Discovery Advances Knowledge About Link Between Herpes and HIV Infection
Research offers new insight on the biological chain of events leading to HIV infection in individuals with genital herpes. The finding may provide scientists with new targets as they seek to develop HIV prevention drugs.
NEW YORK (30 June 2011)—Currently little is known about the process of HIV infection, that is, what happens after the virus enters the body. This lack of clarity makes it difficult to develop HIV prevention products. However, it has been documented that individuals with herpes simplex virus 2 (HSV-2) are three times more likely to contract HIV than those uninfected by herpes.
This is in part due to inflammation and ulcers related to herpes infection. But those with HSV-2 are at higher risk for HIV even after receiving treatment to eliminate symptoms of HSV-2. This means that physical symptoms do not entirely explain the increased risk of HIV infection associated with HSV-2. In fact, it has been shown that HSV-2 infection can influence how the immune system responds to HIV infection.
New research led by the Population Council’s Elena Martinelli and published today in PLoS Pathogens finds that HSV-2 infection of dendritic cells, a specific type of immune cell, fuels HIV replication. Previous research at the Population Council contributed to determining the critical role of dendritic cells in the onset of HIV infection. The new study indicates that HSV-2 infection induces the ability of dendritic cells to produce retinoic acid, a substance that increases HIV infection in cell cultures.
Retinoic acid is also known to induce the expression of α4β7, an HIV receptor previously identified by Elena Martinelli and colleagues at the US National Institutes of Health (NIH).  Immune cells expressing this receptor are highly susceptible to HIV infection. Notably, the new study found that HSV-2 rectal infection in macaques increases the number of cells of expressing α4β7 at the site of HSV-2 infection.
"Our findings suggest retinoic acid and integrin α4β7 may contribute to increasing the risk of HIV infection in HSV-2-positive people. Integrin α4β7 marks cells directed to the gut tissue, where HIV is harbored and proliferates. This sequence may result in an environment that heightens susceptibility to HIV infection," says Martinelli.
The new findings could help scientists as they work to develop prevention methods that inhibit the ability of HIV to replicate at the time of transmission.
This work was supported by the NIH grant R37 AI040877, the NIH base grant RR00164, and in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E.
Article: Martinelli, Elena, Hugo Tharinger, Ines Frank, James Arthos, Michael Piatak Jr., Jeffrey D. Lifson, James Blanchard, Agegnehu Gettie, and Melissa Robbiani. 2011. “HSV-2 infection of dendritic cells amplifies a highly susceptible HIV-1 cell target.” PLoS Pathogens 7(6): e1002109. doi:10.1371/journal.ppat.1002109. (PDF)
Related project: Transmission of Immunodeficiency Viruses
1. Freeman, E.E., H.A. Weiss, J.R. Glynn, P.L. Cross, J.A. Whitworth et al. 2006. "Herpes simplex virus 2 infection increases HIV acquisition in men and women: Systematic review and meta-analysis of longitudinal studies," AIDS 20(1): 7383.
2. Lingappa, J.R., J.M. Baeten, A. Wald, J.P. Hughes, K.K. Thomas et al. 2010. "Daily acyclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: A randomised placebo-controlled trial," Lancet 375(9717): 824833.
3. Arthos, J., C. Cicala, E. Martinelli, K. Macleod, D. Van Ryk et al. 2008. "HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells," Nature Immunology 9(3): 301309.
4. Cicala, C., E. Martinelli, J.P. McNally, D.J. Goode, R. Gopaul et al. 2009. "The integrin alpha4beta7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1," Proceedings of the National Academy of Sciences of the United States of America 106(49): 2087720882.
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