Cocaine Differentially Modulates Chemokine Production by Mononuclear Cells from Normal Donors and Human Immunodeficiency Virus Type 1-Infected Patients

Abstract

Earlier studies have supported a significant role for cocaine in the susceptibility to and the progression of human immunodeficiency virus type 1 (HIV-1) infection. Recently, several unique HIV-1 entry coreceptors (e.g., CCR5 and CCR3) and a trio of HIV-1-specific suppressor chemokines, namely, RANTES (regulatedupon-activation T expressed and secreted), macrophage inflammatory protein 1␣ (MIP-1␣) and MIP-1␤, were identified. Although cocaine has been linked to the immunopathogenesis of HIV-1 infection, the corresponding cellular and molecular mechanism(s) have not been well defined. We hypothesize that cocaine mediates these pathologic effects through the downregulation of HIV-1-suppressing chemokines and/or upregulating HIV-1 entry coreceptors in HIV-1-infected subjects, resulting in disease progression to AIDS. Our results show that cocaine selectively downregulates endogenous MIP-1␤ secretion by normal peripheral blood mononuclear cells (PBMC), while cocaine did not affect the MIP-1␤ production by PBMC from AIDS patients. Cocaine also selectively suppresses lipopolysaccharide-induced MIP-1␤ production by PBMC from HIV-infected patients. Further, cocaine significantly downregulates endogenous MIP-1␤ gene expression, while it upregulates HIV-1 entry coreceptor CCR5 by normal PBMC. These studies suggests a role for cocaine as a cofactor in the pathogenesis of HIV infection and support the premise that cocaine increases susceptibility to and progression of HIV-1 infection by inhibiting the synthesis of HIV-1 protective chemokines and/or upregulating the HIV-1 entry coreceptor, CCR5.

Morphine Enhances HIV Infection of Neonatal Macrophages

“…Our data showing that morphine modulated expression of MIP-1␤ and CCR5 receptor are supported by several recently reported observations (47-49). Nair et al (47) recently reported that cocaine selectively down-regulates endogenous MIP-1␤ secretion and up-regulates CCR5 expression by adult peripheral blood monocytes, suggesting a mechanism by which cocaine increases susceptibility of peripheral blood monocytes to HIV infection. Morphine induces CCR5 expression in a human T-lymphoid cell line (CEMx174) (48).…”

κ-Opioid Receptor Ligands Inhibit Cocaine-Induced HIV-1 Expression in Microglial Cells

“…Based upon the report of other investigators (Nair et al, 2000) that the stimulatory effect of cocaine on HIV-1 expression in PBMCs is associated with up-regulation of the viral entry chemokine coreceptor CCR5, we next investigated whether cocaine would also induce up-regulation of CCR5 in microglial cells, and if so, whether KOR ligands would inhibit this phenomenon. As shown in Fig.…”

“…Although several research groups have shown that cocaine potentiates HIV-1 expression in peripheral blood mononuclear cell (PBMC) cultures (Peterson et al, 1992;Bagasra and Pomerantz, 1993;Nair et al, 2000;Roth et al, 2002) by a mechanism that seems to involve up-regulation of the HIV-1 entry chemokine coreceptor CCR5 (Nair et al, 2000), little or nothing is known about the effects of cocaine on HIV-1 expression in microglial cells. Thus, we hypothesized in the present study that cocaine would potentiate viral expression in microglial cells.…”

“…Based upon a substantial literature demonstrating that substances of abuse, such as cocaine and opiates, can both impair the function of CD4 ϩ lymphocytes and macrophages (Klein et al, 1993, Mao et al, 1996, Baldwin et al, 1997, Eisenstein and Hilburger, 1998Friedman et al, 2003) and potentiate the expression of HIV-1 in these cells (Peterson et al, 1990(Peterson et al, , 1992Bagasra and Pomerantz, 1993;Nair et al, 2000, Li et al, 2002Roth et al, 2002;Steele et al, 2003), it has been postulated that abuse of these drugs may serve as a cofactor in the progression of HIV-1 infection. The role of substances of abuse in development of HIV-1-associated dementia (HAD), one of the most devastating complications of AIDS, is supported by a growing body of epidemiological and histopathological evidence (Wang et al, 1995;Davies et al, 1997;Bell et al, 1998;Bouwan et al, 1998;Goodkin et al, 1998;Tomlinson et al, 1999), as well as by studies of molecular mechanisms whereby drugs of abuse and HIV-1 interact in causing neuronal death (Nath et al, 2002).…”

Proteomic analysis of the effects of cocaine on the enhancement of HIV-1 replication in normal human astrocytes (NHA)

“…NHA were treated with and without cocaine-hydrochloride (Sigma-Aldrich, St. Louis MO); time and concentration used were based on previous studies that produced a maximum biological response without causing toxicity to the target cells (Nair et al, 2000;Nair et al, 2001;Nair et al, 2004;Nair et al, 2005). Cocaine was dissolved in sterile distilled water and was subsequently diluted in media to the required concentrations.…”