Editors' ChoiceHIV

HIV Under Cover

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Science Translational Medicine  14 Sep 2011:
Vol. 3, Issue 100, pp. 100ec150
DOI: 10.1126/scitranslmed.3003169

Although the widespread use of highly active combination antiretroviral drug therapy has decreased morbidity and mortality among those infected with HIV, a cure that completely eradicates HIV infection has been elusive. A major roadblock is that HIV can hide out in cellular reservoirs and continue to replicate while remaining protected from antiretroviral drugs and the host immune response. How HIV orchestrates escape from drug treatment without developing substantial drug resistance mutations is not well understood. Sigal and colleagues now demonstrate that when HIV infection is transmitted by spreading from cell to cell, which occasionally results in multiple infections per cell, this viral pathogen is better able to withstand the onslaught of antiretroviral drug therapy.

Sigal et al. started with the premise that, if a host cell is bombarded with multiple virions, even in the presence of adequate drug concentrations, the chance that one virion may escape drug pressure is increased. To experimentally validate their proposed model in vitro, the investigators used high and low numbers of HIV virions to infect the permissive MT-4 T cell line in the presence of the antiretroviral agent tenofovir (TDF). They found that at higher virion numbers, HIV was less sensitive to TDF, whereas at lower virion numbers, HIV infection was eradicated across a range of drug concentrations. To compare the effects of drug concentrations on HIV infection due to cell-to-cell spread of virus or cell-free virus, the authors used either cocultures of infected peripheral blood mononuclear cells (PBMCs) mixed with target (uninfected) PBMCs or target cells and cell-free virus in the presence of TDF. They measured the p24 HIV protein by intracellular staining to calculate the fraction of target cells that were infected after 2 days. In the presence of TDF, there was a 30-fold reduction in the rate of infection by cell-free HIV. In contrast, uninfected target PBMCs cocultured with HIV-infected PBMCs were largely insensitive to TDF, showing a mere two-fold decrease in the infection rate. In another experiment, exposing Rev-CEM reporter T cells to high concentrations of a drug combination (TDF and efavirenz), the researchers found that the likelihood of HIV transmission in the cocultured cells was six times as high as that of the cell-free virus. Despite ongoing drug pressure, this reduction in sensitivity to antiretroviral drugs in the cell-to-cell transmission of HIV appears to stand firm over multiple rounds of infection. Using a simulation model, Sigal et al. show that although cell-to-cell spread with multiple infections per cell is predicted to be intermittent, the virus is able to continue to replicate in the presence of drug without developing substantial drug-resistance mutations.

Thus, cell-to-cell spread of HIV starting with a large infectious dose appears to circumvent strong pressure from antiretroviral drugs and may have direct effects on maintaining replicating HIV in cellular reservoirs, which drugs find difficult to penetrate. Although the Sigal et al. study was done in cultured cells in vitro, the findings have important translational implications for drug development while offering a rationale for how HIV is able to replicate in the presence of drugs and the absence of drug-resistance mutations.

A. Sigal et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature 477, 95–98 (2011). [Abstract]

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