KIR3DS1/L1 and HLA-Bw4-80I are associated with HIV disease progression among HIV typical progressors and long-term nonprogressors

Abstract

BackgroundNatural killer (NK) cells have emerged as pivotal players in innate immunity, especially in the defense against viral infections and tumors. Killer immunoglobulin-like receptors (KIRs) – an important recognition receptor expressed on the surface of NK cells – regulate the inhibition and/or activation of NK cells after interacting with human leukocyte antigen (HLA) class I ligands. Various KIR genes might impact the prognosis of many different diseases. The implications of KIR-HLA interaction in HIV disease progression remains poorly understood.MethodsHere, we studied KIR genotypes, mRNA levels, HLA genotypes, CD4+ T cell counts and viral loads in our cohort of Human Immunodeficiency Virus (HIV)-infected individuals, a group that includes HIV long-term nonprogressors (LTNPs) and typical progressors (TPs).ResultsWe found that the frequency of KIR3DS1/L1 heterozygotes with HLA-Bw4-80I gene was much higher in LTNPs than in TPs (P = 0.001) and that the KIR3DL1 homozygotes without HLA-Bw4-80I gene had higher viral loads and lower CD4+ T cell counts (P = 0.014 and P = 0.021, respectively). Our study also confirmed that homozygosity for the HLA-Bw6 allele was associated with rapid disease progression. In addition to the aforementioned results on the DNA level, we observed that higher level expression of KIR3DS1 mRNA was in LTNP group, and that higher level expression of KIR3DL1 mRNA was in TP group.ConclusionsOur data suggest that different KIR-HLA genotypes and different levels of transcripts associate with HIV disease progression.

KIR3DL1 and HLA-B Density and Binding Calibrate NK Education and Response to HIV

“…In instances where HLA expression is diminished, including HIV and HSV (25, 26, 73, 74), highly educated NK cells would be expected to mount the most efficient cytotoxic response. In pathologies where HLA expression persists, uneducated NK cells, lacking receptors to self-HLA and therefore refractory to inhibition, mediate superior clinical outcomes (8, 9, 31, 46, 58).…”

Association of KIR3DL1/S1 and HLA-Bw4 with CD4 T cell counts in HIV-infected Mexican mestizos

“…This association was statistically significant when stage A was compared to stages B + C (OR 1.8, 95 % CI 1.1, 3.1; p = 0.026). Contrarily, the percentage of Bw6 +/+ individuals was higher in stages C (57.9 %) and B (66.7 %) in comparison to those in Patients were stratified into one of two categories, those having high median historic CD4 T cell counts (≥500 CD4 T cells/μL) and those having low historic CD4 T cell counts (<500 cells/μL) based on previously proposed criteria (Jiang et al 2013). KIR and HLA carrier frequencies were compared between these two strata, see Table 4.…”

Elite control of HIV: is this the right model for a functional cure?

“…HLA-B*57 is a Bw4 allele, which is a natural ligand for several KIRs including KIR3DS1 and KIR3DL1, and this combination has been associated with delayed progression to AIDS in noncontrollers [31,32]. It is possible that this relationship is explained by linkage disequilibrium with HLA-B alleles, but a previous study found that these KIRs were enriched in a population of LTNPs who did not possess the HLA-B*57 allele [18]. NK cells expressing the KIR3DS1 allele strongly inhibit HIV replication in target cells in vitro and may be a mechanism of elite control apart from its association with HLA-B alleles [33].…”

“…There is an over-representation of certain MHC class 1 alleles in elite controllers, including class I HLA-B*57 and HLA-B*27 alleles [15][16][17]. Enrichment of specific natural killer (NK) cell immunoglobulin-like receptors (KIR) has also been seen in one study of LTNPs [18], although this finding was not seen in a small cohort of elite controllers [19]. These data argue that sustained host immune responses are a mechanism by which virus is controlled in these individuals.…”