AEGiS-15IAC: Children but not adults mount a secondary immune response to a variant HIV-1 epitope following CTL escape.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Children but not adults mount a secondary immune response to a variant HIV-1 epitope following CTL escape.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. MoOrA1053)

Feeney ME, Draenert R, Roosevelt KA, Tang Y, Pfafferott K, Verrill C, Altfeld M, Walker BD, Goulder PJ
Massachusetts General Hospital and Children's Hospital, Boston, United States

BACKGROUND: HLA-B57 is associated with slow progression to AIDS, and the CTL response of most individuals expressing this allele is dominated by B57-restricted epitopes. Gag epitope TSTLQEQIGW (TW10) is the earliest epitope targeted during acute infection in B57+ subjects. We compared recognition of TW10 and autologous viral variants among perinatally HIV-infected children and adult controls.

METHODS: We identified 15 children and 22 adults expressing HLA-B57, and assessed recognition of B57-TW10 and autologous viral sequence variants by peptide titration in an IFNg Elispot. Responses were confirmed by peptide-specific lines.

RESULTS: TW10 was recognized by 83% (n=12) of acutely infected and 50% (n=22) of chronically infected adults, but only 1 of 15 children (p=0.005). Sequencing of viral isolates from 13 children 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, while recognizing the wild-type TW10 epitope weakly or not at all. In each case, the autologous variant was best recognized. Recognition of viral escape variants was rare among 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. In two such children 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 varia nt were persistently detected whereas no response to the original TW10 epitope was demonstrable. Conclusion Children appear to be uniquely able to mount a secondary immune response to a viral variant following CTL escape. These findings imply greater plasticity in the immune response of young children, perhaps related to the maturational state of CD8 memory cells and/or the number of naïve T cells available for de novo priming.

Keywords: AEGIS, HIV-1, Epitopes, Immunologic Memory, HIV Antigens, HIV Infections, HLA-B Antigens, CD8-Positive T-Lymphocytes, HIV Long-Term Survivors, HIV Core Protein p24, HIV-1 Reverse Transcriptase, HIV, Mutation, Acquired Immunodeficiency Syndrome, HLA-B57, Adult, Child, Humans, Infant, immunology, genetics

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MoOrA1053