Regulation of HIV‐1 transcription at 3% versus 21% oxygen concentration

Abstract

HIV transcription is induced by the HIV‐1 Tat protein, in concert with cellular co‐factors including CDK9, CDK2, NF‐κB, and others. The cells of most of the body's organs are exposed to ∼3–6% oxygen, but most in vitro studies of HIV replication are conducted at 21% oxygen. We hypothesized that activities of host cell factors involved in HIV‐1 replication may differ at 3% versus 21% O₂, and that such differences may affect HIV‐1 replication. Here we show that Tat‐induced HIV‐1 transcription was reduced at 3% O₂ compared to 21% O₂. HIV‐1 replication was also reduced in acutely or chronically infected cells cultured at 3% O₂ compared to 21% O₂. This reduction was not due the decreased cell growth or increased cellular toxicity and also not due to the induction of hypoxic response. At 3% O₂, the activity of CDK9/cyclin T1 was inhibited and Sp1 activity was reduced, whereas the activity of other host cell factors such as CDK2 or NF‐κB was not affected. CDK9‐specific inhibitor ARC was much less efficient at 3% compared to 21% O₂ and also expression of CDK9/cyclin T1‐dependent IκB inhibitor α was repressed. Our results suggest that lower HIV‐1 transcription at 3% O₂ compared to 21% O₂ may be mediated by lower activity of CDK9/cyclin T1 and Sp1 at 3% O₂ and that additional host cell factors such as CDK2 and NF‐κB might be major regulators of HIV‐1 transcription at low O₂ concentrations. J. Cell. Physiol. 221: 469–479, 2009.