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Published online before print October 4, 2005
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0405219

Received for publication April 24, 2005.
Revised September 1, 2005.
Accepted for publication September 12, 2005.

Article

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

Michael D. Roth *, Katherine M. Whittaker {dagger}, Ruth Choi {dagger}, Donald P. Tashkin *, and Gayle Cocita Baldwin {dagger}@

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

@ To whom correspondence should be addressed. E-mail: gbaldwin{at}mednet.ucla.edu.


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Abstract

Cocaine is associated with an increased risk for, and progression of, clinical disease associated with human immunodeficiency virus (HIV) infection. A human peripheral blood leukocyte-severe combined immunodeficiency (huPBL-SCID) model, in which human peripheral blood mononuclear cells were implanted into SCID mice 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). 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 the 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. Expression of CXCR4 was not altered significantly. 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.

Key Words: CCR5 • CXCR4 • corticosterone human • AIDS