opportunity for HIV to take hold.

‘This result represents a highly encouraging new lead in the search for an effective microbicide to prevent HIV transmission that meets the criteria of safety, affordability and efficacy,’ they wrote.

Even if it was only 60 per cent effective, such a gel could prevent 2.5 million HIV cases over three years, they said.

They said further studies would take place to make sure the gel was preventing HIV and not just delaying it.

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