Recent studies showed that these chemokines specifically block the CCR5 coreceptor and thereby inhibit the entry of HIV-1 into target cells ( 6, 10, 11 for a review, see reference 14). Members of the β-chemokine family, RANTES, macrophage inflammatory protein 1α (MIP-1α), and MIP-1β were shown to inhibit infection of target cells by primary M-tropic virus strains, but not T-cell (T)-tropic virus strains ( 6, 10). Recently, a major HIV-1 coreceptor and β-chemokine receptor, CCR5, was identified for macrophage (M)-tropic HIV-1 strains ( 2, 10).Ĭhemokines are chemoattractant cytokines that have gained major attention because of their specific inhibitory effects on HIV-1 infection ( 6). Although the CD4 molecule is the primary receptor for virus entry, several studies have shown that, in addition to CD4, other coreceptors may be required for efficient viral entry. Human immunodeficiency virus type 1 (HIV-1) mainly infects CD4 + T (T-helper) lymphocytes and macrophages. 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.
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Further, cocaine significantly downregulates endogenous MIP-1β gene expression, while it upregulates HIV-1 entry coreceptor CCR5 by normal PBMC. Cocaine also selectively suppresses lipopolysaccharide-induced MIP-1β production by PBMC from HIV-infected patients. 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.
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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.
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Although cocaine has been linked to the immunopathogenesis of HIV-1 infection, the corresponding cellular and molecular mechanism(s) have not been well defined. 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. 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.