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

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 (B57, B58 : 01 and B81) 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.