Session 66Poster Presentations New Antiretrovirals Session Day and Time: Tuesday 1:30 - 3:30 pm Room: Hall A
560 HIV-gp41 Peptides Based on IL-2 Structural Homologies are More Potent Inhibitors of HIV-1 Replication J.D. Mosca*1, M.G. Lewis2, Q. Sattentau3, P.F. Serres1, P.P. McCann1 1Mymetics Corp, Annapolis, MD; 2Southern Res Inst, Frederick, MD; and 3Imperial Coll of Med, Univ of London, UK
Background: We have constructed a gp41 molecule from a consensus sequence of 32 different strains of HIV-1 as a source for peptides that inhibit HIV replication across multiple HIV-1 isolates. Our modified peptides have been designed to capitalize on the 3-D molecular mimicry we have discovered between HIV-gp41 and IL-2.
Methods: We compared gp41-derived peptides from regions structurally homologous to IL-2 with peptides derived from regions that show little to no IL-2 structural homology. We performed HIV inhibitory assays in human peripheral blood mononuclear cells (hPBMCs) with HIV-1 isolates pre-incubated with various peptide concentrations. The HIV-1 isolates (Clades) tested are from diverse geographic origins, representing the spectrum of known HIV variations. Inhibition of HIV-1 strains was measured by reverse transcriptase activity; representative viruses from each Clade were tested to determine the ability of HIV-gp41 peptides from either the IL-2 homologous region or the non-IL-2 homologous region to inhibit HIV-1 replication.
Results: Ten (10) HIV-1 isolates representative of at least 1 isolate from Clades A through G and O were used to challenge peptide-treated hPBMCs. Three (3) peptides within the homologous region were tested: 1 containing a minimal 29AA element and the other 2 of larger size (36AA and 37AA) that flank the minimal element. Preliminary results show that for Clades E and G, peptides from the non-homologous regions showed similar potency to those in the IL-2 homologous region, but for Clades A, C, D, F, and O, peptides within the IL-2 homologous region were 28-, 66-, 5-, 13-, and 37-times more potent inhibitors of HIV replication than peptides derived from the non-homologous IL-2 regions of HIV-gp41 constructed from our HIV-gp41 consensus sequence template.
Conclusions: HIV-gp41 peptides derived from regions that are structurally homologous to IL-2 show a higher degree of inhibitory activity in the nanomolar concentration range across HIV-1 Clade isolates, and in fact demonstrate a degree of in vitro activity that matches or exceeds the entry-inhibitor agents that have recently been shown to cause significant viral load reductions in human clinical trials.