This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Drug abuse remains one of the major risk factors for the spread of HIV-1 infection with opiates being a principal drug of concern. Opiates have been shown to be determining factors in the rate of progression of AIDS. The sum of various in vitro, animal-model, and epidemiological studies indicates that opiates have conditionally variable effects on HIV-1 disease progression. Immunovirological and pharmacological variability are two major factors that seem to dictate whether HIV-1 infection will progress more rapidly or more slowly in HIV-1 infected opiate-exposed individuals. According to previous studies, the immunovirological effect of an opiate drug such as methadone is not well characterized in an ex vivo human system. The hypothesis to be tested in this proposal is that ex vivo methadone use and withdrawal will enhance HIV-1 infectivity in CD4+ T-lymphocytes by altering cytokine/chemokine profile and upregulating HIV-1 co-receptor and mu-opioid receptor expression.
The specific aims will analyze various immunovirological determinants of HIV-1 infectivity to evaluate the effects of methadone use and withdrawal. CD4+ T-lymphocytes will be obtained from HIV-1 negative healthy volunteers and chronic (more than one year) methadone patients. Cells will be acutely infected with HIV-1SF2 (X4/R5 dual virus strain) and then assayed to determine how ex vivo methadone exposure (10-7 and 10-6 M) and abrupt withdrawal: (1) affects HIV-1 infectivity (using HIV-1 p24 ELISA);(2) disrupt cytokine/chemokine profile (using cytometric bead array and ELISA);and (3) modulates the gene and protein expression of extracellular and intracellular molecules (using flow cytometry, quantitative RT-PCR, and Western blot). Statistical analysis will be used to determine significant differences between the different experimental conditions. This study will reveal new cellular and molecular mechanisms involved in methadone-mediated HIV-1 replication enhancement. This data can be used to design future in vivo longitudinal studies on the immune and viral modulating effects of methadone in HIV-1 infected methadone patients.
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