Abstract
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 environment in vivo. However, the majority of studies on HIV replication and latency are performed under laboratory conditions where HIFs are inactive. We show a role for HIF-2α in restricting HIV transcription via 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-oxygen environment of the lymph node may suppress HIV replication and promote latency. We identify a mechanism that may contribute to the limited efficacy of latency reversing agents in reactivating HIV and suggest new strategies to control latent HIV-1.
Highlights
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
We show that Human immunodeficiency virus (HIV)-1 transcription in activated CD4 T cells is reduced under low-oxygen conditions compared to standard laboratory conditions
Silencing HIF-2α or inhibiting HIF signaling reversed the dampening effect of low oxygen on the viral promoter, suggesting a role for HIF-2α in repressing Human immunodeficiency virus type 1 (HIV-1) transcription in CD4 T cells
Summary
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. Hypoxia can have opposing effects on viral proliferation, inducing the replication of Epstein–Barr virus[3,4,5], Kaposi sarcoma-associated herpesvirus[4,6], human T-cell leukemia virus[7], and human polyomavirus BK8, while suppressing the infectivity of adenovirus[9] and Moloney murine leukemia virus[10]. These contrasting effects are likely to reflect the variable oxygen tension at the sites of virus replication and the complex interplay between viruses and their hosts[11]. Our findings highlight the importance of oxygen availability in regulating HIV replication and identify a mechanism that may contribute to the limited efficacy of current latency-reversing agents to reactivate HIV in vivo
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