Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-HIV activity.
The use of inhibitors of purine nucleoside metabolism has been advocated for the treatment of HIV-1 infection. Abacavir is the first clinically available guanosine analogue HIV-1 reverse transcriptase inhibitor, and the most potent nucleoside analogue yet developed. Mycophenolic acid (MA), a specific inhibitor of lymphocyte proliferation that is currently in use in organ transplantation, acts on inosine monophosphate dehydrogenase to block conversion of inosine monophosphate to guanosine monophosphate. We found abacavir and MA inhibited HIV-1 replication in stimulated peripheral blood mononuclear cells (PBMCs) and in monocyte-derived macrophages (MDMs). Inhibition was potent and synergistic to an extent not previously observed with other antiretroviral combinations. MA was effective at concentrations (0.25 microM) far below those used for immunosuppression in organ transplantation. An HIV strain encoding the M184V mutation was susceptible to the combination of MA and abacavir. However, the combination of MA and zidovudine (ZDV) or stavudine (d4T) was antagonistic. Although the translation of these observations must be carefully evaluated in clinical trials, the judicious combination of antiretrovirals and inhibitors of nucleoside metabolism may emerge as an important strategy in the treatment of HIV infection.
Margolis
D
D
University of Maryland Institute of Human Virology, Department of Microbiology and Immunology, Baltimore 21201, USA.
Heredia
A
A
Gaywee
J
J
Oldach
D
D
Drusano
G
G
Redfield
R
R
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D015224:Dideoxynucleosides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology / Q000821:virology; D009173:Mycophenolic Acid / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*; D000099227:Abacavir
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D004791:Enzyme Inhibitors; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D000099227:Abacavir