Anti-apoptotic Protein BIRC5 Maintains Survival of HIV-1-Infected CD4+ T Cells

Abstract

HIV-1 infection of CD4⁺ T cells leads to cytopathic effects and cell demise, which is counter to the observation that certain HIV-1-infected cells possess a remarkable long-term stability and can persist lifelong in infected individuals treated with suppressive antiretroviral therapy (ART). Using quantitative mass spectrometry-based proteomics, we showed that HIV-1 infection activated cellular survival programs that were governed by BIRC5, a molecular inhibitor of cell apoptosis that is frequently overexpressed in malignant cells. BIRC5 and its upstream regulator OX40 were upregulated in productively and latently infected CD4⁺ T cells and were functionally involved in maintaining their viability. Moreover, OX40-expressing CD4⁺ T cells from ART-treated patients were enriched for clonally expanded HIV-1 sequences, and pharmacological inhibition of BIRC5 resulted in a selective decrease of HIV-1-infected cells in vitro. Together, these findings suggest that BIRC5 supports long-term survival of HIV-1-infected cells and may lead to clinical strategies to reduce persisting viral reservoirs.

Keywords: BIRC5; HIV-1; OX40; Survivin; apoptosis; clonal proliferation; latency; proteomics; viral reservoirs.