Hypoxic microenvironment shapes HIV-1 replication and latency.

Viral replication is defined by the cellular microenvironment and one key factor is local oxygen tension, where hypoxia inducible factors (HIFs) regulate the cellular response to oxygen. Human immunodeficiency virus (HIV) infected cells within secondary lymphoid tissues exist in a low-oxygen or hypoxic environmentin vivo. However, the majority of studies on HIV replication and latency areperformed under laboratory conditionswhere HIFs are inactive. We show a role for HIF-2ain restricting HIV transcriptionvia direct binding to the viral promoter.Hypoxia reduced tumor necrosis factor or histone deacetylase inhibitor, Romidepsin,mediated reactivation of HIV and inhibiting HIF signaling-pathways reversed this phenotype. Our data support a model where the low-oxygenenvironment of the lymph node may suppress HIV replication and promote latency. Weidentifya mechanism that may contribute to the limited efficacy of latency reversing agents in reactivating HIV and suggest new strategies to controllatent HIV-