Background:  ART is highly effective against HIV. However, a host of issues, including viral escape and drug toxicity, suggest that approaches targeting a viral dependent host function may be exploited to target HIV. The HIV-1 gene vpr is implicated in viral pathogenesis. It regulates functions in the host cell including cell cycle arrest apoptosis of T cells and host cell transcription and immune function. Some of these effects are linked to the glucocortoid receptor (GR), however the direct dependence of Vpr or HIV on GR requires clarification.

Methods:  We developed siRNA, which target GR, and developed cell lines that lack GR function. We observed that HIV-1 replicates poorly in these cells. The defect appears to include a block in translocation of the virus PIC to the nucleus. We examined the requirement for GR in SIV infection in vitro. SIV replication was inhibited in GR-cells. These data extend earlier studies using Mifepristone (MIF), a specific inhibitor of GR, which reported that activation of GR was 1 function of Vpr. A preliminary study of MIF effects on SIV replication in chronic infection was designed. Macaques were infected with strain SIV_mac251 for 6+ months were selected for study. All had previously failed therapy of PMPA+ FTC. They exhibited effects of chronic SIV infection including loss of CD4 T cells, decreased platelets and average viral loads over log₁₀⁵. Animals were treated with a 1-month regime intravenous dose of 3.2 mg/kg of MIF daily and monitored for health and viral load compared to a control group.

Results:  All MIF-treated animals’ viral load decreased with an average 1+ log drop and exhibited a rise in CD4 as well as a rise in platelets. The slope of suppression of viral replication by MIF was gradual but more persistent than with PMPA+FTC therapy. There was no evidence of viral escape. Effects of therapy on immune activation are being examined. Following cessation of treatment, viral load rebounded over 2 weeks.

Conclusions:  SIV replication in vivo can be targeted by inhibition of the host GR pathway, suggesting important implications for possible treatment of HIV infection by a well-tolerated oral therapeutic.

Keywords: Glucocortoid Receptor; HIV-1 Vpr; Viral Replication