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The Multiple Roles of Hla in Hiv Immunity and Treatment THE MULTIPLE ROLES OF HLA IN HIV IMMUNITY AND TREATMENT Shayne Loubser A thesis submitted to the faculty of Health Sciences, School of Pathology, University of Witwatersrand, Johannesburg, South Africa in fulfilment of the requirements for the Degree of Doctor of Philosophy in Virology i DECLARATION I, Shayne Loubser, hereby declare that: a) The research reported in this thesis, except where otherwise indicated is my original work. b) This thesis has not been submitted for any degree or examination to any other University c) This thesis does not contain other people’s data, pictures, graphs or information, unless specifically stated as being of sourced from other people. d) This thesis does not contain another person’s writing, unless specifically acknowledged as being sourced from other researchers. Where other written sources have been quoted, then their words have been re-written but the general information attributed to them has been referenced. e) Where I have reproduced a publication of which I am an author or co-author, I have indicated in detail which part of the publication was written by myself alone and have fully referenced such publications. f) This thesis does not contain text, graphics or tables copied and pasted from the internet, unless specifically acknowledged, and the source being listed in the thesis. Signed__________________ Date___________________________ ii DEDICATION I dedicate this manuscript to my son, Liam Shaun Loubser (born 16 September 2002) Walk the path of Science, but don’t be afraid to stop and admire the flowers iii ACKNOWLEDGEMENTS To the study participants, healthy or bearing the burden of HIV-1, my deepest thanks to you for allowing me the opportunity to present this work. This work is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and the National Research Foundation of South Africa. Student support was received from the Poliomyelitis Research Foundation (PRF). Student and project support was received from the Kwa-Zulu Natal Research Institute for Tuberculosis and HIV (K-RITH). To my supervisor, Prof. Caroline T. Tiemessen, thank you for adopting me as your student and for living up to all expectations as a committed, resourceful, capable and approachable mentor. A special note of thanks to Prof. Clive M. Gray, Director of Immunopaedia, for nurturing my interest in Immunology and for initiating my PhD aspirations. To my long time friend and colleague, Dr. Maria “Lucia” Paximadis, thank you for being a believer in me and for playing your invaluable part in my scientific journey, “the long, dark road to enlightenment”. To Heather “HH” Hong, “Bellatrix” Picton, Sir Leonard Damelin, Di Schramm and “Sharry” Shalekoff, m y “senior” colleagues, for assistance, support and conversations. To my fellow PhDs, special thanks to Nikki “Nix” Gentle for sharing her work and to “Mama” Ria Lassauniere and Heather “HH” Hong, for student support and counseling. To my colleagues at the laboratory, Avani, “Gemsquash” and Refilwe for spiritual upliftment. Lastly, to the new recruits, Bianca, Yashini, Sizanani and Ntando, thank you for sharing the experience. iv ABSTRACT South Africa has a national HIV -1 prevalence of 12.2% and due to the large population size of 52.9 million, this equates to a 6.5 million people living with HIV-1. The high HIV-1 prevalence has warranted the scaling up of the national antiretroviral treatment program with over 2 million people accessing treatment since 2012. The population of South Africa is genetically diverse and consists of South African Black (SAB), South African Mixed ancestry (SAM), South African Caucasian (SAC) and South African Indian (SAI) populations that constitute 79.8%, 9.0%, 8.7% and 2.5% of the total population. The reasons for the disproportionate HIV-1 prevalence rates estimated for the different populations (15.0%, 3.1%, 0.3% and 0.8% for the SAB, SAM, SAC and SAI populations, respectively) are unknown; however, host genetic differences may be a contributory factor. Human leukocyte antigen (HLA) class I genes play a crucial role in the antiviral innate and adaptive immune response, since HLA class I proteins present antigenic peptides to CD8+ Cytotoxic T cells (CTLs) of the adaptive immune system and are also involved in the innate immune response via interaction with killer-cell immunoglobulin-like receptors (KIRs) expressed by Natural Killer cells (NK cells). Different HLA class I alleles associate with HIV-1 acquisition and disease progression and some alleles can precipitate adverse antiretroviral drug reactions. HLA class I allele frequencies in the SAC and SAB populations are known, however, limited information is available for the SAI and SAB populations. An immunogenetic characterisation study in healthy SAI (n=50) and SAM (n=50) individuals was performed to establish the prevalence of HLA class I alleles and other host genetic factors including CCR5Δ32, KIR genes, HLA- Bw480I/Bw480T/C1/C2 ligands, HLA-B p2 signal peptide variants and HLA-C 3’untranslated region +263 insertion/deletion variants. The results were compared to the available gene frequencies in healthy SAC and SAB populations and as expected the populations showed distinct differences in the prevalence of several of the genes studied. The comparative analyses are presented in Chapter 3. In Chapter 4, a real-time AS-PCR assay was developed to detect specific HLA class I alleles associated with immune hypersensitivity reaction (IHR) to Abacavir (ABC) and Nevirapine (NVP). IHR can be fatal and develops in HLA-B*57:01 carriers exposed to ABC v and in HLA-B*35:05, -C*04 or -C*08 carriers exposed to NVP. SAI and SAM populations were screened for these alleles and the frequencies compared to SAC and SAB populations. HLA-B*57:01 was prevalent in 8.0%, 12.0% and 8.2% of SAM, SAI and SAC individuals, respectively and absent in the SAB population, while HLA-B*35:05 was present in 6.0% and 1.0% in SAM and SAC populations, respectively and absent in SAC and SAB populations. HLA-C*04 was present at frequencies of 22.0%, 24.0%, 18.6% and 23.7% in SAM, SAI, SAC and SAB populations, respectively, while HLA-C*08 was present at frequencies of 10.0%, 8.0%, 6.9% and 10.2% in SAM, SAI, SAC and SAB populations, respectively. The number of HIV-1 infected South Africans potentially at risk of developing ABC IHR and NVP IHR, was estimated at 14,235 and 2,212,700 people, respectively. Since treatment of HIV-1 infected individuals is underway on a large scale in South Africa and both ABC and NVP are in current use, it was concluded that a substantial number of individuals could benefit from a pre-screening test before treatment is started. The possibility that differences in the prevalence of HLA class I genes and other host genetic factors that have been shown associate with HIV-1 acquisition/transmission might influence HIV-1 prevalence rates in the four populations was explored in Chapter 5. Using new data generated for the SAI and SAM populations and available data for the SAC and SAB populations, a cumulative analysis of genes associated with HIV-1 acquisition and viral load setpoint (VLS) was performed and compared between the populations. Significant results regarding HIV-1 acquisition suggested that more SAB individuals may be susceptible compared to SAI individuals (42.8% vs. 14.0%, respectively; p=0.0002), while more SAI individuals may be resistant compared to SAB individuals (68.0% vs. 31.4%, respectively; p<0.0001). Similarly, significant results regarding genotypes associated with VLS suggested that more SAB individuals may have genotypes associated with high VLS compared to SAI individuals (59.7% vs. 30.0%, respectively; p=0.0003), while more SAI individuals may have a genotypes associated with low VLS compared to SAB individuals (48.0% vs. 13.2%, respectively; p<0.0001). Although not statistically significant, SAM and SAC individuals may also be less susceptible and more resistant to HIV-1 infection compared to SAB individuals. More SAM and SAC individuals have overall genotypes associated with a low VLS compared to SAB individuals, but the frequency of SAM and SAC individuals with overall genotypes associated with a high VLS was similar compared to SAB individuals. Based on extrapolation from these data analysed in healthy individuals, it was concluded that host genetic differences may plausibly influence HIV-1 prevalence in the four populations. vi Next we examined the impact of viral mutagenesis on the role of HLA class I molecules in antiviral immunity studied in HIV-1 infected SAB individuals (Chapter 6). Viral evolution in the gag gene was studied in the context of two common HLA class I alleles present in the SAB population, HLA-B*58:01 and -B*58:02, that associate with opposite clinical outcomes. HLA-B*58:01 is a protective allele associated with low viral load and higher CD4+ T cell count. HLA-B*58:01 (n=5) and HLA-B*58:02 (n=13) carriers, classified as progressors due to CD4+ T cell counts declining to <350 cells/µl, were selected for the study. No significant differences were found between the two groups regarding viral load, CD4+ T cell count or rates of CD4+ T cell decline. Sequences of the gag gene were generated from viral RNA extracted from plasma samples at baseline, 6 months and 12 months that were available prior to initiation of treatment. Deduced Gag protein sequences were examined and CTL escape mutations were identified in HLA -B*58:01-restricted epitopes, while no probable HLA-B*58:02-restricted epitopes were identified. Escape mutations in other HLA class I restricted epitopes, compensatory mutations, NK cell escape mutations and mutations associated with reduced TRIM5α sensitivity were detected in both HLA-B*58:01 and HLA-B*58:02 carriers.
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