Role of human immunodeficiency virus (HIV) type 1 envelope in the anti-HIVactivity of the betulinic acid derivative IC9564

Holz-Smith, SL Sun, IC Jin, L Matthews, TJ Lee, KH Chen, CH

Sl. Holz-smith et al., Role of human immunodeficiency virus (HIV) type 1 envelope in the anti-HIVactivity of the betulinic acid derivative IC9564, ANTIM AG CH, 45(1), 2001, pp. 60-66

44

INGLESE

Article

Microbiology

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY

0066-4804 → ACNP

45

1

2001

60 - 66

ISI

0066-4804(200101)45:1<60:ROHIV(>2.0.ZU;2-C

The betulinic acid derivative IC9564 is a potent anti-human immunodeficienc y virus (anti-HIV) compound that can inhibit both HIV primary isolates and laboratory-adapted strains. However, this compound did not affect the repli cation of simian immunodeficiency virus and respiratory syncytial virus. Re sults from a syncytium formation assay indicated that IC9564 blocked EW typ e 1 (HIV-1) envelope-mediated membrane fusion. Analysis of a chimeric virus derived from exchanging envelope regions between IC9564-sensitive and IC95 64-resistant viruses indicated that regions within gp120 and the N-terminal 25 amino acids (fusion domain) of gp41 are key determinants for the drug s ensitivity. By developing a drug-resistant mutant from the NL4-3 virus, two mutations were found within the gp120 region and one was found within the gp41 region. The mutations are G237R and R252K in gp120 and R533A in the fu sion domain of gp41. The mutations were reintroduced into the NL4-3 envelop e and analyzed for their role in IC9564 resistance. Both of the gp120 mutat ions contributed to the drug sensitivity. On the contrary, the gp41 mutatio n (R533A) did not appear to affect the IC9564 sensitivity. These results su ggest that HIV-1 gp120 plays a key role in the anti-HIV-1 activity of IC956 4.