Background: Individuals expressing the HLA-B57 allele exhibit slow progression to AIDS and in the majority of such individuals the CTL response is dominated by B57-restricted epitopes. The p24 Gag epitope TSTLQEQIGW is the earliest epitope targeted during primary infection in B57⁺ subjects. We compared recognition of TW10 and autologous viral variants among perinatally HIV-infected children and adult controls.

Methods: We studied 15 perinatally HIV-infected children and 22 HIV-infected adults expressing HLA-B57. Responses to 15 B57-restricted CTL epitopes were assessed by ELISpot and sequencing of autologous virus was performed. Recognition of autologous viral sequence variants was compared by peptide titration in an IFN-g ELISpot, and confirmed using peptide-specific cell lines.

Results: In contrast to the adult cohort in which 78% (n = 9) of acutely infected and 50% (n = 22) of chronically infected subjects recognized the HLA-B57 TW10 epitope, only 1 of 15 children studied exhibited an IFNg response to TW10 (p <0.005). Sequencing of autologous virus from 13 pediatric subjects revealed that all possessed mutations within this epitope, suggesting universal escape from TW10. Surprisingly, the majority of these pediatric subjects demonstrated a robust response to the autologous variant peptide, while recognizing the wild type TW10 epitope weakly or not at all. In each case, the autologous peptide variant was the best recognized. Recognition of the viral escape variant was not seen among HLA-B57⁺ adult subjects. At least three of the pediatric subjects inherited HLA-B57 from their HIV-negative fathers, making it highly unlikely that B57 escape mutations were vertically transmitted at birth. In 2 such children (born to an HIV⁺ B57^- mother and an HIV^-B57⁺ father), longitudinal viral sequencing of the mother and child confirmed that the wild type TW10 epitope was transmitted to the infant and subsequently mutated.  Following this mutation CD8 cells targeting the circulating autologous variant were persistently detected whereas no response to the original TW10 epitope was seen.

Conclusions:  Children appear to be uniquely able to mount a secondary immune response to a viral variant following CTL escape. These findings imply that there is greater plasticity in the immune response of infants and young children, perhaps related to the maturational state of CD8 memory cells or to the relative proportion of naïve T cells available for de novo priming.

Keywords: HIV-specific CTL; viral escape; perinatally-acquired HIV