THE INHIBITION OF HIV‐1 TRANSCRIPTION BY HYPOXIA

Abstract

The hypoxic response plays a key role in the body’s reaction to the impaired tissue perfusion and chronic pulmonary complications associated with sickle cell anemia disease, as well as to anemia in general, whether complicating hemoglobinopathies such as sickle cell disease or infections such as HIV disease. Progression of HIV occurs more slowly in SCD patients, whereby the hypoxic response is stimulated by the severe inherited anemia. HIV transcription is controlled by the HIV-1 Tat protein, which encourages phosphorylation of the C-terminal domain of RNA polymerase-II by CDK9/cyclin T1. We have previously shown that protein phosphatase-1 (PP1) regulates Tat-induced HIV-1 transcription. PP1 interacts with the Tat protein and disruption of this association prevents induction of HIV-1 transcription. Here we have shown that PP1 dephosphorylates CDK9 and also that expression of nuclear inhibitor of PP1 (NIPP1) prevents HIV-1 transcription and viral replication. Recently it has been shown that PP1 activity is decreased during hypoxia, by the association of PP1 with NIPP1. We hypothesize that decreased PP1 activity during hypoxia would adversely affect HIV-1 transcription and viral replication. We have also found that HIV-1 transcription was inhibited in transiently affected 293-T and Hela cells that were cultured under low oxygen tensions (3%–6%). We also observed inhibition of HIV-1 transcription and viral replication in CEM T cells that were infected with pseudotyped HIV-1 virus or treated with purified Tat protein. Investigation into the effects of hypoxia on viral replication and HIV-1 transcription could offer new possibilities for treatment against the HIV-1 virus.