title: Early evolution of human leucocyte antigen-associated escape mutations in variable Gag proteins predicts CD4+ decline in HIV-1 subtype C-infected women.
abstract: HIV-1 escape from cytotoxic T-lymphocytes results in the accumulation of human leucocyte antigen (HLA)-associated mutations in the viral genome. To understand the contribution of early escape to disease progression, this study investigated the evolution and pathogenic implications of cytotoxic T-lymphocyte escape in a cohort followed from infection for 5 years.
  
  
  
  Viral loads and CD4 cell counts were monitored in 78 subtype C-infected individuals from onset of infection until CD4 cell count decline to less than 350 cells/μl or 5 years postinfection. The gag gene was sequenced and HLA-associated changes between enrolment and 12 months postinfection were mapped.
  
  
  
  HLA-associated escape mutations were identified in 48 (62%) of the participants and were associated with CD4 decline to less than 350 cells/μl (P = 0.05). Escape mutations in variable Gag proteins (p17 and p7p6) had a greater impact on disease progression than escape in more conserved regions (p24) (P = 0.03). The association between HLA-associated escape mutations and CD4 decline was independent of protective HLA allele (B57, B58 : 01 and B81) expression.
  
  
  
  The high frequency of escape contributed to rapid disease progression in this cohort. Although HLA-adaption in both conserved and variable Gag domains in the first year of infection was detrimental to long-term clinical outcome, escape in variable domains had greater impact.
authors.affiliation: aDivision of Medical Virology, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town and National Health Laboratory Services bCentre for the AIDS Program of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa cDepartment of Biomedical Laboratory Sciences, College of Medicine and Health Sciences, University of Rwanda, Butare, Rwanda dDivision of Immunology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town and National Health Laboratory Services, South Africa.
authors.forename: Denis R
authors.initials: DR
authors.lastname: Chopera
authors.forename: Roman
authors.initials: R
authors.lastname: Ntale
authors.forename: Nonkululeko
authors.initials: N
authors.lastname: Ndabambi
authors.forename: Nigel
authors.initials: N
authors.lastname: Garrett
authors.forename: Clive M
authors.initials: CM
authors.lastname: Gray
authors.forename: David
authors.initials: D
authors.lastname: Matten
authors.forename: Quarraisha
authors.initials: Q
authors.lastname: Abdool Karim
authors.forename: Salim
authors.initials: S
authors.lastname: Abdool Karim
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
mesh_terms: D018791:CD4 Lymphocyte Count; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology*; D005838:Genotype; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D020125:Mutation, Missense; D012641:Selection, Genetic; D019562:Viral Load
chemical_list: D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag