Oxygen Levels and HIV-1 Transcription.

HIV-1 progression may be faster and survival shorter in HIV-positive patients with higher iron stores. Some studies indicate that iron stimulates HIV-1 viral replication and iron chelation decreases viral replication in cultured cells. Iron depletion may remove iron from prolyl hydroxylases and increases HIF-1a protein level thus mimicking hypoxia. Recent studies indicate that moderate hypoxia (3–6% O₂) may be the physiological O₂ concentration that macrophages and T cells encounter in certain organs in vivo. Cellular metabolism of macrophages and T cells cultured at atmospheric 21% O₂ is significantly different from cells cultured at 3–6% O₂ [1] . Interestingly, HIV-1 progression might be slower in sickle cell disease patients who have anemia-related hypoxia [2]. HIV-1 replicates efficiently in activated T cells or macrophages, in part due to the increased levels of NF-kB that enhance HIV-1 transcription in cooperation with HIV-1 Tat. HIV-1 Tat induces transcription of HIV-1 genes by recruiting host cell Cdk9/cyclin T1 to TAR RNA. Our recent studies point to a host cell kinase, CDK2, that phosphorylates HIV-1 Tat and induces HIV-1 transcription [3]. We also showed that iron chelators reduce cellular activity of CDK2 and inhibit HIV-1 transcription [4]. Here we analyzed the effect of 3% versus 21% O₂ concentration on HIV-1 transcription and replication and cellular activities of CDK2 and CDK9. Using reporter assays, we found that 3% O₂ inhibited HIV-1 Tat-induced transcription and viral replication. CDK9 activity but not CDK2 activity was inhibited in the cells cultured under 3% O₂. Thus inhibition of CDK2 by iron chelators that we previously observed might not be directly related to upregulation of HIF1a. Rather, our results indicate that HIV-1 transcription is suppressed at physiological oxygen levels likely due to deregulation of CDK9 thus providing a new insight into the HIV-1 latency. These findings suggest that consideration should be given to studying the effect of small molecular inhibitors of HIF-1 on HIV-1 transcription and replication.