Regulation of HIV-1 Transcription at 3% Versus 21% Oxygen Concentration

HIV transcription is induced by the HIV-1 Tat protein, in concert with cellular co-factors including CDK9, CDK2, NF-kappa B, and others. The cells of most of the body's organs are exposed to similar 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% O-2, and that such differences may affect HIV-1 replication. Here we show that Tat-induced HIV-1 transcription was reduced at 3% 02 compared to 21% O-2. HIV-1 replication was also reduced in acutely orchronically infected cells cultured at 3% O-2. compared to 21% O-2. 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% O-2, the activity of CDK9/ cyclin TI was inhibited and SpI activity was reduced, whereas the activity of other host cell factors such as CDK2 or NF-kappa B was not affected. CDK9-specific inhibitor ARC was much less efficient at 3% compared to 21% 02 and also expression of CDK9/cyclin T -dependent I kappa B inhibitor a was repressed. Our results suggest that lower HIV-1 transcription at 3% 02 compared to 21% 02 may be mediated by lower activity of CDK9/cyclin T I and SpI at 3% 02 and that additional host cell factors such as CDK2 and NF-kappa B might be major regulators of HIV-1 transcription at low O-2 concentrations. J. Cell. Physiol. 221: 469-479, 2009. (C) 2009 Wiley-Liss, Inc.