title: Impact of HLA selection pressure on HIV fitness at a population level in Mexico and Barbados.
abstract: Previous studies have demonstrated that effective cytotoxic T lymphocyte (CTL) responses drive the selection of escape mutations that reduce viral replication capacity (VRC). Escape mutations, including those with reduced VRC, can be transmitted and accumulate in a population. Here we compared two antiretroviral therapy (ART)-naive HIV clade B-infected cohorts, in Mexico and Barbados, in which the most protective HLA alleles (HLA-B*27/57/58:01/81:01) are differentially expressed, at 8% and 34%, respectively. Viral loads were significantly higher in Mexico than in Barbados (median, 40,774 versus 14,200; P < 0.0001), and absolute CD4(+) T-cell counts were somewhat lower (median, 380/mm(3) versus 403/mm(3); P = 0.007). We tested the hypothesis that the disparate frequencies of these protective HLA alleles would be associated with a higher VRC at the population level in Mexico. Analysis of VRC in subjects in each cohort, matched for CD4(+) T-cell count, revealed that the VRC was indeed higher in the Mexican cohort (mean, 1.13 versus 1.03; P = 0.0025). Although CD4 counts were matched, viral loads remained significantly higher in the Mexican subjects (P = 0.04). This VRC difference was reflected by a significantly higher frequency in the Barbados cohort of HLA-B*27/57/58:01/81:01-associated Gag escape mutations previously shown to incur a fitness cost on the virus (P = 0.004), a difference between the two cohorts that remained statistically significant even in subjects not expressing these protective alleles (P = 0.01). These data suggest that viral set points and disease progression rates at the population level may be significantly influenced by the prevalence of protective HLA alleles such as HLA-B*27/57/58:01/81:01 and that CD4 count-based guidelines to initiate antiretroviral therapy may need to be modified accordingly, to optimize the effectiveness of treatment-for-prevention strategies and reduce HIV transmission rates to the absolute minimum.
  
  
  OBJECTIVE
  Immune control of HIV at an individual level is strongly influenced by the HLA class I genotype. HLA class I molecules mediating effective immune control, such as HLA-B*27 and HLA-B*57, are associated with the selection of escape mutants that reduce viral replicative capacity. The escape mutants selected in infected patients can be transmitted and affect the viral load and CD4 count in the recipient. These findings prompt the hypothesis that the frequency of protective alleles in a population may affect viral set points and rates of disease progression in that population. These studies in Mexico and Barbados, where the prevalence rates of protective HLA alleles are 8% and 34%, respectively, support this hypothesis. These data suggest that antiretroviral therapy (ART) treatment-for-prevention strategies will be less successful in populations such as those in Mexico, where viral loads are higher for a given CD4 count. Consideration may therefore usefully be given to ART initiation at higher absolute CD4 counts in such populations to optimize the impact of ART for prevention.
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom claudia_juarez_m@yahoo.co.uk.
authors.forename: Claudia I
authors.initials: CI
authors.lastname: Juarez-Molina
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Payne
authors.affiliation: Centre for Research in Infectious Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico.
authors.forename: Maribel
authors.initials: M
authors.lastname: Soto-Nava
authors.affiliation: Centre for Research in Infectious Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico.
authors.forename: Santiago
authors.initials: S
authors.lastname: Avila-Rios
authors.affiliation: Centre for Research in Infectious Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico.
authors.forename: Humberto
authors.initials: H
authors.lastname: Valenzuela-Ponce
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Adland
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
authors.forename: Ellen
authors.initials: E
authors.lastname: Leitman
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
authors.forename: Jacqui
authors.initials: J
authors.lastname: Brener
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenchhoff
authors.affiliation: Ladymeade Reference Unit, Queen Elizabeth Hospital, Bridgetown, Barbados.
authors.forename: Songee
authors.initials: S
authors.lastname: Branch
authors.affiliation: Ladymeade Reference Unit, Queen Elizabeth Hospital, Bridgetown, Barbados.
authors.forename: Clive
authors.initials: C
authors.lastname: Landis
authors.affiliation: Centre for Research in Infectious Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Reyes-Teran
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Goulder
mesh_terms: D000328:Adult; D001460:Barbados; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D008297:Male; D008800:Mexico; D008875:Middle Aged; D044469:Racial Groups / Q000235:genetics*; D019562:Viral Load; D014779:Virus Replication; D055815:Young Adult
chemical_list: D015235:HLA-B Antigens