Ex vivo modeling of the effects of mycophenolic acid on HIV infection: considerations for antiviral therapy.
Mycophenolate mofetil (MMF), the bioavailable form of mycophenolic acid (MPA), has been proposed as adjuvant therapy for human immunodeficiency virus type 1 (HIV-1) infection. MPA can inhibit viral replication and might blunt virus-induced immunopathology. However, other effects of this inhibitor might be detrimental in an HIV-infected patient. We therefore studied the effect of MPA on selected cellular processes of relevance to HIV infection. We found that MPA did not alter the expression of the primary HIV coreceptor CCR5 on primary resting lymphocytes, but modestly increased CCR5 expression after activation. Conversely, MPA modestly decreased the secretion of the CCR5 ligand RANTES in resting lymphocytes, but had no effect after activation. It has been suggested that the use of inhibitors of host nucleoside metabolism may enhance clinical toxicities induced by HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs). We found no evidence that MPA induced mitochondrial dysfunction or enhanced dysfunction induced by NRTIs in an HepG2 cell line model of mitochondrial toxicity. Further, MPA did not selectively enhance apoptosis in HIV-1-infected lymphocytes. Our findings support the testing of MMF to augment suppression of viral replication. However, careful study will be required to demonstrate that MMF is beneficial when used without antiretroviral therapy, to inhibit residual replication, or to deplete the pool of latently infected nonactivated cells.
Kaur
Rupinderjeet
R
Department of Medicine, Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Klichko
Vladimir
V
Margolis
David
D
D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000032:analysis / Q000235:genetics; D003576:Electron Transport Complex IV / Q000032:analysis / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D019713:Receptors, CCR5 / Q000032:analysis / Q000235:genetics
D018946:Chemokine CCL5; D012333:RNA, Messenger; D019713:Receptors, CCR5; D003576:Electron Transport Complex IV; D009173:Mycophenolic Acid