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- 2,093 HLA-B*4201+ ART-naive female adults from 5 cohorts with chronic C-clade infection were studied to determine factors controlling immunodominance. Immunodominant hierarchy of response observed across 20 HLA-B*4201-restricted epitopes was not linked to peptide-B*4201 binding affinity or stability. Immunodominance correlated instead with the particular amino acid residues within (TCRβ) TRB sequences. Extreme TCR biases towards generating identical or 'public' epitope-specific TCRs in multiple individuals therefore were statistically the greatest influence upon Immunodomination.
- 13 B*4201+-restricted novel epitopes were identified by EliSpot screening of 181 females with 410 HIV-1 OLPs.
- 11 different public clonotypes were identified and were used by the top 3 ranked immunodominant epitope-specificities.
- 6/10 most immunodominant epitopes were Gag/Pol/Vpr-specific and 100% showed selection pressure on HIV. Of 4 epitopes that were Nef/Vif-specific and among most immunodominant, only 25% i.e one epitope experienced selection pressure in the virus.
- Novel epitope RPGGKKHYM from OLP Gag-3 (EKIRLRPGGKKHYMLKHL) had a targeting frequency of ˜18% of 154 HLA-B*4201+ subjects. Immunodominance rank was 9/20 tested epitopes. Gag RM9-specific responses showed significantly lower median viral loads (VL).
- Gag-RM9-HLA-B*4202's binding affinity, Kd = 7 nM; stability, K1/2 = 6.2h.
- Escape mutations associated with higher VL set points were found in 92% B*4201+ subjects for Gag-RM9. 4 polymorphisms were selected by HLA-B*4201 in this epitope, H28R, H28S, M30R and M30K.
Henrik N Kløverpris, Reuben McGregor, James E. McLaren, Kristin Ladell, Mikkel Harndahl, Anette Stryhn, Jonathan M. Carlson, Catherine Koofhethile, Bram Gerritsen, Can Keşmir, Fabian Chen, Lynn Riddell, Graz Luzzi, Alasdair Leslie, Bruce D. Walker, Thumbi Ndung'u, Søren Buus, David A. Price, and Philip J. Goulder. CD8+ TCR Bias and Immunodominance in HIV-1 Infection. J. Immunol., 194(11):5329-5345, 1 Jun 2015. PubMed ID: 25911754.
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