Non-steroidal anti-inflammatory drugs increase the antiretroviral activity of nucleoside reverse transcriptase inhibitors in HIV type-1-infected T-lymphocytes: role of multidrug resistance protein 4.
BACKGROUND
The multidrug resistance proteins (MRPs) form a subfamily within the ATP binding cassette transporters that confer resistance to a variety of structurally unrelated compounds. MRP4 has been reported to transport antiretroviral drugs out of cells in an active process. Although the main therapeutic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are their ability to inhibit cyclooxygenase activity, in recent years, some pharmacological effects independent of this action have been described, such as inhibition of the activity of MRP4.


METHODS
Detection of MRP4 expression was carried out by Western blot analysis, immunofluorescence and flow cytometry in peripheral blood lymphocytes (PBLs). Cells were infected with HIV type-1(NL4.3) isolate, and treated with antiretroviral drugs plus different NSAIDs. Agp24 was measured by ELISA 3 days post-infection. Intracellular [(3)H] zidovudine (AZT) was quantified by a scintiller counter. Expression of different cell markers was assessed by flow cytometry.


RESULTS
NSAIDs, as well as probenecid, were able to potentiate the antiretroviral effect of several nucleoside reverse transcriptase inhibitors (NRTIs). PBLs expressed MRP4 and treatment with ibuprofen did not affect this expression. However, MRP4 expression increased following phytohaemaglutinin and AZT treatment. This decrease of Agp24 was correlated with an increase in the intracellular AZT concentration. This effect was unrelated to changes on expression of CD4, CXCR4, cell viability or activation. Interestingly, patients treated with highly active antiretroviral therapy, who had a detectable viral load, presented a higher expression of MRP4 than those with an undetectable viral load.


CONCLUSIONS
NSAIDs can improve the antiretroviral activity of NRTIs, increasing their intracellular concentration by blocking MRP4. This finding could have implications for success of antiviral therapy.
Clemente
Ma Isabel
MI
Laboratory Inmuno-Biología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Alvarez
Susana
S
Serramía
Ma Jesús
MJ
Turriziani
Ombretta
O
Genebat
Miguel
M
Leal
Manuel
M
Fresno
Manuel
M
Muñoz-Fernández
Ma Angeles
MA
D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D004357:Drug Synergism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*
D019380:Anti-HIV Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D018894:Reverse Transcriptase Inhibitors; C073492:ABCC4 protein, human