382 - Abstract (11th CROI)

Session 59 Poster Abstracts
Viral Lineages and Evolution
Wednesday, 1:30 - 3:30 pm
Poster Hall

382

CTL Responses as Major Selective Forces Shaping the Course of HIV-1 Evolution in vivo
Y Liu*¹, H Zhao¹, I Genowati¹, J McNevin², D C Nickle¹, D Shriner¹, K Wong¹, J Cao², K Davis¹, L Rose¹, M J McElrath², and J I Mullins¹
¹Univ. of Washington, Seattle, USA and ²Fred Hutchinson Cancer Res. Ctr., Seattle, WA, USA

Background: CD8⁺ cytotoxic T-lymphocyte (CTL) responses are thought to be critical for controlling HIV-1 infection. CTL escape mutants have been detected during both acute and chronic infection. However, the magnitude of this response, relative to other selective forces that may shape the evolving HIV-1 population, have not been addressed. In this study, we identified sites within the evolving HIV-1 population that were experiencing evolutionary pressure and then compared these sites to epitopes that were recognized or had escaped CTL responses.

Methods: Whole viral genome sequences were obtained from days 8 and 826 after the onset of symptoms and seven targeted gene fragments were obtained at 10 additional time points over the first 2.5 years of infection in a patient from the Seattle Primary Infection Cohort. Approximately 1 month after infection, whole viral genome sequences were obtained from his transmitting partner, who had been HIV-1-positive for 10 years. Computational analyses were used to identify sites having experienced diversifying or directional selection. CTL responses were evaluated by ELISPOT using overlapping peptides generated from HIV-1-LAI and from autologous sequences.

Results: In all, 65 sites were identified as having experienced either diversifying or directional selection; 14 were in confirmed CTL epitopes; 14 others were within ELISpot-positive 15-mer peptides, 3 were in potential helper T-lymphocyte epitopes, and 11 in peptides that remain to be tested. Peptides encompassing the remaining 23 sites, 17 of which were in env, were ELISpot-negative. Two sites predicted to have experienced directional selection but for which the corresponding peptides were ELISpot-negative were found in epitopes predicted for the partner’s HLA type.

Conclusions: Our data demonstrate that CTL responses are one of, if not the major selective force shaping the natural course of HIV-1 evolution, strongly contributing to the positive selective pressure experienced by viral genes other than env.

Keywords: CTL responses; positive selection; HIV-1 evolution