Role of lymphocyte multidrug resistance protein 1 in HIV infection: expression, function, and consequences of inhibition.
The multidrug resistance protein 1 (MRP1) is a drug transporter that protects cells from oxidative stress, which increases HIV-1 replication. The aim of this study was to characterize the expression, function, and role of lymphocyte MRP1 in HIV-1 infection and its modulation by antiretroviral drugs such as the protease inhibitors (PIs). Peripheral blood mononuclear cells (PBMCs) from HIV-positive individuals do not show significant alterations of MRP1 expression despite highly active antiretroviral therapy and HIV plasma viral load levels; however, they exhibit different intracellular MRP1 expression as compared with healthy subjects. By contrast, MRP efflux function is increased in subjects with primary HIV infection and becomes defective in later stages of the infection. PI- and probenecid (PBCD)-mediated inhibition of MRP lowers the in vitro stress-induced response of lymphoid cells by reducing the level of the specific reactive oxygen species superoxide anion and hydrogen peroxide. Finally, the blockade of MRP by PBCD and PIs down-modulates HIV-1 replication by a mechanism independent of inhibition of the HIV-1 protease. Our results are consistent with a model wherein HIV replication is favored by the MRP1-related oxidative stress and inhibition of MRP1 may contribute to the antiviral activity of PIs.
Lucia
Mothanje Barbara
MB
Department of Infectious Diseases, Catholic University, Rome, Italy. mothluc@tiscali.it
Savarino
Andrea
A
Straface
Elisabetta
E
Golotta
Caterina
C
Rastrelli
Elena
E
Matarrese
Paola
P
Rutella
Sergio
S
Malorni
Walter
W
Cauda
Roberto
R
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000378:metabolism; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D003593:Cytoplasm / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000502:physiology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects / Q000302:isolation & purification; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007963:Leukocytes, Mononuclear; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction; D011339:Probenecid / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D016896:Treatment Outcome; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D006861:Hydrogen Peroxide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011339:Probenecid; D013481:Superoxides; C421109:multidrug resistance-associated protein 1