307   Low Concentrations of Mycophenolic Acid Augment the Antiretroviral Activity of Abacavir (ABC), Didanosine (DDI), Tenofovir (TFV), and the Combination of ABC and DDI In Vitro.

M. Hossain* and D. Margolis.
Dallas VA Med. Ctr. and Univ. of Texas Southwestern Med. Ctr., Dallas.

Background:Mycophenolic acid (MPA), an inosine monophosphate dehydrogenase inhibitor, shows anti-HIV activity in vitro. We tested the combined effect of MPA with ABC, DDI and TFV against wild-type and nucleoside-resistant (NR) HIV-1 in PHA-stimulated PBMCs.

Methods:10⁶stimulated PBMCs were infected with 1000 TCID₅₀of HIV-1 for 2 hours. 2 × 10⁵PBMCs were seeded at 200ml/well in triplicate with appropriate drugs. On day 7, cell-free supernatants were harvested and p24 was measured by antigen capture assay. Cellular proliferation in culture in the presence and absence of drugs was measured using an MTT assay.

Results:Due to protein binding in vivo, trough levels of mycophenolate, when used in transplant medicine, approximate more than 250 nM in vitro. We tested the effect of 0 to 500 nM MPA in the presence or absence of 4mM ABC on the replication of NR clones DRSM34 and MDRV1. A dose-dependent antiviral effect of MPA and an augmentation of ABC effect across this concentration range was seen. MPA enhanced the antiviral effect of TFV across a range of MPA concentrations in both wild-type HXB2 and TFV-resistant strain HIV_K65R. In the presence of the combination of ABC (0—2.0mM) and DDI (0—7.5mM), MPA enhanced the antiviral effect against HXB2 and DRSM34 in a dose-dependent manner. Little or no effect of MPA, ABC, DDI and TFV on proliferation of cells was seen.

Conclusions:MPA increases the antiviral effect of ABC, DDI and TFV in vitro in a dose-dependent manner. Antiviral effects of MPA may be clinically achievable without inducing immunosuppression. These findings provide further rationale for the clinical testing of the use of mycophenolate with ABC, DDI, and TFV.