Alter, G. et al. Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J. Exp. Med. 204, 3027-3036

Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, MA 02129, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 12/2007; 204(12):3027-36. DOI: 10.1084/jem.20070695
Source: PubMed


Decline of peak viremia during acute HIV-1 infection occurs before the development of vigorous adaptive immunity, and the level of decline correlates inversely with the rate of AIDS progression, implicating a potential role for the innate immune response in determining disease outcome. The combined expression of an activating natural killer (NK) cell receptor, the killer immunoglobulin-like receptor (KIR) 3DS1, and its presumed ligand, human leukocyte antigen (HLA)-B Bw4-80I, has been associated in epidemiological studies with a slow progression to AIDS. We examined the functional ability of NK cells to differentially control HIV-1 replication in vitro based on their KIR and HLA types. NK cells expressing KIR3DS1 showed strong, significant dose- and cell contact-dependent inhibition of HIV-1 replication in target cells expressing HLA-B Bw4-80I compared with NK cells that did not express KIR3DS1. Furthermore, KIR3DS1+ NK cells and NKLs were preferentially activated, and lysed HIV-1 infected target cells in an HLA-B Bw4-80I-dependent manner. These data provide the first functional evidence that variation at the KIR locus influences the effectiveness of NK cell activity in the containment of viral replication.

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    • "Genetic data has shown a consistent association between certain NK cell Killer Inhibitory Receptor alleles of the KIR3DL1 locus with lower viral loads and/or delayed progression to AIDS [34], [35], [36]. In vitro, NK cells expressing these protective NK alleles have been shown to produce more IFN-gamma [37], have increased poly-functionality [38], [39], and mediate stronger inhibition of HIV-1 replication [40]. The function of both NK cells and plasmacytoid dentritic cells (pDC) is retained in long-term non-progressors and elite controllers [10], [39], [41]. "
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    ABSTRACT: HIV-1 infected viremic controllers maintain durable viral suppression below 2000 copies viral RNA/ml without anti-retroviral therapy (ART), and the immunological factor(s) associated with host control in presence of low but detectable viral replication are of considerable interest. Here, we utilized a multivariable analysis to identify which innate and adaptive immune parameters best correlated with viral control utilizing a cohort of viremic controllers (median 704 viral RNA/ml) and non-controllers (median 21,932 viral RNA/ml) that were matched for similar CD4+ T cell counts in the absence of ART. We observed that HIV-1 Gag-specific CD8+ T cell responses were preferentially targeted over Pol-specific responses in viremic controllers (p = 0.0137), while Pol-specific responses were positively associated with viral load (rho = 0.7753, p = 0.0001, n = 23). Viremic controllers exhibited significantly higher NK and plasmacytoid dendritic cells (pDC) frequency as well as retained expression of the NK CD16 receptor and strong target cell-induced NK cell IFN-gamma production compared to non-controllers (p<0.05). Despite differences in innate and adaptive immune function however, both viremic controllers (p<0.05) and non-controller subjects (p<0.001) exhibited significantly increased CD8+ T cell activation and spontaneous NK cell degranulation compared to uninfected donors. Overall, we identified that a combination of innate (pDC frequency) and adaptive (Pol-specific CD8+ T cell responses) immune parameters best predicted viral load (R2 = 0.5864, p = 0.0021, n = 17) by a multivariable analysis. Together, this data indicates that preferential Gag-specific over Pol-specific CD8+ T cell responses along with a retention of functional innate subsets best predict host control over viral replication in HIV-1 infected viremic controllers compared to chronically-infected non-controllers.
    PLoS ONE 07/2014; 9(7):e103209. DOI:10.1371/journal.pone.0103209 · 3.23 Impact Factor
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    • "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]. Several lines of evidence indicate that NK cell functions during HIV-1 infection vary considerably according to the polymorphic nature of killer cell immunoglobulin receptors (KIR) and their natural ligands, especially human leukocyte antigen (HLA) molecules [2], [3], [4], [5]. 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]. "
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    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 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.
    PLoS ONE 06/2014; 9(6):e99353. DOI:10.1371/journal.pone.0099353 · 3.23 Impact Factor
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    • "In addition, the frequency of KIR3DS1+KIR3DL1− NK cells is increased in HLA-Bw480I+ individuals, both at acute and chronic stages of HIV infection compared to healthy controls (73). The protective effect of KIR3DS1 in HIV infection was further strengthened by evidence that individuals carrying both KIR3DS1 and HLA-Bw480I suppress HIV replication in vitro to a greater extent than NK cells from individuals carrying KIR3DS1 in the absence of HLA-Bw480I, or vice versa, carrying HLA-Bw480I in the absence of KIR3DS1 (56). In addition, purified KIR3DS1+KIR3DL1− NK cells from HLA-Bw480I+ individuals suppressed HIV replication in vitro to a much greater extent than KIR3DS1−KIR3DL1+ and KIR3DS1−KIR3DL1− NK cells (56), indicating that the effect of KIR3DS1 is likely to be mediated by KIR3DS1+ NK cells, and not by KIR3DS1+ T cells. "
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    ABSTRACT: Expression of non-rearranged HLA class I-binding receptors characterizes human and mouse NK cells. The postulation of the missing-self hypothesis some 30 years ago triggered the subsequent search and discovery of inhibitory MHC-receptors, both in humans and mice. These receptors have two functions: (i) to control the threshold for NK cell activation, a process termed "licensing" or "education," and (ii) to inhibit NK cell activation during interactions with healthy HLA class I-expressing cells. The discovery of activating forms of KIRs (aKIR) challenged the concept of NK cell tolerance in steady state, as well as during immune challenge: what is the biological role of the activating KIR, in particular when NK cells express aKIRs in the absence of inhibitory receptors? Recently it was shown that aKIRs also participate in the education of NK cells. However, instead of lowering the threshold of activation like iKIRs, the expression of aKIRs has the opposite effect, i.e., rendering NK cells hyporesponsive. These findings may have consequences during NK cell response to viral infection, in cancer development, and in the initial stages of pregnancy. Here we review the current knowledge of activating KIRs, including the biological concept of aKIR-dependent NK cell education, and their impact in health and disease.
    Frontiers in Immunology 04/2014; 5:184. DOI:10.3389/fimmu.2014.00184
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