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

&NA; 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. Graphical Abstract Figure. No caption available. HighlightsHIV‐1‐infected CD4+ T cells activate cellular survival programsCD4+ T cells upregulate BIRC5 and OX40 during latent and productive HIV‐1 infectionOX40+CD4+ T cells from ART‐treated patients are enriched for clonal HIV‐1 sequencesInhibition of BIRC5 reduces the frequency of CD4+ T cells encoding for intact HIV‐1 &NA; The host factors that promote the survival and persistence of HIV‐infected CD4+ T cells are not clear. Kuo et al. demonstrate that the anti‐apoptotic protein BIRC5 and its upstream regulator OX40 can promote survival of HIV‐1‐infected reservoir CD4+ T cells, specifically during clonal proliferation. These findings point to clinical strategies that may reduce persisting viral reservoirs.