KIR2DS4 promotes HIV-1 pathogenesis: new evidence from analyses of immunogenetic data and natural killer cell function.

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.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.Full-length KIR2DS4 promotes HIV-1 pathogenesis during chronic infection, probably through the maintenance of an excessively pro-inflammatory state

Associations of full-length <i>KIR2DS4</i> gene with longitudinal viral load (VL) and CD4⁺ T-cell (CD4) count in 207 youth with chronic (seroprevalent) HIV-1 infection.

<p><b>Notes</b>: The overall <i>r</i>² = 0.039 and 0.033 in the multivariable models for VL and CD4 count, respectively. There is no clear interaction between full-length <i>KIR2DS4</i> (gene) and sex (<i>p</i> = 0.274).</p

Linear correlation between HIV-1-related outcomes and KIR2DS4 expression in the absence of antiretroviral therapy.

<p>Results are based on data from 23 subjects with full-length <i>KIR2DS4</i> gene (samples drawn from a single visit). <b>A</b>. Correlation of KIR2DS4 expression with plasma HIV-1 viral load (VL) at the time of sampling. <b>B</b>. Correlation with CD4⁺ T-cell (CD4) count (cells/µL) at the time of sampling. In each panel, solid and dotted lines correspond to the projected trend line and its 95% confidence intervals, respectively (by linear regression).</p

<i>KIR2DS4</i> gene expression and natural killer (NK) cell function in subjects with chronic HIV-1 infection.

<p><b>A</b>. Flow cytometry gating strategy for NK cells. <b>B</b>. Staining of membrane-bound KIR2DS4 on cells derived from subjects with full-length <i>KIR2DS4</i> gene (g+), to facilitate the sorting of two populations positive (p+) or negative (p−) for the gene product. <b>C</b>. Staining of membrane-bound KIR2DS4 on cells derived from subjects with truncated KIR2DS4 gene only, i.e., negative for full-length <i>KIR2DS4</i> gene and gene product (g−/p−). <b>D</b>. Percentage of NK cells expressing KIR2DS4 before and after stimulation with HLA-deficient target cells (K562 and 221). <b>E</b>. Distribution of NK cell subsets among 43 subjects with and without the full-length <i>KIR2DS4</i> genotype. <b>F–H</b>. Representative results for staining cell surface CD107a (lysosomal-associated membrane protein 1) and intracellular IFN-γ or MIP-1β before (red) and after (blue) stimulation with K562 cells. In <b>D</b> and <b>E</b>, the horizontal bars connected by a vertical line correspond to the median and interquartile range.</p

Characteristics of two study populations with longitudinal and cross-sectional data, respectively.

<p><b>Notes</b>: HIV-1 viral load (VL) in plasma (RNA copies/mL) and CD4⁺ T-cell (CD4) count in peripheral blood (cells/µL) are the two outcomes (see text). The two subgroups with existing PBMC samples share similar features at study entry (<i>p</i>>0.45 in all comparisons).</p

Assessment of polyfunctional profile of natural killer (NK) cells during chronic HIV-1 infection.

<p>Results are obtained after stimulation with K562 cells and subtraction of background staining. <b>A</b>. Functional properties of NK cells grouped by presence (+) and absence (−) of full-length <i>KIR2DS4</i> (g = gene) and membrane-bound KIR2DS4 receptor (p = product), as gauged by production of CD107a, IFN-γ and MIP-1β. <b>B</b>. Summary data for mono- and poly-functional NK cells. <b>C</b>. Distribution of polyfunctional NK cells. <b>D</b>. Distribution of NK cells NK cells producing MIP-1β alone. The g+/p+ and g+/p− cells are derived from individuals carrying full-length <i>KIR2DS4</i> gene, while the g−/p− NK cells are derived from individuals with truncated <i>KIR2DS4</i> gene only. In <b>C</b> and <b>D</b>, the horizontal bars connected by a vertical line correspond to the median and interquartile range.</p