Overall, this study demonstrates that HIF-1α plays a crucial role in HIV-1 pathogenesis by promoting viral replication and the release of EVs that orchestrate lymphocyte- and macrophage-mediated inflammatory responses.<b>IMPORTANCE</b> Human immunodeficiency virus type 1 (HIV-1) is a very important global pathogen that preferentially targets CD4<sup>+</sup> T cells and causes acquired immunodeficiency syndrome (AIDS) if left untreated.