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Published online before print October 4, 2005

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(Journal of Leukocyte Biology. 2005;78:1198-1203.)
© 2005 by Society for Leukocyte Biology

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

Michael D. Roth^*, Katherine M. Whittaker, Ruth Choi, Donald P. Tashkin^* and Gayle Cocita Baldwin^,1

^* Divisions of Pulmonary and Critical Care Medicine and
Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles

¹ Correspondence: Division of Hematology-Oncology, 11-934 Factor, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1678. E-mail: gbaldwin{at}mednet.ucla.edu

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 -1 receptors in immune cells in vitro and in vivo. Consistent with these reports, a selective -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 -1 receptors and by modulating the expression of HIV coreceptors.

Key Words: CCR5 • CXCR4 • corticosterone • AIDS • xenograft