title: Early immune adaptation in HIV-1 revealed by population-level approaches.
abstract: BACKGROUND
  The reproducible nature of HIV-1 escape from HLA-restricted CD8+ T-cell responses allows the identification of HLA-associated viral polymorphisms "at the population level" - that is, via analysis of cross-sectional, linked HLA/HIV-1 genotypes by statistical association. However, elucidating their timing of selection traditionally requires detailed longitudinal studies, which are challenging to undertake on a large scale. We investigate whether the extent and relative timecourse of immune-driven HIV adaptation can be inferred via comparative cross-sectional analysis of independent early and chronic infection cohorts.
  
  
  RESULTS
  Similarly-powered datasets of linked HLA/HIV-1 genotypes from individuals with early (median < 3 months) and chronic untreated HIV-1 subtype B infection, matched for size (N > 200/dataset), HLA class I and HIV-1 Gag/Pol/Nef diversity, were established. These datasets were first used to define a list of 162 known HLA-associated polymorphisms detectable at the population level in cohorts of the present size and host/viral genetic composition. Of these 162 known HLA-associated polymorphisms, 15% (occurring at 14 Gag, Pol and Nef codons) were already detectable via statistical association in the early infection dataset at p ≤ 0.01 (q < 0.2) - identifying them as the most consistently rapidly escaping sites in HIV-1. Among these were known rapidly-escaping sites (e.g. B*57-Gag-T242N) and others not previously appreciated to be reproducibly rapidly selected (e.g. A*31:01-associated adaptations at Gag codons 397, 401 and 403). Escape prevalence in early infection correlated strongly with first-year escape rates (Pearson's R = 0.68, p = 0.0001), supporting cross-sectional parameters as reliable indicators of longitudinally-derived measures. Comparative analysis of early and chronic datasets revealed that, on average, the prevalence of HLA-associated polymorphisms more than doubles between these two infection stages in persons harboring the relevant HLA (p < 0.0001, consistent with frequent and reproducible escape), but remains relatively stable in persons lacking the HLA (p = 0.15, consistent with slow reversion). Published HLA-specific Hazard Ratios for progression to AIDS correlated positively with average escape prevalence in early infection (Pearson's R = 0.53, p = 0.028), consistent with high early within-host HIV-1 adaptation (via rapid escape and/or frequent polymorphism transmission) as a correlate of progression.
  
  
  CONCLUSIONS
  Cross-sectional host/viral genotype datasets represent an underutilized resource to identify reproducible early pathways of HIV-1 adaptation and identify correlates of protective immunity.
authors.forename: Eric
authors.initials: E
authors.lastname: Martin
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Anh Q
authors.initials: AQ
authors.lastname: Le
authors.forename: Denis R
authors.initials: DR
authors.lastname: Chopera
authors.forename: Rachel
authors.initials: R
authors.lastname: McGovern
authors.forename: Manal A
authors.initials: MA
authors.lastname: Rahman
authors.forename: Carmond
authors.initials: C
authors.lastname: Ng
authors.forename: Heiko
authors.initials: H
authors.lastname: Jessen
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: M-J
authors.initials: MJ
authors.lastname: Milloy
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
mesh_terms: D000222:Adaptation, Physiological; D003430:Cross-Sectional Studies; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D057131:Immune Evasion; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D015395:Histocompatibility Antigens Class I; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus