Inhibition of HIV-1 in Sickle Cell Disease Peripheral Blood Mononuclear Cells.

The hypoxic response is an important component of the body 's reaction to impaired tissue oxygenation associated with the anemia and vasoocclusive episodes of sickle cell disease (SCD). It has been reported that HIV infection progresses relatively slowly in patients with SCD (Am J Hematol 1998; 59:199-207). We recently showed that HIV-1 transcription and replication is significantly reduced in cells cultured at 3% versus 21% oxygen (J Cell Physiol 2009; in press). Our previous studies indicated that protein phosphatase-1 (PP1) interacts with HIV-1 transcriptional activator, Tat, and thereby participates in the regulation of HIV-1 transcription. Sickle cell patients are in chronically hypoxic state and we hypothesized that HIV-1 replication in their peripheral blood mononuclear cells (PBMCs) would be slower then in controls.

We isolated PBMCs from patients with SCD and from normal subjects, activated the cells with phytohemagglutinin and IL-2 for 24 h, and infected with pseudotyped HIV-1 virus expressing Luciferase. The infected cells were cultured at 3% of oxygen for 72 h.

We show here that PP1 association with cellular regulatory subunits is modified and that PP1 activity is significantly reduced by 20-40% in different cell lines at 3% versus 21% oxygen. One round of replication of pseudotyped HIV-1 Luciferase virus normalized to the number of the cells in culture was significantly reduced in SCD PBMCs comparing to normal controls.

Our results provide a direct evidence of that HIV-1 replication may be slower in SCD-derived PBMCs. In future, we will analyze PP1 activity and the association of PP1 with regulatory subunits in SCD PBMCs. Understanding of how oxygen status influences HIV-1 replication might open new possibilities for treatment of hidden HIV-1 reservoirs that harbor non-replicating HIV-1 virus.

This work was supported by NHLBI Research Grant 2 R25 HL003679-08 from the National Institutes of Health and The Office of Research on Minority Health.

No relevant conflicts of interest to declare.