Session 66Poster Presentations New Antiretrovirals Session Day and Time: Tuesday 1:30 - 3:30 pm Room: Hall A
564a Potent in vivo anti-R5-HIV effects of AK602, a novel spirodiketopiperazine (SDP)-containing HIV-specific CCR5 inhibitor, in hu-PBMC-NOD-SCID mice H Nakata *1, K Maeda1, Y Kawano 2, T Miyakawa1, S Shibayama 3, M Matsuo 3, Y Takaoka3, Y Koyanagi2, H Mitsuya1,4 1Kumamoto University School of Medicine, Kumamoto,Japan; 2Tohoku University Graduate School of Medicine, Sendai,Japan; 3Ono Pharmaceutical Co LTD, Osaka,Japan; and 4National Cancer Institute, Bethesda, MD
Background: CCR5 represents a major chemokine receptor which R5-HIV exploits in its entry to target cells, thus serving as an attractive target for possible intervention of HIV infection. AK602, a novel agent (MW: 614) containing a unique SDP group, which potently blocks in vitro the infectivity and replication of a wide spectrum of R5-HIV with subnanomolar IC50 values but with partial/moderate inhibition of CC chemokine-CCR5 interactions, was administered to human peripheral blood mononuclear cells-transplanted,gamma-chain-knocked-out,hu-PBMC-NOD-SCID mice and its in vivo anti-HIV effects were examined.
Method: Human PBMC (1x107) were intraperitoneally (ip) transplanted to each NOD-SCID mouse on day -16; the mice were then infected ip with R5-HIV (2000 TCID50) on day 0 and the ip administration of AK602 (120 mg/kg/day, bid: n=8) or didanosine (ddI, 50 mg/kg/day, bid: n=9) was begun on day 1. The immunological/virological monitoring was performed periodically until the mice were sacrificed on day 16.
Results: In infected, untreated mice (n=7), human CD4/CD8 ratios were 0.67 on average on day 9, which further downed to 0.08 (range 0.02-0.17) [1.0 (0.5-1.5) in uninfected mice (n=7)] by day 16; the number of HIV-RNA copies in serum rose to 103-105/ml by day 5, reaching an average of 106/ml on day 16; the number of intracellular HIV-DNA copies was 1.2x105/105 CD4+ cells; and the level of p24 in serum was 1.3x105 pg/ml on day 16. In infected but treated with AK602 (n=8) and ddI (n=9), CD4/CD8 ratios were 0.9 (0.2-1.9) and 1.4 (0.4-2.7)[p=0.001 and 0.001 compared to infected/untreated mice]; HIV-RNA copy numbers 1.5x104 (7x103-4x104) and 7.1x103 (3x103-104)/ml [p=0.001 and 0.001]; HIV DNA numbers 2.4x103(2x102-8x103) and 3.3x102 (102-8x102)/105 CD4+ cells [p=0.001 and 0.001]; and p24 levels 9.0x103 (8x102-2x104) and 2.1x103 (102-104)[p=0.001 and 0.001], respectively, when examined on day 16. No apparent agent-specific side effects were identified in either of the treated groups.
Summary: AK602 exerted significant antiviral effects against R5-HIV in infected hu-PBMC NOD-SCID mice, inhibiting CD4 decrease and suppressing by ~2 logs serum HIV-RNA, intracellular HIV-DNA, and serum p24 levels. These data warrant that AK602 (and its comparable analogs) be further developed as a potential therapeutic for HIV infection.
