Vertical T cell immunodominance and epitope entropy determine HIV-1 escape
Michael K.P. Liu, … , Andrew McMichael, Nilu Goonetilleke
Michael K.P. Liu, … , Andrew McMichael, Nilu Goonetilleke
Published December 10, 2012
Citation Information: J Clin Invest. 2013;123(1):380-393. https://doi.org/10.1172/JCI65330.
View: Text | PDF
Research Article AIDS/HIV

Vertical T cell immunodominance and epitope entropy determine HIV-1 escape

Abstract

HIV-1 accumulates mutations in and around reactive epitopes to escape recognition and killing by CD8+ T cells. Measurements of HIV-1 time to escape should therefore provide information on which parameters are most important for T cell–mediated in vivo control of HIV-1. Primary HIV-1–specific T cell responses were fully mapped in 17 individuals, and the time to virus escape, which ranged from days to years, was measured for each epitope. While higher magnitude of an individual T cell response was associated with more rapid escape, the most significant T cell measure was its relative immunodominance measured in acute infection. This identified subject-level or “vertical” immunodominance as the primary determinant of in vivo CD8+ T cell pressure in HIV-1 infection. Conversely, escape was slowed significantly by lower population variability, or entropy, of the epitope targeted. Immunodominance and epitope entropy combined to explain half of all the variability in time to escape. These data explain how CD8+ T cells can exert significant and sustained HIV-1 pressure even when escape is very slow and that within an individual, the impacts of other T cell factors on HIV-1 escape should be considered in the context of immunodominance.

Authors

Michael K.P. Liu, Natalie Hawkins, Adam J. Ritchie, Vitaly V. Ganusov, Victoria Whale, Simon Brackenridge, Hui Li, Jeffrey W. Pavlicek, Fangping Cai, Melissa Rose-Abrahams, Florette Treurnicht, Peter Hraber, Catherine Riou, Clive Gray, Guido Ferrari, Rachel Tanner, Li-Hua Ping, Jeffrey A. Anderson, Ronald Swanstrom, Myron Cohen, Salim S. Abdool Karim, Barton Haynes, Persephone Borrow, Alan S. Perelson, George M. Shaw, Beatrice H. Hahn, Carolyn Williamson, Bette T. Korber, Feng Gao, Steve Self, Andrew McMichael, Nilu Goonetilleke

×

Figure 1

Shifting immunodominance of CD8+ T cell responses induced in early HIV-1 infection.

Options: View larger image (or click on image) Download as PowerPoint
Shifting immunodominance of CD8+ T cell responses induced in early HIV-1...
Subject CH131 was detected in acute HIV-1 infection (Fiebig stages I/II), just prior to peak viremia. HIV-1–specific CD8+ T cell responses in PBMCs were mapped using ex vivo IFN-γ ELISpot against autologous, overlapping peptides spanning the subject’s T/F virus (solid colored lines). Distinct CD8+ T cell immunodominance was observed as early as peak viremia (red dotted line). See inset for greater detail. Above the panel, the blue text indicates the days from Fiebig stages I/II when SGA sequencing was performed. Sequence at day 0 was used to deduce the T/F and subsequent sequencing used to track emerging ns mutations in the virus population. Below this text, colored bars represent the changes in the epitope sequence of the corresponding (color-matched) T cell response, with black vertical lines showing days to 50% T/F virus sequence. As the virus escapes, T cell responses often decline, after which new or subdominant T cell responses become immunodominant. The HXB2 location of each reactive peptide epitope and, if known, the HLA restriction is identified to the left of the bar. A positive T cell response required a background subtracted response of >30 SFU per million PBMCs and >4× background.