Cocaine and sigma-1 receptors modulate HIV infection, chemokine receptors, and the HPA axis in the huPBL-SCID model.
Cocaine is associated with an increased risk for, and progression of, clinical disease associated with human immunodeficiency virus (HIV) infection. A human xenograft model, in which human peripheral blood mononuclear cells were implanted into severe combined immunodeficiency mice (huPBL-SCID) and infected with a HIV reporter virus, was used to investigate the biological interactions between cocaine and HIV infection. Systemic administration of cocaine (5 mg/kg/d) significantly increased the percentage of HIV-infected PBL (two- to threefold) and viral load (100- to 300-fold) in huPBL-SCID mice. Despite the capacity for cocaine to increase corticosterone and adrenocorticotropic hormone levels in control mice, the hypothalamic-pituitary-adrenal axis was suppressed in HIV-infected animals, and corticosterone levels were further decreased when animals were exposed to HIV and cocaine. Activating huPBL in vitro in the presence of 10(-8) M cocaine increased expression of CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) coreceptors. Expression of CCR5 was also increased at early time-points in the huPBL-SCID model following systemic exposure to cocaine (54.1+/-9.4% increase over control, P<0.01). This effect preceded the boost in viral infection and waned as HIV infection progressed. Cocaine has been shown to mediate immunosuppressive effects by activating sigma-1 receptors in immune cells in vitro and in vivo. Consistent with these reports, a selective sigma-1 antagonist, BD1047, blocked the effects of cocaine on HIV replication in the huPBL-SCID mouse. Our results suggest that systemic exposure to cocaine can enhance HIV infection in vivo by activating sigma-1 receptors and by modulating the expression of HIV coreceptors.
Roth
Michael D
MD
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1678, USA.
Whittaker
Katherine M
KM
Choi
Ruth
R
Tashkin
Donald P
DP
Baldwin
Gayle Cocita
GC
D000818:Animals; D003042:Cocaine / Q000633:toxicity*; D019970:Cocaine-Related Disorders / Q000150:complications / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D005029:Ethylenediamines / Q000494:pharmacology; D005260:Female; D006678:HIV / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D019713:Receptors, CCR5 / Q000187:drug effects / Q000276:immunology; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000276:immunology; D019707:Receptors, Chemokine / Q000187:drug effects* / Q000276:immunology; D017480:Receptors, sigma / Q000187:drug effects* / Q000276:immunology; D014183:Transplantation, Heterologous; D019562:Viral Load; D000097605:Sigma-1 Receptor
D003042:Cocaine; D005029:Ethylenediamines; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin