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

Abstract

Background: Natural 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.

Methods: Here, 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).

Results: We 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.

Conclusions: Our data suggest that different KIR-HLA genotypes and different levels of transcripts associate with HIV disease progression.

Figure 1

Association of HLA-B gene with HIV disease progression. Shown are results for the comparisons of the frequency of individuals in various study groups carrying a particular gene. (A) HLA-B gene frequencies among the “high CD4⁺ T cell count” group (light grey) and the “low CD4⁺ T cell count” group (dark grey) are shown. The data show that subjects who had at least one copy of the HLA-Bw4-80I gene had higher CD4⁺ T cell counts (P = 0.015). However, HLA-Bw6 homozygotes had lower CD4⁺ T cell counts (P = 0.023). (B) HLA-B gene frequencies among the “high viral load” group (light grey) and the “low viral load” group (dark grey) are shown. (C) HLA-B allele frequencies among TPs (light grey) and LTNPs (dark grey) are shown. The data show that the proportion of people who had at least one copy of the HLA-Bw4-80I gene was higher among LTNPs than among TPs (P = 0.006). However, the proportion of HLA-Bw6 homozygotes was significantly lower among LTNPs than among TPs (P = 0.014).

Figure 2

KIR3DS1 and KIR3DL1 mRNA levels of different groups. Shown are KIR transcript levels reflecting the relative expression of KIR3DS1 and KIR3DL1 mRNA normalized to GAPDH mRNA in total RNA preparations. Reported values are ratios of KIR and GAPDH concentrations. The lines denoted the medians. (A) KIR3DS1 mRNA levels of the “high CD4⁺ T cell count” group experienced a significant increase compared to KIR3DS1 mRNA levels in the “low CD4⁺ T cell count” group (P = 0.01). (B) KIR3DS1 mRNA levels of the “high viral load” group experienced a significant decrease compared to those in the “low viral load” group (P = 0.006). (C) Levels of KIR3DS1 mRNA in TPs were significantly lower than in LTNPs (P = 0.003). (D) KIR3DL1 mRNA levels in the “high CD4⁺ T cell count” group experienced a significant decrease compared to those in the “low CD4⁺ T cell count” group (P = 0.041). (E) There was no statistical difference between levels of KIR3DL1 mRNA in the “high viral load” group and the “low viral load” group (P = 0.067). (F) KIR3DL1 mRNA levels of TPs were significantly higher than those of LTNPs (P = 0.023). (G) The electrophoretogram was shown to demonstrate the RT-PCR specificity. The PCR reaction only generates a single band. Lane 1, 2 and 3 were for KIR3DL1, and lane 4, 5 and 6 were for KIR3DS1 using different primer concentration.

Figure 3

Correlation between KIR3DS1 mRNA levels and CD4⁺ T cell counts and viral loads among HIV infected individuals. (A) KIR3DS1 mRNA levels positively correlated with CD4⁺ T cell counts (P = 0.022, r = 0.431). (B) KIR3DS1 mRNA levels and viral loads shared no correlation (P = 0.12, r = −0.3). P-values < 0.05 were considered statistically significant.