| Human Immunodeficiency Virus Type-1 (HIV-1) latency has created a tremendous challenge for new drug therapies and disease eradication. Although the exact mechanism of HIV-1 latency is unknown, it is possible that hypoxia could be a contributing factor. Hypoxia is the state of inadequate oxygenation and is known to be present in HIV-1 patients. Hypoxia may affect host cell factors that are involved in the regulation of HIV-1 transcription, and if so, offer more insight into the various mechanisms of HIV-1 replication and latency. In this study, cultured T cells and monocytes were placed under low oxygen concentrations to determine the effects of hypoxia on expression and activity of host cell factors that are involved in HIV-1 transcription. Our studies revealed that hypoxia significantly reduced Tat-mediated HIV-1 transcription and viral replication in cells transfected with reporter genes or chronically infected with HIV-1. Kinase assays also revealed that hypoxia caused a disruption in the association of CDK9 and cyclin T1, major co-factors in HIV-1 Tat transcription. In addition, our phosphorylase-a phosphatase experiments revealed that while protein phosphatase-1 (PP1) activity is down during hypoxia, it is not likely due to its association with the nuclear inhibitor of PP1 (NIPP1), but could offer an explanation for the disruption in the CDK9/cyclin T1 complex. This suggests that another inhibitor of PP1 may be involved. This HIV-1 research was designed to investigate the molecular mechanisms of HIV-1 transcription and also to determine the effects of hypoxia on HIV-1 transcription. The results indicate that hypoxia does affect HIV-1 transcription. Gaining more insight into the various mechanisms of HIV-1 replication, can lead to the development of a treatment modality that will be effective in the inhibition of HIV. |
