P33.11 LB
Background: Due to their anti-inflammatory properties, glucocorticoids (GCs) are widely used therapeutically. In the female genital tract, inflammation correlates with increased HIV infection, suggesting the use of GCs in multipurpose prevention therapy. However, the effects of different GCs and the role of the glucocorticoid receptor (GR) in HIV infection and the mechanisms involved are unknown, and are likely to be relevant to HIV-1 prevention strategies.
Methods: PBMCs or End1/E6E7 endocervical epithelial cells were incubated with different GCs. PBMCs were infected with virus prepared from HIV-1BAL-LUC IMCs. Inflammatory markers were measured by qRT-PCR or FACs. GR function was assessed by western blotting, ChIP and siRNA experiments.
Results: Infection assays in PBMCs showed that while Dex and CORT113176 increased infection, pre-treatment with the GR antagonist RU486 and a selective GR modulator CORT108297 did not increase, but potentially had a protective effect, consistent with a role for the GR in HIV-1 infection. Differential regulation of GILZ, IL6 and RANTES genes by different GCs indicated a mechanism whereby some GCs increase, while others protect against HIV infection. Furthermore, Vpr was found to activate the GR, resulting in repression of both basal and induced cytokine genes in the absence of GCs.
Conclusions: HIV exploits the host GR to favor viral infection via several strategies. In the absence of GCs, the viral protein Vpr modulates GR activity to change expression of basal and induced cytokine genes, suggesting that GR levels play a critical role in HIV pathogenesis. GR agonists repress immune function, while at the same time increase HIV-1 infection, suggesting their use should be avoided in high risk areas. Selective GR modulators exhibit variable effects on HIV-1 replication and gene-specific effects on expression of cytokine genes. Some show potential application for combination therapy in the female genital tract by both repression of RANTES and repression of HIV-1 infection.
