title: Role of Baseline pol Genotype in HIV-1 Fitness Evolution.
abstract: Viral fitness can be modified upon development of antiretroviral drug resistance, usually by selection of compensatory mutations. In this study, we have used HIV-1 isolates from individuals receiving a protease inhibitor (PI)-based regimen to analyze the impact of basal genetic background on viral fitness evolution. Paired plasma samples and HIV-1 isolates were obtained from 10 PI-naive HIV-infected individuals enrolled in 2 different studies of combination antiretroviral therapy. Genomic regions from pol and env were sequenced. Viral fitness was measured using growth competition experiments followed by heteroduplex tracking analysis. Baseline genotypic analyses of pol showed that 9 of 10 viruses had a different degree of secondary mutations in the protease gene at codons associated with PI resistance (i.e., 10I, 36I, 63P, 71T, and 77I). After 48 weeks of PI-based therapy, a strong correlation was observed between protease genetic divergence and viral fitness difference (r = 0.78, P = 0.03), but not with reverse transcription or Env divergence, suggesting that genotypic changes in the protease gene were driving HIV-1 evolution in these patients. As expected, an inverse correlation was observed between the number of protease and reverse transcription primary mutations and viral fitness (r = -0.65, P < 0.0001). However, our results suggest that the preexistence of secondary mutations in protease genetic background may have implications in HIV-1 fitness evolution and virologic response to antiretroviral therapy.
authors.affiliation: Department of Virology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Weber
authors.forename: Hector R
authors.initials: HR
authors.lastname: Rangel
authors.forename: Bikram
authors.initials: B
authors.lastname: Chakraborty
authors.forename: Michael L
authors.initials: ML
authors.lastname: Marotta
authors.forename: Hernan
authors.initials: H
authors.lastname: Valdez
authors.forename: Katrien
authors.initials: K
authors.lastname: Fransen
authors.forename: Eric
authors.initials: E
authors.lastname: Florence
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Connick
authors.forename: Kimberly Y
authors.initials: KY
authors.lastname: Smith
authors.forename: Robert L
authors.initials: RL
authors.lastname: Colebunders
authors.forename: Alan
authors.initials: A
authors.lastname: Landay
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kuritzkes
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
authors.forename: Guido
authors.initials: G
authors.lastname: Vanham
authors.forename: Miguel E
authors.initials: ME
authors.lastname: Quiñones-Mateu
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D019380:Anti-HIV Agents / Q000627:therapeutic use; D001483:Base Sequence; D018791:CD4 Lymphocyte Count; D015752:Genes, env; D015751:Genes, pol; D014644:Genetic Variation; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000145:classification / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000097:blood
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D012367:RNA, Viral