Cocaine and σ-1 receptors modulate HIV infection, chemokine receptors, and the HPA axis in the huPBL-SCID model

Abstract

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.

Molecular mechanisms involving sigma receptor–mediated induction of MCP-1: implication for increased monocyte transmigration

“…34 Intriguingly, systemic exposure to cocaine is known to enhance HIV-1 infection in vivo by activating -1R and, subsequently, by modulating the expression of HIV coreceptors. 35 Consistent with this finding, cocaine-mediated induction of MCP-1 involved binding to -1R, as evidenced by abrogation of cocaine-induced effect in the presence of -1R antagonist, BD1047. -1Rs that are located in the lipid raft microdomains of the endoplasmic reticulum are known to translocate into the plasma membrane after activation.…”

Chronic cocaine exposure in the SCID mouse model of HIV encephalitis

“…For example, in vitro experiments suggest that HIV replication is maximally stimulated by 24 hours of exposure to nanomolar cocaine concentrations and normalizes to control levels at higher concentrations (Peterson et al, 1991;Peterson et al, 1992). A similar increased HIV replication, as well as altered immune cell populations in peripheral tissues, was reported following a 5 mg/kg dose of cocaine in SCID mice (Roth et al, 2002;Roth et al, 2005). Although these reports suggest that cocaine doses lower than the 20 mg/kg dose used in the present experiment might enhance HIVE parameters, whether these lower doses are relevant to the drug's rewarding/reinforcing effects in SCID mice is unknown.…”

Potentiation of HIV-1 Expression in Microglial Cells by Nicotine: Involvement of Transforming Growth Factor-β1

“…Whereas it is well recognized that microglia play an important role in the neuropathogenesis of HIV-1 and that drugs of abuse appear to foster the development of HIV-associated dementia (HAD), before this study, essentially nothing was known about the effects of nicotine on HIV-1-infected human microglial cells and whether this addictive substance could impact the neuropathogenic mechanisms of HIV-1. Other drugs of abuse, such as opiates and cocaine, have been shown to enhance HIV-1 replication in mononuclear phagocytes (Peterson et al 1991;Ho et al 2003;Roth et al 2005) and mounting evidence suggests that these drugs foster the neuropathogenesis of HIV-1 (Tomlinson et al 1999;Nath et al 2002;Bell 2004). Because of the widespread dependence on nicotine in opiate-and cocaine-addicted individuals, it is possible that nicotine could confound some of the effects attributed to opiates and cocaine on HIV-1 neuropathogenesis.…”