title: Increasingly successful highly active antiretroviral therapy delays the emergence of new HLA class I-associated escape mutations in HIV-1.
abstract: BACKGROUND
  HLA class I-restricted cytotoxic T lymphocytes and highly active antiretroviral therapy (HAART) exert strong selective pressures on human immunodeficiency virus type 1 (HIV-1), leading to escape mutations compromising virologic control. Immune responses continue to shape HIV-1 evolution after HAART initiation, but the extent and rate at which this occurs remain incompletely quantified. Here, we characterize the incidence and clinical correlates of HLA-associated evolution in HIV-1 Pol after HAART initiation in a large, population-based observational cohort.
  
  
  METHODS
  British Columbia HAART Observational, Medical Evaluation and Research cohort participants with available HLA class I types and longitudinal posttherapy protease/reverse transcriptase sequences were studied (n = 619; median, 5 samples per patient and 5.2 years of follow-up). HLA-associated polymorphisms were defined according to published reference lists. Rates and correlates of immune-mediated HIV-1 evolution were investigated using multivariate Cox proportional hazard models incorporating baseline and time-dependent plasma viral load and CD4 response data.
  
  
  RESULTS
  New HLA-associated escape events were observed in 269 (43%) patients during HAART and occurred at 49 of 63 (78%) investigated immune-associated sites in Pol. In time-dependent analyses adjusting for baseline factors, poorer virologic, but not immunologic, response to HAART was associated with increased risk of immune escape of 1.9-fold per log(10) viral load increment (P < .0001). Reversion of escape mutations following HAART initiation was extremely rare.
  
  
  CONCLUSIONS
  HLA-associated HIV-1 evolution continues during HAART to an extent that is inversely related to the virologic success of therapy. Minimizing the degree of immune escape could represent a secondary benefit of effective HAART.
authors.affiliation: BC Centre for Excellence in HIV/AIDS, Vancouver, Canada.
authors.forename: David J H F
authors.initials: DJ
authors.lastname: Knapp
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.forename: Sheng Yuan
authors.initials: SY
authors.lastname: Huang
authors.forename: Brian
authors.initials: B
authors.lastname: Wynhoven
authors.forename: Winnie W Y
authors.initials: WW
authors.lastname: Dong
authors.forename: Theresa
authors.initials: T
authors.lastname: Mo
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D001955:British Columbia; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019562:Viral Load; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D054302:pol Gene Products, Human Immunodeficiency Virus