AEGiS-11IAC: The protease inhibitor KNI-272 inhibits HIV-1 infection in vivo in the HuPBMC-SCID mouse model.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

The protease inhibitor KNI-272 inhibits HIV-1 infection in vivo in the HuPBMC-SCID mouse model.

Int Conf AIDS 1996 Jul 7-12; 11:221 (abstract no. Tu.A.262)
Ussery MA, Wood O, Broud D, Bacho M, Kunder S, Papermaster S, Kiso Y, Black P; FDA, Rockville, MD, USA. Fax: 301-594-6289. E-mail: USSERY@CDER.FDA.GOV.

OBJECTIVE: To evaluate the antiviral activity of KNI-272, an HIV-1 protease inhibitor, 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 KNI-272 was i.p., bid, for total daily doses of 20, 50, or 100 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: A significant proportion of samples from animals treated with the 50 and 100 mg/kg/day doses did not have detectable levels of HIV in PC and LN sites. The average HIV titer (TCID/106 cells) decreased in PC from 390 to 29 and 23 at the 50 and 100 mg/kg/day doses, respectively, and in LN from 850 to 6.6 and not detectable at the 50 and 100 mg/kg/day doses, respectively. Blood cells showed a decrease from 440 TCID/ml to 18 at the highest dose tested. Spleen cells were the only tissue in which KNI-272 did not reduce virus recovery. Additionally, viral load was quantitated by the NASBA assay, and the results were generally consistent with those of cocultures. Antiviral effects also correlated with the protection of human CD4 lymphocytes (assayed by flow cytometry) from the cytotoxic effects of HIV infection, with a dose-dependent restoration of CD4/CD8 ratio by KNI-272. In a subsequent experiment, levels of HIV recovery from tissues were much higher, but the results followed those described above. The antiviral effect of KNI-272 at 100 mg/kg/day was again observed in PC, LN, and blood cells (but not splenocytes), but the magnitude of the antiviral effects was more modest than in the previous experiment. Further experiments are underway to confirm and expand these results.

CONCLUSIONS: The protease inhibitor KNI-272 inhibited HIV-1 replication in vivo in the HuPBMC-SCID mouse model. KNI-272 is currently in clinical trials.

Keywords: AEGIS, HIV-1, Mice, SCID, HIV Protease Inhibitors, Oligopeptides, HIV Infections, Zidovudine, Anti-HIV Agents, HIV, Virus Replication, CD4-Positive T-Lymphocytes, HIV Protease, HIV Core Protein p24, Reverse Transcriptase Inhibitors, kynostatin 272, Mice, Animal, Adult, Female, Human, virology, ICA11

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TuA262