AEGiS-11IAC: T-20, a novel inhibitor of HIV-1 fusion, blocks recovery of infectious HIV-1 and inhibits viral load in vivo in the HuPBMC-SCID mouse model.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

T-20, a novel inhibitor of HIV-1 fusion, blocks recovery of infectious HIV-1 and inhibits viral load in vivo in the HuPBMC-SCID mouse model.

Int Conf AIDS 1996 Jul 7-12; 11:221 (abstract no. Tu.A.263)
Black PL, Wood O, Broud D, Bacho M, Kunder S, Papermaster S, Lambert D, Barney S, Ussery M; FDA, Rockville, MD, USA. Fax: 301-594-6289. E-mail: BLACKP@CDER.FDA.GOV.

OBJECTIVE: To determine the antiviral efficacy of T-20, a novel inhibitor of HIV-1 fusion, in vivo.

METHODS: Female SCID mice (5-7 wk old) received 5X107 adult human PBMC i.p. Two weeks after reconstitution, mice were infected i.p. on day 0 with 103 TCID50 HIV-1 9320 (passed in PBMC, AZT-sensitive isolate A018, D. Richman). Treatment with T-20 was i.p., bid, for total daily doses of 2, 20, or 200 mg/kg, beginning on day -1. The extent of infection in blood cells, splenocytes, lymph nodes (LN), and peritoneal cells (PC) was assayed by quantitative coculture with human PBMC blasts 1 wk later. Viral loads(HIV-1 RNA) in plasma and in tissues were measured by NASBA assay.

RESULTS: T-20 (pentafuside, DP-178), a 36-mer synthetic peptide derived from the HIV-1 gp41 transmembrane protein, is a selective and potent inhibitor of HIV-1 fusion (IC50=1 ng/ml) and infection in vitro. Pharmacokinetic studies in rodents revealed a surprisingly long half-life in circulation (t_=2.4 hr), with sustained levels above the IC50 for at least 6 hr. Therefore, we tested the ability of t-20 to inhibit HIV-1 replication in vivo in the HuPBMC-SCID mouse model of HIV-1 infection. Infectious HIV-1 was recovered from none of the tissues from the animals treated with the 200 mg/kg/day dose. Furthermore, the two lower doses of T-20 reduced the recovery of HIV-1 from cells in PC, LN, and blood, but not from spleen. Additionally, viral load was quantitated by the NASBA assay, and the results were generally consistent with those of cocultures. Low levels of HIV-1 RNA were detected in the plasma and cells of some, but not all, animals treated with the highest dose of T-20. This treatment dropped mean viral load in LN by greater than 6 logs (8.2 copies/106 cells) compared with saline treatment (1.7x107 copies/106 cells). Antiviral effects also correlated with the protection of human CD4 lymphocytes (assayed by flow cytometry) from the cytotoxic effects of HIV infection, for T-20 restored the CD4/CD8 ratio in a dose-dependent manner.

CONCLUSIONS: T-20 is a potent inhibitor of HIV-1 replication in vivo in the HuPBMC-SCID mouse model. These results support the potential therapeutic efficacy of T-20 and this novel class of antiviral agents.

Keywords: AEGIS, Viral Load, HIV-1, Mice, SCID, HIV Infections, HIV Envelope Protein gp41, Anti-HIV Agents, Zidovudine, Virus Replication, CD4-Positive T-Lymphocytes, HIV Protease Inhibitors, Antiviral Agents, Peptide Fragments, Antigens, CD4, pentafuside, DP 178, Mice, Animal, Adult, Female, Human, In Vitro, virology, ICA11

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TuA263