Viral Adaptation against KIR2D-associated gag Immune Pressure and Their Effect on Clinical Outcome among HIV-1 CRF01_AE-infected Thais
Masahiko Mori*1,2,3, N Wichukchinda4, R Miyahara1, M Yasunami1, and K Ariyoshi1
1Inst of Tropical Med, Nagasaki Univ, Japan; 2Japan Fndn for AIDS Prevention, Tokyo; 3Univ of Oxford, UK; and 4Ministry of Publ Hlth, Nonthaburi, Thailand
Background: Natural killer (NK) cell contribution to HIV viral control through killer-immunoglobulin like receptor (KIR) and their ligand HLA allele combination, then existing of viral adaptation against immune pressure by NK cell also have been reported recently. However, compared to the information of cytotoxic T lymphocyte (CTL) epitopes and their associated mutations, those of HLA-KIR, especially KIR2D, are sparse.
Methods: We recruited 216 HIV-1 CRF01_AE-infected treatment-naïve Thai patients and collected their gag sequence, KIR2D, HLA, and clinical outcome (CD4+ T cell count and viral load) data. Then we statistically analyzed KIR2D-HLA_C-associated gag mutation or preservation sites by Fisher exact test with 95% confidential interval and odds ratio, excluding the sites which were included in previously reported CTL epitopes to avoid overestimation; CD4+ T cell count and viral load difference between associated site positives and negatives by Mann-Whitney U test; and associated sites number in individual and clinical outcome association by Kruskal-Wallis test.
Results: Among 216 individuals, their median CD4+ T cell count was 164/µL (range 0 to 1664) and viral load was 5.2 log copies/mL (2.6 to 6.5). About KIR2D and its ligand expression, 2DL2-C1 (28.7%), 2DL3-C1 (94.4%), 2DS2-C1 (34.3%), 2DL1-C2 (27.8%), and 2DS1-C2 (12.0%) were identified. Nineteen KIR2D-HLA_C-associated immune pressure sites in gag were identified. Among them, 5 (2DL2-C1-associated E93X [p = 0.022] and T122X [p = 0.012], 2DL3-C1-associated T115X [p = 0.015], 2DS2-C1-associated M31M [p = 0.037, preserved], and L470X [p = 0.009]) scored significantly higher viral load among their positives. Then the number of 2DS2-C1-associated sites in each individual significantly correlated with CD4+ T cell count negatively (p = 0.027), and with viral load positively (p = 0.010).
Conclusions: Several NK cell-mediated gag immune pressure sites and responsible KIR2D-HLA_C information were identified with significant clinical outcome difference among HIV-1 CRF01_AE-infected Thais. This data proved viral adaptation against immune pressure by NK cell, and will contribute to reveal the mechanism of viral evolution against innate immunity.