Choice of antiretroviral therapy differentially impacts survival of HIV-infected CD4 T cells

Abstract

Background: HIV eradication strategies are now being evaluated in vitro and in vivo. A cornerstone of such
approaches is maximal suppression of viral replication with combination antiretroviral therapy (ART). Since many
antiretroviral agents have off target effects, and different classes target different components of the viral life cycle,
we questioned whether different classes of ART might differentially affect the survival and persistence of
productively HIV-infected CD4 T cells.
Methods: In vitro infections of primary CD4 T cells using clinical isolates of HIV-1 that were either protease inhibitor
susceptible (HIV PI-S), or resistant (HIV PI-R) were treated with nothing, lopinavir, efavirenz or raltegravir. Cell viability,
apoptosis, and the proportion of surviving cells that were P24 positive was assessed by flow cytometry.
Results: In HIV PI-S infected primary cultures, all three antiretroviral agents decreased viral replication, and reduced
the total number of cells that were undergoing apoptosis (P < 0.01) similarly. Similarly, in the HIV PI-R infected
cultures, both efavirenz and raltegravir reduced viral replication and reduced apoptosis compared to untreated
control (P < 0.01), while lopinavir did not, suggesting that HIV replication drives T cell apoptosis, which was confirmed
by association by linear regression (P < 0.0001) . However since HIV protease has been suggested to directly induce
apoptosis of infected CD4 T cells, and HIV PI are intrinsically antiapoptotic, we evaluated apoptosis in productively
infected (HIV P24+) cells. More HIV p24 positive cells were apoptotic in the Efavirenz or raltegravir treated cultures than
the lopinavir treated cultures (P = 0.0008 for HIV PI-R and P = 0.06 for the HIV PI-S), indicating that drug class impacts
survival of productively infected CD4 T cells.
Conclusions: Inhibiting HIV replication with a PI, NNRTI or INSTI reduces total HIV-induced T cell apoptosis. However,
blocking HIV replication with PI but not with NNRTI or INSTI promotes survival of productively HIV-infected cells. Thus,
selection of antiretroviral agents may impact the success of HIV eradication strategies