The role of killer immunoglobulin-like receptors (KIR) and specific human leukocyte antigen (HLA) class I molecules in control of HIV-1 infection

• Main Author: Gentle, Nikki Lynne
• Format: Others
• Language: en
• Published: 2015
• Online Access: http://hdl.handle.net/10539/18671

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg 2015 === The classical human leukocyte antigen (HLA) class I molecules are important regulators of both the adaptive and innate immune responses to viral infection. Genetic variability within these loci determines the nature of the interaction between both the T cell receptor (TCR) on CD8+ T cells and specific killer immunoglobulin-like receptors (KIR) on the surface of natural killer (NK cell). Both of these interactions have previously been demonstrated to be important in determining the course of HIV-1 disease outcome. We therefore examined patterns of genetic variability within both of these complex gene families in individuals from the Black South African population group, contrasting them with genetic variability observed within the corresponding loci in Caucasian South Africans and demonstrated associations between specific genetic variants within the HLA and KIR gene complexes and HIV-1 control in the Black South African population. Examination of genetic diversity within the KIR gene complex in the Black and Caucasian South African population groups revealed these two population groups differed significantly with respect to their KIR2DS1 and KIR3DS1 gene frequencies, as well as with respect to the full-length (KIR2DS4f) and truncated (KIR2DS4v) forms of KIR2DS4. Like KIR2DS1 and KIR3DS1, KIR2DS4v was most frequently observed in the Caucasian population group, while KIR2DS4f was more frequently observed within the Black population group. These differences could be attributed to the different frequency distributions of specific telomeric KIR haplotype motifs within these two population groups. These findings are of particular importance in the South African context, given the associations of KIR2DS4 and KIR3DS1 with both HIV-1 transmission and disease progression. An insertion-deletion (indel) polymorphism within the 3' untranslated region (UTR) of HLA-C has also been shown to be involved in the regulation of HLA-C expression. Individuals who carry a deletion at this position exhibit increased HLA-C expression, which associates with lower viral set point in HIV-1 infected individuals. This 263 indel (rs67384697) is reported to be in strong linkage disequilibrium (LD) with a single nucleotide polymorphism (SNP) 35 kilobases upstream of HLA-C (-35T/C; rs9264942) in Caucasian individuals, making this SNP a potential marker for both HLA-C expression and HIV-1 disease progression. We therefore examined genetic variation within the UTRs of the HLA-C alleles present in Black and Caucasian South Africans and identified two overlapping haplotypes encompassing the 263 indel and another indel at position 230 in both populations, which we propose may act in concert to regulate levels of HLA-C expression. Concomitant evaluation of variability at the -35 SNP revealed this polymorphism to be an inappropriate marker for either indel in these populations. Recently, individual polymorphic amino acids within the classical HLA class I loci, located predominantly within the peptide binding groove, have been shown to be strongly associated with HIV-1 control. We, therefore, examined patterns of genetic variability within and across the HLA class I loci in Black South African HIV-1 progressors and –controllers. Our findings confirmed those from other populations, demonstrating the importance of HLA-B residues 67, 70, 97 and 116 in determining disease outcome, while also identifying additional residues in HLA-A and -B that may potentially contribute to determining differential disease outcome in this population. Variability at these residues likely impacts the specificity of the peptide bound by the HLA molecule, resulting in differential regulation of both cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses. No significant associations were observed between HIV- 1 control and variability within either the HLA-C peptide binding groove or the 3’ UTR. Finally, we examined the role of genetic variability within the KIR gene complex in regulating HIV-1 control by examining patterns of genetic variability within this locus in Black South African HIV-1 progressors and –controllers. We found loss of control to be significantly associated with specific KIR haplotype motifs lacking KIR2DS4 and KIR3DL1, while maintenance of viral control was found to be associated with possession of KIR haplotypes containing the centromeric cB01 motif. Furthermore, elite controllers were more frequently found to be in possession of cB01 motifs containing KIR2DS5, rather than KIR2DS3. In light of the strong linkage disequilibrium observed across this region, KIR2DS3 and KIR2DS5 are thought act as markers for specific allelic variants of the inhibitory receptors KIR2DL1 and KIR2DL2, which are known to mediate differential inhibition of NK cell function. Collectively, these data represent the first comprehensive description of genetic variability within the KIR gene complex in Black South Africans and provide the valuable insights into the role of these receptors in mediating control of HIV-1 infection through interaction with their HLA class I -encoded ligands.