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C. Flexner* and R. R. Speck
Johns Hopkins Univ., Baltimore, MD
P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) are members of a class of highly conserved inducible transmembrane ATP-binding transporters; their physiologic function is poorly understood. Over-expression of these transporters is associated with cellular efflux of a variety of drugs. We evaluated production of HIV-1 antigens (p24 and RT) from viral particles in supernatant of control CEM cells and CEM cells that over-expressed P-gp or MRP1, and were infected with HIV-1IIIB. P-gp expression reduced HIV-1 replication by a factor of at least 40- to 70-fold, compared to control CEM cells. P-gp expression did not alter the amount of HIV protein produced after transfection with the IIIB (HXB2neo) genome, suggesting that inhibition of replication occurred at the level of viral binding or entry. In membrane density studies, P-gp preferentially associated with lipid rafts (glycolipid-enriched membrane; GEM domains), which have recently been shown to be an important site for cellular binding and egress of HIV. MRP1 expression increased HIV-1 replication by a factor of 170- to 470-fold, compared to control CEM cells. Selective inhibitors of MRP1 and P-gp partially reversed the effects of these transporters on HIV replication. Exposure to antiretroviral drugs like zidovudine has been shown to induce expression of P-gp. Although this process would be expected to lower intracellular concentrations of drugs that are substrates for P-gp, the potential impact of this protein on HIV must also be considered. Reduced HIV replication, or protection from HIV infection in cells expressing P-gp would offset lower intracellular drug concentrations.
Session 8. Symposium
HIV Vaccine Development
Monday, 2:00-4:00pm
Ballroom IV-VII
© 8th Conference on Retroviruses and Opportunistic Infections