title: Within-host co-evolution of Gag P453L and protease D30N/N88D demonstrates virological advantage in a highly protease inhibitor-exposed HIV-1 case.
abstract: To better understand the mechanism of HIV group-specific antigen (Gag) and protease (PR) co-evolution in drug-resistance acquisition, we analyzed a drug-resistance case by both bioinformatics and virological methods. We especially considered the quality of sequence data and analytical accuracy by introducing single-genome sequencing (SGS) and Spidermonkey/Bayesian graphical models (BGM) analysis, respectively. We analyzed 129 HIV-1 Gag-PR linkage sequences obtained from 8 time points, and the resulting sequences were applied to the Spidermonkey co-evolution analysis program, which identified ten mutation pairs as significantly co-evolving. Among these, we focused on associations between Gag-P453L, the P5' position of the p1/p6 cleavage-site mutation, and PR-D30N/N88D nelfinavir-resistant mutations, and attempted to clarify their virological significance in vitro by constructing recombinant clones. The results showed that P453L(Gag) has the potential to improve replication capacity and the Gag processing efficiency of viruses with D30N(PR)/N88D(PR) but has little effect on nelfinavir susceptibility. Homology modeling analysis suggested that hydrogen bonds between the 30th PR residue and the R452Gag are disturbed by the D30N(PR) mutation, but the impaired interaction is compensated by P453L(Gag) generating new hydrophobic interactions. Furthermore, database analysis indicated that the P453L(Gag)/D30N(PR)/N88D(PR) association was not specific only to our clinical case, but was common among AIDS patients.
authors.affiliation: School of Biomedical Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Shibata
authors.forename: Wataru
authors.initials: W
authors.lastname: Sugiura
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Ode
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Iwatani
authors.forename: Hironori
authors.initials: H
authors.lastname: Sato
authors.forename: Hsinyi
authors.initials: H
authors.lastname: Tsang
authors.forename: Masakazu
authors.initials: M
authors.lastname: Matsuda
authors.forename: Naoki
authors.initials: N
authors.lastname: Hasegawa
authors.forename: Fengrong
authors.initials: F
authors.lastname: Ren
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage*; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D020125:Mutation, Missense; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease