Distinctive NK-cell receptor repertoires sustain high-level constitutive NK-cell activation in HIV-exposed uninfected individuals

Pasteur Institute, Ho Chi Minh City, Tai nin, Tây Ninh, Vietnam
Blood (Impact Factor: 10.45). 06/2007; 109(10):4296-305. DOI: 10.1182/blood-2006-08-040238
Source: PubMed


We have previously associated high natural killer (NK)-cell activity and protection against HIV-1 infection in Vietnamese exposed uninfected intravascular drug users (EUs). Considering that activating and inhibitory signals sensed by NK-cell receptors regulate NK-cell activation, we performed phenotypic and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) transcript analyses of the NK-cell receptor (NKR) repertoire in 25 EUs, 19 HIV(+) intravenous drug users, and 26 uninfected blood donors. Although NK-cell activation was not linked to a unique NKR repertoire in EUs, various patterns consistent with NK-cell activation were detected in EUs: high KIR3DS1/KIR3DL1 ratio associated with down-regulated KIR3DL1 transcript levels, KIR2DL3(+) low-affinity receptor expansion associated to group HLA-C1 ligand in 2DS2(-)/2DL2(-) EUs, enhanced NKG2C/NKG2A ratio, and increased CD69 expression. Remarkably, EUs exhibited high constitutive degranulation activity in the absence of exogenous stimulation, as shown by the CD107a assay. Furthermore, CD161 expression was increased within the CD107a(+) NK-cell compartment. Our results suggest that in response to viral exposition, particular genetic or regulated features of the NKR repertoire of EUs contribute to their high constitutive NK-cell potential. This might allow NK cells to generate a more rapid and effective immune response to HIV-1, thereby contributing to prevention toward infection.

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    • "Specific primers for the KIR genes of interest were synthesized according to the reported method [22,23]. The glyceraldehyde-3-phosphate dehydrogenase (GADPH) gene was selected as a reference gene to control for different input RNA [24,25]. The primers (forward and reverse sequences) for the KIR3DS1 gene were 5′- CAGCGCTGTGGTGCCTCGC-3′ and 5′-CTGTGACCATGATCACCAT-3′ [22], for the KIR3DL1 gene were 5′-GGACATCGTGGTCACAGGTCC-3′ and 5′- CACTGAGGTCCCAATCAGAATG-3′ [25], for the GAPDH gene were, 5′-GGTGGTCTCCTCTGACTTCAACA-3′ and 5′-GTTGCTGTAGCCAAATTCGTTGT-3′. "
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    ABSTRACT: 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. 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). 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. Our data suggest that different KIR-HLA genotypes and different levels of transcripts associate with HIV disease progression.
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    • "Recent studies have highlighted the importance of HLA-C alleles for HIV viral control, for instance in the population-based study from Africa [27], existence of dominant HLA-C*04-restricted epitopes [28], stimulation of NK cells through HLA-C and Killer-cell Immunoglobulin-like receptors (KIRs) [29], [30], and HLA-C expression control by 35 kb upstream genotype of HLA-C allele and HIV viral control [31]. However, epitope mapping of HLA-C antigens has been held back for several reasons. "
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