Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa

作者：Angelique Hölzemer, Christina Thobakgale, Camilo Andrés Jiménez Cruz, Wilfredo F. García-Beltrán, Jonathan M. Carlson, Nienke H. van Teijlingen, Jaclyn K. Mann, Manjeetha Jaggernath, Seung-Gu Kang, Christian Körner, Amy W. Chung, Jamie L. Schafer, David T. Evans, Galit Alter, Bruce D. Walker, Philip Goulder, Mary Carrington, Pia Hartmann, Thomas Pertel, Ruhong Zhou, Thumbi Ndung’u, Marcus Altfeld · 发表于：PLoS Medicine · 年份：2015 · DOI：10.1371/journal.pmed.1001900 · 被引用次数：83 · 研究领域：Immune Cell Function and Interaction、HIV Research and Treatment、T-cell and B-cell Immunology

BACKGROUND: Viruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune pressure. METHODS AND FINDINGS: Two sequence mutations in p24 Gag associated with the presence of specific KIR/HLA combined genotypes were identified in HIV-1 clade C viruses from a large cohort of infected, untreated individuals in South Africa (n = 392), suggesting viral escape from KIR+ NK cells through sequence variations within HLA class I-presented epitopes. One sequence polymorphism at position 303 of p24 Gag (TGag303V), selected for in infected individuals with both KIR2DL3 and HLA-C*03:04, enabled significantly better binding of the inhibitory KIR2DL3 receptor to HLA-C*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 ± 10.45 standard deviation [SD] and variant mean 44.67 ± 14.42 SD, p = 0.002). Furthermore, activation of primary KIR2DL3+ NK cells from healthy donors in response to HLA-C*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 ± 0.07 standard error of the mean [SEM] and variant mean 0.63 ± 0.07 SEM, p = 0.012). Structural modeling and surface plasmon resonance of KIR/peptide/HLA interactions in the context of the different ...