Antiviral effects of mifepristone on human immunodeficiency virus type-1 (HIV-1): targeting Vpr and its cellular partner, the glucocorticoid receptor (GR).
The HIV-1 viral protein R, Vpr, increases virus replication in T cells and is necessary for the optimal infection of primary monocytes/macrophages and other non-dividing cells. Vpr interacts with the cellular glucocorticoid receptor (GR) and transactivates the HIV-1 LTR through glucocorticoid response element (GRE), an event that can be blocked by the GR antagonist, mifepristone. Results demonstrated that Vpr-induced transactivation of the HIV-1 LTR was inhibited by mifepristone in a dose-dependent manner by >60% at a 10 microM concentration. Infectivity assays using X4 and R5 viruses demonstrated antiviral effects on a dose-dependent regimen of mifepristone. The effects of mifepristone were also tested in latently infected cells that could be activated with extracellular Vpr protein and results indicated specific inhibition of virus reactivation in the presence of this antagonist.
Schafer
Elizabeth A
EA
Department of Infectious Diseases & Microbiology, University of Pittsburgh, Graduate School of Public Health, 130 Desoto Street, Pittsburgh, PA 15261, USA.
Venkatachari
Narasimhan J
NJ
Ayyavoo
Velpandi
V
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D016336:Gene Products, vpr / Q000378:metabolism*; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D016325:HIV Long Terminal Repeat / Q000235:genetics / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000821:virology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000821:virology; D015735:Mifepristone / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015533:Transcriptional Activation; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication / Q000187:drug effects*; D054325:vpr Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D016336:Gene Products, vpr; D016655:HIV Core Protein p24; D011965:Receptors, Glucocorticoid; D054325:vpr Gene Products, Human Immunodeficiency Virus; D015735:Mifepristone