TY - JOUR
T1 - HLA-B*14:02-restricted Env-specific CD8+ T-cell activity has highly potent antiviral efficacy associated with immune control of HIV infection
AU - Leitman, Ellen M.
AU - Willberg, Christian B.
AU - Tsai, Ming Han
AU - Chen, Huabiao
AU - Buus, Søren
AU - Chen, Fabian
AU - Riddell, Lynn
AU - Haas, David
AU - Fellay, Jacques
AU - Goedert, James J.
AU - Piechocka-Trocha, Alicja
AU - Walker, Bruce D.
AU - Martin, Jeffrey
AU - Deeks, Steven
AU - Wolinsky, Steven M.
AU - Martinson, Jeremy
AU - Martin, Maureen
AU - Qi, Ying
AU - Sáez-Cirión, Asier
AU - Yang, Otto O.
AU - Matthews, Philippa C.
AU - Carrington, Mary
AU - Goulder, Philip J.R.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B*14, which protects against HIV disease progression, but the immunodominant HLA-B*14-restricted anti-HIV response is Env specific (ERYLKDQQL, HLA-B*14-EL9). A subdominant HLA-B*14-restricted response targets Gag (DRYFKTLRA, HLA-B*14-DA9). Using HLA-B*14/peptide-saporin-conjugated tetramers, we show that HLA-B*14-EL9 is substantially more potent at inhibiting viral replication than HLA-B*14-DA9. HLA-B*14-EL9 also has significantly higher functional avidity (P < 0.0001) and drives stronger selection pressure on the virus than HLA-B*14-DA9. However, these differences were HLA-B*14 subtype specific, applying only to HLA-B*14:02 and not to HLA-B*14:01. Furthermore, the HLA-B*14-associated protection against HIV disease progression is significantly greater for HLA-B*14:02 than for HLA-B*14:01, consistent with the superior antiviral efficacy of the HLA-B*14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV.
AB - Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B*14, which protects against HIV disease progression, but the immunodominant HLA-B*14-restricted anti-HIV response is Env specific (ERYLKDQQL, HLA-B*14-EL9). A subdominant HLA-B*14-restricted response targets Gag (DRYFKTLRA, HLA-B*14-DA9). Using HLA-B*14/peptide-saporin-conjugated tetramers, we show that HLA-B*14-EL9 is substantially more potent at inhibiting viral replication than HLA-B*14-DA9. HLA-B*14-EL9 also has significantly higher functional avidity (P < 0.0001) and drives stronger selection pressure on the virus than HLA-B*14-DA9. However, these differences were HLA-B*14 subtype specific, applying only to HLA-B*14:02 and not to HLA-B*14:01. Furthermore, the HLA-B*14-associated protection against HIV disease progression is significantly greater for HLA-B*14:02 than for HLA-B*14:01, consistent with the superior antiviral efficacy of the HLA-B*14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV.
KW - CD8 T cells
KW - HIV
KW - HLA-B14
KW - Immune control
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U2 - 10.1128/JVI.00544-17
DO - 10.1128/JVI.00544-17
M3 - Article
C2 - 28878089
AN - SCOPUS:85032297543
VL - 91
JO - Journal of Virology
JF - Journal of Virology
SN - 0022-538X
IS - 22
M1 - e00544-17
ER -