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 fo r the treatment of HIV-I infection. Abacavir is the first clinically availa ble guanosine: analogue HIV-1 reverse transcriptase inhibitor, and the most potent nucleoside analogue yet developed. Mycophenolic acid (MA), a specif ic inhibitor of lymphocyte: proliferation that is currently in use in organ transplantation, acts on inosine monophosphate dehydrogenase to block conv ersion of inosine monophosphate to guanosine monophosphate. We: found abaca vir and MA inhibited HTV-1 replication in stimulated peripheral blood monon uclear 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 mu M ) far below those used for immunosuppression in organ transplantation. An H IV strain encoding the M184V mutation was susceptible to the combination of MA and abacavir. However, the combination of MA and zidovudine (ZDV) or st avudine (d4T) was antagonistic. Although the translation of these observati ons must be carefully evaluated in clinical trials, the judicious combinati on of antiretrovirals and inhibitors of nucleoside metabolism may emerge as an important strategy in the treatment of HIV infection.