Isolation and molecular characterization of a nelfinavir (NFV)-resistant human immunodeficiency virus type 1 that exhibits NFV-dependent enhancement of replication.
During the use of a phenotypic anti-human immunodeficiency virus type 1 (HIV-1) drug resistance assay in a large set of clinical virus isolates, we found a unique variant (CL-4) that exhibited a high level of nelfinavir (NFV) resistance and rather enhanced replication under subinhibitory concentrations of NFV (0.001 to 0.1 micro M). Comparison of gag-pol sequences of the CL-4 variant and its predecessor virus isolates showed a stepwise accumulation of a total of 19 amino acid substitutions in protease (PR) and Gag p17 during 32-month NFV-containing antiretroviral therapy, while other Gag regions including the cleavage sites of the p55 precursor remained highly conserved. To understand the relationship between the genetic and phenotypic changes in CL-4, we constructed chimeric viruses using pNL4-3, replacing the PR, p24PR, or p17PR gene segment of CL-4 or its predecessor. A series of tissue culture infections with the chimeras in the absence or presence of increasing concentrations of NFV demonstrated that only the p17PR segment of CL-4 could confer the NFV-dependent replication enhancement phenotype on NL4-3. Our data suggest a novel adaptation mechanism of HIV-1 to NFV, in which coevolution of Gag and PR genes generates a variant that replicates more efficiently in the cellular environment in the presence of NFV than without the drug.
Matsuoka-Aizawa
Saori
S
AIDS Clinical Center, International Medical Center of Japan, Tokyo, Japan.
Sato
Hironori
H
Hachiya
Atsuko
A
Tsuchiya
Kiyoto
K
Takebe
Yutaka
Y
Gatanaga
Hiroyuki
H
Kimura
Satoshi
S
Oka
Shinichi
S
D015153:Blotting, Western; D024882:Drug Resistance, Viral; D015750:Genes, gag; D015700:HIV Envelope Protein gp41 / Q000378:metabolism; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D019888:Nelfinavir / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
D015700:HIV Envelope Protein gp41; D017320:HIV Protease Inhibitors; D016333:HIV Protease; D019888:Nelfinavir