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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 (regulated-upon-activation T expressed and secreted), macrophage inflammatory protein 1α (MIP-1α) and MIP-1β, 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-1β secretion by normal peripheral blood mononuclear cells (PBMC), while cocaine did not affect the MIP-1β production by PBMC from AIDS patients. Cocaine also selectively suppresses lipopolysaccharide-induced MIP-1β production by PBMC from HIV-infected patients. Further, cocaine significantly downregulates endogenous MIP-1β 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.

It is now well established that parenteral drug abuse is a significant risk factor for contracting human immunodeficiency virus type 1 (HIV-1) infection and subsequently developing AIDS. Earlier studies have shown that morphine can modulate various immune responses and therefore support the premise that morphine is a cofactor in susceptibility to and progression of HIV infection. Dysregulation of interferon (IFN) production, nonspecific apoptosis of T cells, and the immune response to soluble HIV gene products have been associated with potential mechanisms of pathogenesis in HIV disease. The present study was undertaken to examine the immunomodulatory role of morphine on HIV protein-induced lymphocyte proliferative responses, Sendai and Newcastle disease virus-induced alpha IFN (IFN-alpha) and IFN-beta production by lymphocytes and fibroblast cells, respectively, and induction of apoptosis of normal lymphocytes in vitro. Our results demonstrate that HIV protein-induced human lymphocyte proliferative responses were significantly inhibited by morphine in a dose-dependent manner. Furthermore, morphine significantly inhibited both IFN-alpha and IFN-beta production by normal lymphocytes and fibroblasts but induced apoptosis of normal lymphocytes. Inhibition of IFN-alpha production by morphine could be reversed by the opiate receptor antagonist naloxone. This suggests that the immunomodulatory effects of morphine are mediated through the opioid receptor. These studies support a role of morphine as a cofactor in the pathogenesis of HIV infection and describe some of the possible pathologic mechanisms which underlie the immunoregulatory effects of morphine.

While considerable progress in examining the course of human immunodeficiency virus (HIV) infection in adults has been made, a better understanding of the natural history of perinatal HIV infection remains to be obtained. Dysregulation of the production and functions of various cytokines, especially the interferons (IFNs), during HIV infections has been reported. Using an in vitro model system, we examined the effects of the HIV type 1 envelope protein, gp120 (10, 50, and 100 ng/ml), on gamma IFN (IFN-gamma) and IFN-alpha production by lymphocytes from neonates and adults and also examined the potential regulatory effects of gp120 on phorbol 12-myristate acetate (PMA)- and Sendai virus-induced IFN-gamma and IFN-alpha production by lymphocytes. PMA at a concentration of 50 ng/ml plus 50 ng of calcium ionophore A23187 per ml was used to induce IFN-gamma, while 150 hemagglutinating units of Sendai virus was used to induce IFN-alpha production. The antiviral activity of both IFN-alpha and IFN-gamma in leukocyte culture supernatants was assayed on BG-9 cells by a dye uptake technique using vesicular stomatitis virus as a challenge virus. Placental cord blood leukocyte (CBL) samples from healthy, term infants and adult peripheral blood leukocytes (APBL) produced no IFN in response to gp120. However, CBL produced significantly decreased levels of IFN-gamma compared with APBL in response to PMA plus ionophore. gp120 significantly suppressed both Sendai virus-induced IFN-alpha and PMA-induced IFN-gamma production by both CBL and APBL in a dose-dependent manner. However, gp120-induced suppression of IFN-alpha and IFN-gamma was significantly greater with CBL than with APBL. Treatment of CBL and APBL with gp120 did not induce any phenotypic alteration of the CD45 RO+ subset. Increased suppression of IFN-alpha and IFN-gamma production by gp120 in neonates may partially explain their apparent increased susceptibility to the clinical progression of HIV infections compared with that of adults.