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Title: Killer immunoglobulin-like receptor polymorphism in a Chinese HIV-1 infection cohort
Author: Wang, Linghang
ISNI:       0000 0004 5914 5466
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2014
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Genetic and functional studies have demonstrated that KIR gene polymorphism, including different haplotypes, allelic polymorphisms and different expression levels of KIRs, may all play a part in the association with HIV-1 infection outcome. Currently, there are very few studies focusing on the association between KIR and HIV in the Chinese population. In this project, we started to look at the polymorphism of KIRs in a unique chronic HIV-1 infected cohort (SM cohort), evaluating the impact of KIR and KIR-HLA interactions in terms of HIV-1 infection progression. The SM cohort is unique because the major factors such as viral strain, transmission route and timing of infection, which could affect the natural history of HIV-1, have been narrowly controlled. Through comparison with a healthy control population, some genetic associations were identified. The frequency of KIR2DL3 was lower in the “slow progressors” group; the compound genotype of KIR3DS1+ Bw4 homozygotes was significantly lower in the “slow progressors” group; additionally, group B genotypes (multiple activating genes) were shown to be likely to mount a greater immune pressure on HIV-1. In terms of KIR footprints, several amino acid positions were identified for which the substitution of an amino acid may be ascribed to the immune response from KIR-modulated NK cells rather than from HLA restricted CTL immune pressure. In Chapter 4, we report a novel method to sequence the entire locus of KIR3DL1/S1. Two specific pairs of primers have been successfully designed and tested to amplify KIR3DL1 and KIR3DS1 exclusively. Using this novel sequencing method, we showed the polymorphism of this locus at a 6-digit level. 8 new KIR3DS1 alleles, 12 new KIR3DL1 alleles, 1 new KIR3DL1 gene and 1 new KIR3DS1 gene have been identified in this study. In Chapter 5, we used a valuable acute HIV-1 infection cohort to further study associations between KIRs and the clinical outcomes. It was interesting to find that the frequency of KIR3DS1 was significantly lower in the slow progressors group (31%) than in the acute group (40.7%), which implies that KIR3DS1 plays a role in HIV-1 disease progression. There are two other trends demonstrated in this study. One trend was that positive KIR2DL2 and/or KIR2DS2 (they are in strong linkage disequilibrium with each other) were associated with a higher set point viral load (at 3 month) (p=0.06). Another trend was that KIR3DS1 might have an association with disease progression (p=0.057). Overall, in this study, the role of KIRs and KIR/HLA interactions were evaluated in acute and chronic HIV-1 infection, which has provided important information for further study.
Supervisor: Rowland-Jones, Sarah ; Dong, Tao Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Clinical genetics ; Infectious diseases ; Gene medicine ; Genetics (medical sciences) ; Immunology ; Viruses ; polymorphism ; sequencing ; alleles