Dose proportional inhibition of HIV-1 replication by mycophenolic acid and synergistic inhibition in combination with abacavir, didanosine, and tenofovir.
Mycophenolate mofetil (MMF), a therapeutically used inhibitor of inosine monophosphate dehydrogenase is hydrolyzed to its active metabolite mycophenolic acid (MPA) in vivo. MPA exhibits anti-HIV activity in vitro. We tested MPA alone and in combination with abacavir (ABC), didanosine (DDI), lamivudine (3TC) and tenofovir (TFV) against wild-type human immunodeficiency virus type-1 (HIV-1) and nucleoside reverse transcriptase inhibitor (NRTI)-resistant HIV-1. MPA (62.5-500 nM), when combined with ABC or DDI, synergistically enhanced activity against wild-type HIV and the NRTI-resistant HIV clone DRSM34. MPA also enhanced the activity of TFV against both wild-type HXB2 and TFV-resistant strain HIV(K65R), in a more than additive manner. No significant antiproliferative effect of MPA (< or =0.25 microM) alone or in the presence of ABC, DDI and TFV was observed. This indicates that the antiviral effects of MMF may be clinically achievable without fully blocking T-cell proliferation or inducing immunosuppression. These findings provide further rationale for the clinical testing of MMF in combination with ABC, DDI, and TFV.
Hossain
Mohammad M
MM
Department of Internal Medicine, Division of Infectious Diseases, North Texas Veterans Health Care Systems, Dallas, TX, USA.
Coull
Jason J
JJ
Drusano
George L
GL
Margolis
David M
DM
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002478:Cells, Cultured; D016049:Didanosine / Q000494:pharmacology*; D015224:Dideoxynucleosides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D009173:Mycophenolic Acid / Q000494:pharmacology*; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D000068698:Tenofovir; D014779:Virus Replication / Q000187:drug effects*; D000099227:Abacavir
D000225:Adenine; D016049:Didanosine; D015224:Dideoxynucleosides; D004791:Enzyme Inhibitors; D009173:Mycophenolic Acid; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000099227:Abacavir