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NIH researchers show how anti-HIV drug acts to block herpes virus
Newfound effectiveness of tenofovir due to higher concentrations in vaginal gel form
An anti-HIV drug also discovered to stop the spread of the genital herpes virus [Genital Herpes - STD information from CDC ] does so by disabling a key DNA enzyme of the herpes virus, according to findings by researchers at the National Institutes of Health and other institutions.
The study was published online in Cell Host and Microbes and was conducted by researchers at the Catholic University of Leuven, Belgium; the University of Rome; Gilead Sciences, Inc., Foster City, Calif; and the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
The findings explain the results of a recent clinical trial [ Effectiveness and safety of tenofovir gel, an antire... [Science. 2010] - PubMed - NCBI ] showing that the anti-HIV drug tenofovir, when it is formulated as a vaginal gel, could reduce the risk of herpes simplex virus (HSV) infections — as well as HIV infections — in women.
Tenofovir taken orally had been demonstrated to inhibit reproduction of HIV, but had not been known to block the genital herpes virus.
"HIV infection is closely associated with herpes viral infection. When people with genital herpes are exposed to HIV, they are more likely to become infected than are people who do not carry the herpes virus," said Leonid Margolis, Ph.D., head of the Section on Intercellular Interactions at NICHD and one of the authors of the study. "Human tissues convert tenofovir to a form that suppresses HIV. We found that this form of tenofovir also suppresses HSV. This discovery may help to identify drugs to treat the two viruses even more effectively."
Discoveries leading to new uses for previously approved drugs have the potential to save millions of dollars, Dr. Margolis said. New drugs typically undergo years of testing for safety and effectiveness before they are approved for patients. Finding new uses for an approved drug increases the value of the initial investment in testing, because most of the testing has previously been completed.
The researchers examined individual cells and groups of cells infected with HSV and found that high concentrations of tenofovir prevent the ability of this virus to reproduce. They also confirmed that tenofovir itself did not damage the cells. These tests included the type of cells that line the vagina, which are targets for infection with HSV and HIV.
Tenofovir is converted by cellular enzymes to another chemical form. The researchers found that this form of tenofovir suppresses not only HIV, but HSV as well. Specifically, the researchers showed that this active form of tenofovir can disable an enzyme that the virus needs to reproduce.
The researchers also examined the effects of tenofovir in tissues samples. They injected HSV into tonsil tissue and cervix tissue, and then applied tenofovir. They found that after 12 days, levels of the virus were only 1 to 13 percent of viral levels in untreated tissue. Tenofovir also blocked viral reproduction in tissue infected with both HIV and HSV simultaneously.
Using tenofovir to treat lab mice infected with the herpes virus also prevented symptoms of the disease and prolonged the animals' survival, the researchers found.
The vaginal gel showed activity against HSV apparently because of the high concentration of tenofovir that it contains. In contrast, when tenofovir is taken orally, tissue levels do not reach sufficient levels to significantly affect HSV.
"When using the gel, the amount of tenofovir on the affected tissues is about 100 times the amount in the body when taking tenofovir in pill form," said Dr. Margolis. "That explains why its anti-herpes activity wasn't noticed before. Thus, under proper conditions, an anti-HIV drug becomes an anti-HSV drug."
In previous research, Dr. Margolis' team showed that an anti-HSV drug, acyclovir, is converted inside the infected cells into an anti-HIV drug. They now believe the next step will be to find the form in which such drugs are most potent against both viruses at the same time.
Study authors were: Graciela Andrei, Robert Snoeck, and Jan Balzarini (senior author), Joost van den Oord, Catholic University of Leuven; Emanuela Balestra, Carlo-Federico Perno (senior author), University of Rome; Tomas Cihlar, Gilead Sciences; and Andrea Lisco, Christophe Vanpouille, Andrea Introini, and Leonid Margolis (senior author) NICHD.
About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute's website at http://www.nichd.nih.gov/.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov/.
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NIH researchers show how anti-HIV drug acts to block herpes virus, October 20, 2011 News Release - National Institutes of Health (NIH)
Science. 2010 Sep 3;329(5996):1168-74. Epub 2010 Jul 19.
Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women.
Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, Kharsany AB, Sibeko S, Mlisana KP, Omar Z, Gengiah TN, Maarschalk S, Arulappan N, Mlotshwa M, Morris L, Taylor D; CAPRISA 004 Trial Group.
Source
Centre for the AIDS Program of Research in South Africa (CAPRISA), Durban 4013, South Africa. caprisa@ukzn.ac.zaErratum in
- Science. 2011 Jul 29;333(6042):524.
Abstract
The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18- to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.Comment in
Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women
Effectiveness and safety of tenofovir gel, an antire... [Science. 2010] - PubMed - NCBI
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