56   Reduced Activation and Apoptosis of Peripheral CD3⁺/ CD4⁺T Cells Persists After Viral Rebound in AIDS Patients Treated with Mycophenolate Mofetil (MMF).

J. J. Coull*²and D. M. Margolis¹.
¹Univ. of Texas Southwestern Med. Ctr. at Dallas and²Dallas VA Med. Ctr., Dallas, TX.

Background:Mycophenolate Mofetil, used as an immunosuppressant in transplantation, is hydrolyzed after oral absorption to mycophenolic acid (MPA). As little as 125 nM MPA has significant antiviral activity in vitro, but 2 µM MPA has been reported to induce apoptosis in activated PBMCs. A cohort of patients with AIDS (CD4⁺31+12 cells/ml; median 28), multidrug resistant HIV, and few therapeutic options were administered MMF 250 mg bid with other antiretrovirals in a compassionate pilot study.

Methods:Four subjects had virological failure of salvage therapy with MMF. FACS was performed at baseline while failing prior therapy and at week 16 (6 weeks or more after viral rebound to baseline). PBMCs were immediately analyzed for the early apoptosis marker Annexin-V, cellular activation marker CD69, Fas ligand, and the marker of cellular proliferation Ki-67.

Results:At 24 weeks (12 to 20 weeks after viral rebound), CD4⁺cells in this group had increased 31+9 cells/ µl (median 28). CD3⁺apoptosis decreased markedly from baseline (50.8+14.7%, median 45.5%) to week 16 (23.0+11.6%, median 17.6%). Cellular activation also decreased (47.1+4.2% [median 44.3%] to 14.7+4.1% [median 10.6%]). Apoptosis and activation of CD4⁺cells also decreased in subjects with sufficient cells for analysis at baseline. We observed no change in Fas ligand and a slight decrease in Ki-67 at week 16. We also found that 81.2% of cells that were highly activated were also Annexin-V⁺.

Conclusions:MMF may induce a range of immunological effects across a range of doses. Our results suggest that MMF reduced the level of activated lymphocytes, might have contributed to apoptosis of highly activated cells, but did not increase apoptosis in total CD3⁺or CD4⁺T cells. In addition to direct inhibition of reverse transcription, MPA may decrease the pool of activated T cells that support HIV-1 replication by inhibiting cellular activation globally and induce apoptosis in cells that are already strongly activated. The immunological effects of MPA deserve further study in the settings of salvage, intensification, and initial antiretroviral therapy.