Merino Aimee M, Dugast Anne-Sophie, Wilson Craig M, Goepfert Paul A, Alter Galit, Kaslow Richard A, Tang Jianming
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, United States of America.
PLoS One. 2014 Jun 5;9(6):e99353. doi: 10.1371/journal.pone.0099353. eCollection 2014.
KIR2DS4 gene variants encode full-length and truncated protein products, with only the former serving as membrane-bound receptors to activate natural killer (NK) cells. We have previously shown that full-length KIR2DS4 was associated with relatively high viral load and accelerated heterosexual HIV-1 transmission. Our objective here was to provide confirmatory data and to offer new insights about the potential mechanisms.
METHODOLOGY/PRINCIPAL FINDINGS: Mixed models for repeated (longitudinal) outcome measurements on 207 HIV-1 seropositive American youth revealed an association of full-length KIR2DS4 with relatively high viral load and low CD4+ T-cell count (p<0.01 for both). Depending on KIR2DS4 expression (presence or absence) on cell surface, NK cells from 43 individuals with untreated, chronic HIV-1 infection often differed in functional properties, including degranulation and secretion of IFN-γ and MIP-1β. In particular, polyfunctional NK cells were enriched in the KIR2DS4-positive subset.
CONCLUSIONS/SIGNIFICANCE: Full-length KIR2DS4 promotes HIV-1 pathogenesis during chronic infection, probably through the maintenance of an excessively pro-inflammatory state.
KIR2DS4基因变体编码全长和截短的蛋白质产物，只有前者作为膜结合受体激活自然杀伤（NK）细胞。我们之前已经表明，全长KIR2DS4与相对较高的病毒载量和加速异性恋HIV-1传播有关。我们在此的目的是提供确证数据，并对潜在机制提供新的见解。
方法/主要发现：对207名HIV-1血清阳性美国青年进行重复（纵向）结局测量的混合模型显示，全长KIR2DS4与相对较高的病毒载量和低CD4 + T细胞计数相关（两者p<0.01）。根据细胞表面KIR2DS4的表达（存在或不存在），来自43名未经治疗的慢性HIV-1感染者的NK细胞在功能特性上常常有所不同，包括脱颗粒以及IFN-γ和MIP-1β的分泌。特别是，多功能NK细胞在KIR2DS4阳性亚群中富集。
结论/意义：全长KIR2DS4可能通过维持过度促炎状态促进慢性感染期间的HIV-1发病机制。
