A proteomics screen of HIV-1 ASP interactors reveals multifaceted effects on host cell homeostasis

Nearly four decades after the identification of the HIV-1 antisense gene asp, the function of its protein product remains unclear. Evidence of ASP expression in vivo and the high degree of conservation of the asp gene among pandemic HIV-1 strains suggest a beneficial role for the virus. Using a mass spectrometry (MS)-based proteomics screen for ASP interactors, we identified nuclear, cytosolic, and mitochondrial host factors, congruent with variable sub-cellular ASP localization. A majority of the host factors identified in the MS screen are involved in pathways essential for host cell homeostasis, including DNA damage repair, intracellular protein transport, mitochondrial function and protein translation. Validating the biological relevance of these findings, we demonstrate that ASP shuttles to the nucleus to promote DNA damage repair and cell viability in response to genotoxic stress. We also finds that ASP promotes translation of mitochondrially encoded host proteins involved in cellular respiration and contributes to maintain mitochondrial membrane potential. Together, these studies identify ASP as a modulator of two major pathways of cellular homeostasis in infected cells, which has direct implications for HIV-1 persistence, spread, and the long-term survival of the viral reservoir.