Session 60Poster Presentations Primary HIV/SIV Infection Session Day and Time: Tuesday 1:30 - 3:30 pm Room: Hall A
506 Pre-Exisiting HIV-specific CD8+ CTL Fail to Prevent HIV Infection in an HIV Sero-discordant Couple S. Fidler*1, S. Pinheiro2, C. Nicholson1, T. Dong2, H-T. Zhang3, J. Clarke1, R. Phillips3, S. Rowland-Jones2, J. Weber1 1Imperial Coll, London, UK; 2Inst of Molecular Med, Oxford, UK; and 3Dunn Sch, Univ of Oxford, UK
Background: Despite repeated exposure to HIV-1, rare subjects persistently fail to become infected. Resistance to HIV maybe associated with HIV-specific CD8+ cytotoxic lymphocyte (CTL) responses. Therefore, HIV vaccine development has aimed at generating high frequency HIV-specific CD8+ CTLs.
Study Design: Longitudinal prospective cohort study
Methods: Twenty (20) HIV serodiscordant couples were recruited over 3 yrs. Entry criteria included a clear history of sexual exposure to their HIV+ partner, although continued exposure was strongly discouraged. Couples were in (> 3 years) monogamous relationships, sequential sampling was taken from both participants. The highly-exposed persistently seronegative (HEPS) partner was tested on each time point for HIV antibody, RNA by bDNA and by DNA PCR. HIV-specific CD8+ CTL, and CD4+ T-helper responses were elicited using interferon gamma production in ELISpot assays to optimal HIV-derived peptides, in addition to tetramer and intracellular cytokine staining assays. HIV isolated from the HIV+ partner at each time point was sequenced across RT, protease, and gag, characterized for chemokine receptor usage, TCID50, and growth kinetics in the HIV- partners' PBMC compared with unexposed controls. HLA-typing and chemokine polymorphism genotyping was performed.
Results: We demonstrate high frequencies of HIV-specific CTL responses in all HEPS donors on at least one time point. For the one HEPS subject who became infected, repeated exposure to the same virus source resulted in established infection, despite the presence of detectable CD8+ CTL directed against epitopes in gag and nef. This couple shared the B8 HLA genotype. Neither expressed chemokine polymorphisms associated with resistance to infection or delayed disease progression. There was no evidence of transmitted viral immune escape. Sequencing in gag and nef revealed no significant mutations between the donor and recipient sequences, but confirmed the source of viral infection. Seroconversion illness was symptomatic and subsequent disease course for the recipient was rapidly progressing.
Conclusions: All HEPS studied showed evidence of HIV-specific CD8+ CTL at one or more time points. In one case, pre-existing HIV-specific CD8+ CTL directed against 2 epitopes in gag and nef failed to protect against transmission following repeated viral exposure. There was no evidence of transmitted viral immune escape.
