Natural Killer Cell Responses to HIV-1 Peptides are Associated With More Activating KIR Genes and HLA-C Genes of the C1 Allotype

Abstract

Background What characterizes individuals whose natural killer (NK) cells are able to respond to HIV-1 peptides is not known. Methods The association between NK cell responses and KIR gene profiles and HLA-B and HLA-C alleles was investigated among 76 HIV-1-infected women in South Africa previously categorized as responders (n = 39) or nonresponders (n = 37) to HIV-1 peptide pools in a whole blood intracellular cytokine assay. Viral load was significantly lower and CD4 T-cell counts higher among responders compared with nonresponders (P = 0.023 and P = 0.030, respectively). Results Possession of one HLA-C1 allele associated with increased magnitude of NK cell responses to Env (P = 0.031) and significantly decreased viral load (P = 0.027) compared with its absence. There was a trend to increased possession of KIR2DL3+HLA-C1 in responders (71.8% vs 51.4%, P = 0.098) and decreased possession of KIR2DL3/2DL3+C2C2 (2.6% vs 16.2%, P = 0.053). A total of 64.1% of responders versus 32.4% of nonresponders had 13 or more KIR genes (P = 0.0067). Notably, the 13-KIR gene containing the Bx21 genotype (has eight inhibitory and three activating genes KIR2DS2, 2DS4, 2DS5) showed substantially higher representation among the responders (28.2% vs 2.6%, P = 0.001). A significantly higher proportion of responders had both KIR2DS2 and KIR2DS5 compared with either gene alone (72.4% vs 37%; P = 0.015). At least one HLA-C1 allele together with 13 or more KIR genes was associated with NK cell responsiveness (48.7% vs 13.5%; P = 0.001). Conclusion NK cell responses to HIV-1 peptides are more likely to occur among individuals with a genotype supporting a more activating NK cell phenotype and who possess at least one HLA-C1 allele.

Frequent and Strong Antibody-Mediated Natural Killer Cell Activation in Response to HIV-1 Env in Individuals with Chronic HIV-1 Infection

“…Our studies described above detecting NK cell activation in response to HIV-1 peptides in whole blood are in line with previous reports (9,27,30,31). However, previous studies have come to different conclusions regarding the mechanisms responsible for these HIV-1-specific NK cell responses (27,29). We therefore compared NK cell activation following stimulation with peptide pools in whole blood versus freshly isolated PBMCs in six subjects who demonstrated strong NK cell responses to HIV-1 antigens upon screening and returned for follow-up visits.…”

“…However, some of these two groups have come to different conclusions regarding the mechanisms involved in mediating these peptide-specific NK cell responses, with some groups suggesting that NK cell responses to HIV-1 peptides depend on the presence of antibodies directed against HIV-1 (25, 27) and another group suggesting that KIR and HLA genotypes are most likely involved (29). In line with these previous observations, we demonstrate that NK cells can respond to HIV-1 peptides in a whole-blood assay.…”

“…NK cell responses to HIV-1 peptides have been recently described by different groups studying HIV-1 clade B and clade C in chronically infected individuals (7,8,27,(29)(30)(31). However, some of these two groups have come to different conclusions regarding the mechanisms involved in mediating these peptide-specific NK cell responses, with some groups suggesting that NK cell responses to HIV-1 peptides depend on the presence of antibodies directed against HIV-1 (25, 27) and another group suggesting that KIR and HLA genotypes are most likely involved (29).…”

“…We therefore investigated whether the HLA and KIR genotypes accounted for the differences in individuals with NK cells that responded to HIV-1 peptides (responders), and those that did not (nonresponders), in our cohort, as previously suggested by others (15,18,19,29). However, we observed no significant differences in HLA and KIR genotypes between the two groups after controlling for multiple comparisons (see Table S1 in the supplemental material), suggesting that mechanisms other than KIR and HLA genotypes might account for the differences in NK cell responsiveness observed in this cohort.…”

“…Furthermore, recent studies suggested that these responses are mediated by antibodies (27) and can mediate sufficient immune pressure to drive viral escape by the selection of sequence mutations (8). However, studies by different groups have resulted in different conclusions regarding the precise mechanism by which NK cells recognize HIV-1 antigens and whether these responses are mediated through CD16 or other NK cell receptors, such as killer immunoglobulin-like receptors (KIR) (27,29,30).…”