Early evolution of human leucocyte antigen-associated escape mutations in variable Gag proteins predicts CD4+ decline in HIV-1 subtype C-infected women. (14th January 2017)

• Record Type: Journal Article
• Authors: Chopera, Denis R.; Ntale, Roman; Ndabambi, Nonkululeko; Garrett, Nigel; Gray, Clive M.; Matten, David; Abdool Karim, Quarraisha; Abdool Karim, Salim; Williamson, Carolyn
• Is Part Of: AIDS. Volume 31:Number 2(2017)
• Publication Date: 2017-01-14
• Subjects: CD4+ decline -- cytotoxic T-lymphocyte escape -- disease progression -- Gag -- HLA-associated; AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome; AIDS (Disease); Periodicals; Periodicals; 616.9792005
• DOI: 10.1097/QAD.0000000000001298
• Languages: English
• ISSNs: 0269-9370

Abstract

Abstract : Objective: 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. Methods: 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. Results: 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 (B * 57, B * 58 : 01 and B * 81) expression. Conclusion: 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. Abstract : Supplemental Digital Content is available in the text