title: Impact of HIV type 1 protease, reverse transcriptase, cleavage site, and p6 mutations on the virological response to quadruple therapy with saquinavir, ritonavir, and two nucleoside analogs.
abstract: Genotype alterations of HIV-1 protease, reverse transcriptase, cleavage sites p7/p1 and p1/p6, as well as p6(gag) and transframe protein p6* were studied in an observational cohort of 42 individuals who received antiretroviral therapy consisting of saquinavir, ritonavir, and two nucleoside analogs. In a multivariate logistic regression analysis, the prior protease inhibitor experience (odds ratio, 6.20; 95% CI, 1.22-31.38) and the presence of primary protease mutations (odds ratio, 9.99; 95% CI, 1.05-94.72) were independently associated with virological failure. Moreover, a trend was observed in that individuals with N-terminal amino acid insertions in the proline-rich motif of the p6(gag) protein were less likely to experience virological failure (OR, 0.17; 95% CI, 0.02-1.35; p = 0.09). In contrast, the presence of secondary protease, reverse transcriptase, or cleavage site mutations was not independently associated with treatment failure. However, mutations at cleavage site p7/p1 (p = 0.01) and C-terminal p6* mutations (p = 0.02) were both associated with primary protease mutations. In conclusion, the presence of primary protease mutations was the most important predictor of the subsequent virological response. Moreover, there is some evidence that insertions in the proline-rich area of the p6(gag) protein may affect the virological response. The relationship between mutations of cleavage sites or C-terminal p6* residues and protease mutations suggests that these alterations may serve a compensatory role, increasing viral fitness.
authors.affiliation: National Centre in HIV Epidemiology and Clinical Research, Sydney NSW 2010, Australia.
authors.forename: G R
authors.initials: GR
authors.lastname: Kaufmann
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: P
authors.initials: P
authors.lastname: Cunningham
authors.forename: M
authors.initials: M
authors.lastname: Mukaide
authors.forename: M
authors.initials: M
authors.lastname: Kondo
authors.forename: M
authors.initials: M
authors.lastname: Imai
authors.forename: J
authors.initials: J
authors.lastname: Zaunders
authors.forename: D A
authors.initials: DA
authors.lastname: Cooper
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002213:Capsid / Q000235:genetics; D036022:Capsid Proteins; D015331:Cohort Studies; D004279:DNA, Viral; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D015683:Gene Products, gag / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009705:Nucleosides / Q000627:therapeutic use; D011237:Predictive Value of Tests; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use; D019258:Saquinavir / Q000627:therapeutic use; D017211:Treatment Failure; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D036022:Capsid Proteins; D004279:DNA, Viral; D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; C071884:NCP7 protein, Human immunodeficiency virus 1; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C083868:gag protein p1, Human immunodeficiency virus; C083002:p6 gag protein, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D016333:HIV Protease; D019258:Saquinavir; D019438:Ritonavir