AEGiS-11IAC: T-20 and T-1052, novel inhibitors of HIV fusion, block infection of human macrophages by HIV-1.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

T-20 and T-1052, novel inhibitors of HIV fusion, block infection of human macrophages by HIV-1.

Int Conf AIDS 1996 Jul 7-12; 11:24 (abstract no. LB.A.6015)
Black P, Wood O, Bacho M, Lambert D, Guthrie K, Barney S, Ussery M; U.S.F.D.A., Rockville, MD. Fax: (301) 594-6289. E-mail: blackp@cder.fda.gov.

OBJECTIVE: To determine the antiviral activity of T-20 and T-1052, novel inhibitors of HIV fusion, in human macrophages. Method: Monocyte/macrophage (MM) cultures were derived from healthy adult human peripheral blood mononuclear cells (PBMC) by adherence to plastic and were maintained in culture with granulocyte-macrophage colony-stimulating factor (GM-CSF). The MM cultures were infected with the macrophage-tropic BAL strain of HIV-1 after 2 weeks in culture. T-20 (0.1-100 micrograms/ml) or T-1052 (0.01-10 micrograms/ml) was added to the cultures at the time of infection. One week after infection, supernatants were removed and assayed for p24 by ELISA and for HIV-1 RNA by NASBA. MM cultures were washed and refed with fresh medium containing GM-CSF and T-20 or T-1052. After another week of culture, supernatants were removed and assayed for p24 and HIV-1 RNA. MM cultures were washed and refed with fresh medium containing GM-CSF, but no drug. After another week of culture, supernatants were removed and assayed for p24 and HIV-1 RNA.

RESULTS: T-20 (pentafuside, DP-178), alpha 36-mer synthetic peptide derived from the HIV-1 gp41 transmembrane protein, is a selective and potent inhibitor of HIV-1 fusion and infection in human PBMC in vitro. It shows activity against HIV-1, but not HIV-2 or SIV. T-20 also has activity in vivo against HIV-1 in the HuPBMC-SCID mouse model, and it is slated for clinical trials later this year. T-1052, an early-stage preclinical backup lead peptide derived from the gp41 transmembrane protein of HIV-2, shows potent and selective activity in vitro against HIV-1, HIV-2, and SIV in PBMC. In MM cultures T-20 inhibited p24 production in the supernatant with an IC(50) of 3 micrograms/ml and IC(90) of 10 micrograms/ml. Similarly, T-20 inhibited HIV-1 RNA in the MM supernatants with an IC(50) of 2 micrograms/ml and IC(90)of 11 micrograms/ml. T-1052 had 100-1000 times as much antiviral activity in MM cultures, with an IC(50) less than 0.01 micrograms/ml and IC(90) of 0.01 micrograms/ml. At concentrations of T-1052 greater than or equal to 0.1 micrograms/ml, no p24 could be detected in the MM culture supernatants. T-20 and T-1052 both had somewhat lower IC(50) values in assays of HIV-1 infectivity in human PBMC, but T-1052 was still relatively 100-200 times more active than T-20.

CONCLUSIONS: T-20 and T-1052 are potent inhibitors of HIV-1 replication in vitro in human macrophages as well as in human PBMC. These results support the potential therapeutic efficacy of this novel class of antiviral agents.

960707
LBA6015