Enhanced replicative capacity and pathogenicity of HIV-1 isolated from individuals infected with drug-resistant virus and declining CD4+ T-cell counts

Virologic failure on continuous antiretroviral therapy (ART) is associated with variable changes in CD4 T-cell counts: peripheral CD4 T-cell counts decrease in conjunction with a resurgence of plasma virus (nonresponders) or remain stable or continue to increase despite ongoing virus replication (discordant responders). This study found that HIV-1 isolated from nonresponders had significantly greater replicative capacity in activated peripheral blood mononuclear cells (PBMCs) as well as an enhanced ability to induce apoptosis in both HIV-1-infected and HIV-1-uninfected CD4 T cells compared with virus isolated from discordant responders. Enhanced replicative capacity in PBMCs of virus isolated from nonresponders was inhibited by AMD3100, a CXCR4 antagonist. Virus quasispecies isolated from PBMCs from nonresponders used both CC chemokine receptor 5 (CCR5) and CX chemokine receptor 4 (CXCR4) for entry, in contrast to virus isolated from PBMCs from discordant responders, which predominantly used CCR5. In contrast, virus isolated from plasma from both groups predominantly used CCR5. In summary, although drug resistance may lead to impaired viral fitness, the capacity of virus quasispecies from PBMCs to use CXCR4 may have significant consequences on viral replicative capacity and potentially on clinical outcome.