ABSTRACT:
When evaluated clinically, abacavir is the most potent HIV-1 nucleoside reverse transcriptase inhibitor (NRTI) yet developed, but its effect is blunted in subjects with prior exposure to NRTIs. Mycophenolic acid (MA), a selective inhibitor of lymphocyte proliferation currently in use in organ transplantation, inhibits inosine monophosphate dehydrogenase, blocking the synthesis of guanosine monophosphate. As abacavir is converted into a 2'-deoxyguanosine analogue NRTI within cells, we tested the in vitro antiviral effect of abacavir and MA. Abacavir and Ma profoundly inhibit HIV-1 replication in stimulated PBMCs and in monocyte-derived macrophages (MDMs). Inhibition was synergistic to an extent not previously observed with other antiretroviral combinations. When modeled using the Greco equation, the interaction parameter a was 8.205, nearly eightfold higher than the combination of abacavir and amprenavir, drugs shown to be highly synergistic in vitro. The IC50 for MA was 0.1 µM, 10- to 100-fold below trough levels seen clinically in organ transplant patients. In the presence or absence of abacavir, o.35 µM MA had little effect on cell proliferation whereas in the presence of 0.5 µM MA, HIV clones encoding M181V mutations display sensitivity to abacavir comparable to wild-type HIV. Further studies using HIV clones encoding multiple abacavir resistance mutations are ongoing. Of note, the combination of MA and zidovudine or stavudine was antagonistic, likely due to the inhibition of thymidine phosphorylation by MA. These findings must be corroborated by clinical trials, but the judicious use of selective inhibitors of nucleoside metabolism may extend the use of abacavir and other NRTIs in patients with treatment experience and drug-resistant HIV.
