P glycoprotein in human immunodeficiency virus type 1 infection and therapy.

Abstract

With the advent and widespread use of potent antiretroviral therapy in the mid-1990s, the clinical course of human immunodeficiency virus (HIV) type 1 (HIV-1) infection has changed dramatically in a substantial proportion of HIV-1-infected individuals. This has led to a significant decline in the incidence of AIDS and AIDS-related morbidity and mortality in the developed world (30, 84, 96, 102). Protease inhibitors in combination with inhibitors of HIV-1 reverse transcriptase cause a dramatic reduction in plasma viremia, with the plasma HIV-1 RNA load being below the limit of detection in many patients (52, 56). However, with the currently available drugs, complete eradication of HIV-1 from an infected person is not achieved because of the persistence of latently infected, resting CD4+ T cells harboring replication-competent HIV-1 and because of ongoing low-level viral replication (23, 24, 33, 42, 45, 117, 150, 153). One cause of ongoing viral replication can be suboptimal penetration of drugs into anatomical sanctuary sites like the central nervous system. It has been suggested that drug transporters like P glycoprotein (P-gp) may contribute to this suboptimal penetration. Such drug transporters might also lower intracellular drug levels, thereby limiting the therapeutic efficacies of antiviral drugs in peripheral blood mononuclear cells (PBMCs) (15), including CD4+ T cells (68). P-gp, a plasma membrane protein encoded by the multidrug resistance (MDR) gene, was discovered in 1976 (71) and functions as an ATP-dependent drug efflux pump (118). It is a transporter of a wide range of compounds, including hydrophobic amphipathic drugs, calcium channel blockers, antihistamines, peptides, and steroids. The function of P-gp is thoroughly investigated in the oncology field because of its ability to induce resistance to anticancer therapy by pumping the drugs out of tumor cells (50, 78). In this minireview we summarize the possible roles of P-gp in HIV-1 infection and therapy.