Cooperative contribution of gag substitutions to nelfinavir-dependent enhancement of precursor cleavage and replication of human immunodeficiency virus type-1.
We previously described a clinical human immunodeficiency virus type-1 (HIV-1) isolate, CL-4, which showed nelfinavir (NFV)-dependent enhancement of replication (Matsuoka-Aizawa, S., Sato, H., Hachiya, A., Tsuchiya, K., Takebe, Y., Gatanaga, H., Kimura, S., Oka, S, 2003. Isolation and molecular characterization of a nelfinavir (NFV)-resistant human immunodeficiency virus type 1 that exhibits NFV-dependent enhancement of replication. J. Virol. 77, 318-327.). To identify the responsible region(s) of HIV-1 proteins for such replication enhancement, we constructed a panel of recombinant HIV-1 clones harboring portions of the Gag and protease of CL-4 and analyzed their replication capabilities and Gag processing patterns. Our data suggested that the substitutions in the matrix and N-terminal half of capsid of CL-4 were indispensable for the NFV-dependent enhancement of replication and that NFV facilitated the cleavage between the matrix and capsid of the Gag precursor harboring these substitutions. The substitutions in C-terminal half of capsid rather decreased the cleavability of Gag precursor and NFV counteracted such negative impact. Efficient replication enhancement with NFV can be observed only in the presence of the substitutions in entire Gag and protease of CL-4.
AIDS Clinical Center, International Medical Center of Japan, 1-21-1, Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
Saori
S
Matsuoka-Aizawa
Hiroyuki
H
Gatanaga
Hironori
H
Sato
Kazuhiko
K
Koike
Satoshi
S
Kimura
Shinichi
S
Oka
D000595:Amino Acid Sequence; D015153:Blotting, Western; D002213:Capsid / Q000821:virology; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D004198:Disease Susceptibility; D024882:Drug Resistance, Viral / Q000235:genetics; D015683:Gene Products, gag / Q000235:genetics* / Q000378:metabolism; D016333:HIV Protease / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D019888:Nelfinavir / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics*
D036022:Capsid Proteins; D015683:Gene Products, gag; D016333:HIV Protease; D019888:Nelfinavir