Abstract
BackgroundThe Human Immunodeficiency Virus type-1 (HIV-1) spreads by cell-free diffusion and by direct cell-to-cell transfer, the latter being a significantly more efficient mode of transmission. Recently it has been suggested that cell-to-cell spread may permit ongoing virus replication in the presence of antiretroviral therapy (ART) based on studies performed using Reverse Transcriptase Inhibitors (RTIs). Protease Inhibitors (PIs) constitute an important component of ART; however whether this class of inhibitors can suppress cell-to-cell transfer of HIV-1 is unexplored. Here we have evaluated the inhibitory effect of PIs during cell-to-cell spread of HIV-1 between T lymphocytes.ResultsUsing quantitative assays in cell line and primary cell systems that directly measure the early steps of HIV-1 infection we find that the PIs Lopinavir and Darunavir are equally potent against both cell-free and cell-to-cell spread of HIV-1. We further show that a protease resistant mutant maintains its resistant phenotype during cell-to-cell spread and is transmitted more efficiently than wild-type virus in the presence of drug. By contrast we find that T cell-T cell spread of HIV-1 is 4–20 fold more resistant to inhibition by the RTIs Nevirapine, Zidovudine and Tenofovir. Notably, varying the ratio of infected and uninfected cells in co-culture impacted on the degree of inhibition, indicating that the relative efficacy of ART is dependent on the multiplicity of infection.ConclusionsWe conclude that if the variable effects of antiviral drugs on cell-to-cell virus dissemination of HIV-1 do indeed impact on viral replication and maintenance of viral reservoirs this is likely to be influenced by the antiviral drug class, since PIs appear particularly effective against both modes of HIV-1 spread.
Highlights
The Human Immunodeficiency Virus type-1 (HIV-1) spreads by cell-free diffusion and by direct cell-to-cell transfer, the latter being a significantly more efficient mode of transmission
Protease inhibitors effectively inhibit cell-to-cell transfer of HIV-1 To investigate the effect of Protease Inhibitors (PIs) on cell-to-cell spread of HIV-1 we used a well-established T cell co-culture system, the validation of which is extensively described elsewhere [31,32,33,34]
HIV-1 infected Jurkat T cells were either untreated or pre-incubated with the PI Lopinavair (LPV) or Darunavir (DRV), incubated with uninfected target T cells (Jurkat-1G5) and cell-to-cell spread of HIV-1 was measured by quantitative real-time PCR to enumerate the appearance of de novo HIV-1 DNA pol copies that arise from reverse transcription within the newly infected T cell population
Summary
The Human Immunodeficiency Virus type-1 (HIV-1) spreads by cell-free diffusion and by direct cell-to-cell transfer, the latter being a significantly more efficient mode of transmission. It has been suggested that cell-to-cell spread may permit ongoing virus replication in the presence of antiretroviral therapy (ART) based on studies performed using Reverse Transcriptase Inhibitors (RTIs). Recent treatment intensification studies with the Integrase Inhibitor (INI) Raltegravir have noted an increase in episomal DNA and a reduction in the size of the latent reservoir [2,3,4]. These studies suggest that there is ongoing residual viral replication, which may be suppressed by addition of INIs to existing treatment regimens
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