[Potential of integrase inhibitors to deplete HIV reservoirs or prevent their replenishment]

Abstract

The early establishment of an HIV-1 reservoir with integrated provirus in the DNA of cells with latent infection hampers viral eradication, despite maintenance of viral loads lower than 50 copies/mL for years. By early initiation of highly suppressive antiretroviral therapy (ART), the half-life of this reservoir could be as short as 4.6 months and require only 7.7 years for complete elimination. The constant presence of low-grade viral replication probably indefinitely replenishes this resting CD4+ T cell reservoir. This reservoir probably results from both the release of virus stored in latently-infected cells that have become activated and from residual replication of some still-activated cells. This also allows new resistant mutants selected after therapeutic failure to be incorporated into the reservoir. Raltegravir has been demonstrated to significantly reduce elimination times in the first two viral decay phases after initiation of ART. On starting the second phase, the viral load was 70% lower in patients treated with raltegravir than in those treated with efavirenz. Through its late mechanism of action in the HIV-1 cell cycle, this drug could induce greater decreases in proviral DNA than other antiretroviral agents. The presence of unintegrated HIV DNA under prolonged effective ART indicates that either there is continual low-level viral replication or that this unintegrated DNA can persist for prolonged periods. In both cases, intensification of ART with raltegravir could provide beneficial effects on the speed of elimination of the HIV-1 reservoir.