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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Available from: Truong Xuan Lien, Oct 06, 2015
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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.
    BMC Infectious Diseases 08/2013; 13(1):405. DOI:10.1186/1471-2334-13-405 · 2.61 Impact Factor
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    • "In our study, we demonstrated the positive impact of previously activated, memory-type NK cells in mice persistently infected with mCMV on the priming of retrovirus-specific CD8 T cells. In high-risk HIV-exposed seronegative individuals, an increased NK cell activity has been found, indicating that NK cells might also be involved in the resistance against primary HIV-1 infection [39,40]. "
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    ABSTRACT: Background Co-infection of HIV patients with cytomegalovirus (CMV) is associated with enhanced AIDS progression and CMV end-organ diseases. On the other hand, persistent CMV infection has recently been shown to decrease tumor relapse and protect against lethal bacterial infection. The influence of persistent CMV on the outcome of an acute retroviral superinfection is still unknown. Results Here we show that a persistent murine CMV (mCMV) infection surprisingly confers higher resistance to a primary Friend retrovirus infection (FV) of mice. Decreased FV titers and augmented FV-specific CD8 T-cell responses were found in mCMV infected mice during primary FV superinfection. NK cells produced higher amounts of IFNgamma after FV infection of persistently mCMV infected mice suggesting that these cells were involved in the ‘protective’ effect. Depletion of NK1.1+ cells or neutralization of IFNgamma during FV superinfection abrogated the mCMV-mediated effect. Conclusion Our data demonstrate for the first time that a persistent CMV infection induces long-lasting NK cell responses that can enhance immunity to primary retroviral infections. To our knowledge, studies investigating primary HIV infection have not analyzed the role of the CMV seropositivity in these patients. Our observations suggest that NK cells in CMV seropositive individuals might contribute to the control of primary HIV infection.
    Retrovirology 06/2013; 10(1):58. DOI:10.1186/1742-4690-10-58 · 4.19 Impact Factor
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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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    ABSTRACT: Class I HLA's polymorphism has hampered CTL epitope mapping with laborious experiments. Objectives are 1) to evaluate the novel in silico model in predicting previously reported epitopes in comparison with existing program, and 2) to apply the model to predict optimal epitopes with HLA using experimental results. We have developed a novel in silico epitope prediction method, based on HLA crystal structure and a peptide docking simulation model, calculating the peptide-HLA binding affinity at four amino acid residues in each terminal. It was applied to predict 52 HIV best-defined CTL epitopes from 15-mer overlapping peptides, and its predictive ability was compared with the HLA binding motif-based program of HLArestrictor. It was then used to predict HIV-1 Gag optimal epitopes from previous ELISpot results. 43/52 (82.7%) epitopes were detected by the novel model, whereas 37 (71.2%) by HLArestrictor. We also found a significant reduction in epitope detection rates for longer epitopes in HLArestrictor (p = 0.027), but not in the novel model. Improved epitope prediction was also found by introducing both models, especially in specificity (p<0.001). Eight peptides were predicted as novel, immunodominant epitopes in both models. This novel model can predict optimal CTL epitopes, which were not detected by an existing program. This model is potentially useful not only for narrowing down optimal epitopes, but predicting rare HLA alleles with less information. By introducing different principal models, epitope prediction will be more precise.
    PLoS ONE 07/2012; 7(7):e41703. DOI:10.1371/journal.pone.0041703 · 3.23 Impact Factor
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