Abstract
Background 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 FindingsMixed 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/SignificanceFull-length KIR2DS4 promotes HIV-1 pathogenesis during chronic infection, probably through the maintenance of an excessively pro-inflammatory state.
Highlights
As the primary effector cells mediating innate immunity, natural killer (NK) cells are capable of directly destroying virus-infected cells or releasing cytokines to further modulate adaptive immune responses [1]
The association between full-length KIR2DS4 and relatively low CD4 count in chronically infected American youth corroborates our original data from HIV-1-infected Zambians who lacked CD4 data
Beyond demonstrating a consistent relationship between fulllength KIR2DS4 and enhanced HIV-1 pathogenesis in both Africans infected with HIV-1 subtype C viruses and North Americans infected with HIV-1 subtype B, our ex vivo and in vitro data further point to potential mechanisms for KIR2DS4-related NK cell functions
Summary
As the primary effector cells mediating innate immunity, natural killer (NK) cells are capable of directly destroying virus-infected cells or releasing cytokines to further modulate adaptive immune responses [1]. KIR gene products are stochastically expressed on NK cells and the balance between activating and inhibitory KIRs is critical to cytolysis and other immune function (e.g., cytokine secretion) [6]. Inhibitory KIRs are characterized by long cytoplasmic tails (designated by ‘‘L’’ in the gene name) that carry an immunoreceptor tyrosine-based inhibition motif (ITIM), which interacts with Src homology 2–containing tyrosine phosphatases [7]. Activating KIRs have short (S) cytoplasmic tails that mediates interaction with DAP12, a cytoplasmic protein with an immunoreceptor tyrosine-based activation motif (ITAM) [8]. 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. Our objective here was to provide confirmatory data and to offer new insights about the potential mechanisms
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