Doctoral Degrees (Obstetrics and Gynaecology)

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Browsing Doctoral Degrees (Obstetrics and Gynaecology) by browse.metadata.advisor "De Jong, Geertje"

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    Molecular-genetic investigation into host susceptibility and variability to HIV/AIDS in the South African population
    (Stellenbosch : Stellenbosch University, 2003-12) Pretorius, Gideon Stephan; Kotze, Maritha J.; De Jong, Geertje; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Obstetrics and Gynaecology .
    ENGLISH ABSTRACT: The risk of human immunodeficiency virus type-1 (HIV-1) infection and rate of progression towards development of the acquired immunodeficiency syndrome (AIDS) is determined by a combination of viral characteristics, immune function and host genetic variation. Although mutations of the chemokine and chemokine co-receptor genes and allelic variation of the major histocompatibility complex (MHC) have been studied extensively, variation in these host genetic factors does not explain the differences in HIV/AIDS susceptibility in all cases. This study represents the first analysis of new candidate genes implicated in iron metabolism and immune function in relation to HIV-1 disease in the African context. Both case-control association studies and genotype-phenotype correlations were performed to determine the potential functional significance of genetic variants that may be involved, either directly or indirectly, in susceptibility to HIV-1 disease in the South African population. Genotyping was performed to identify potentially important polymorphisms in the solute carrier family 11 member 1 (SLC11A 1), haemochromatosis (HFE) and protein-tyrosine phosphatase receptor-type C (PTPRC/CD45) genes in HIV-seropositive versus HIVseronegative individuals. This was followed by HLA-B27 genotyping in HIV-1 infected individuals with known disease status to determine the potential impact of combined genotypes for different mutations identified in the same study cohort. Preferential association with any of the mutations screened for in the CCR5, SLC 11A1, HFE or CD45 genes were not detected in HLA-B27 positive individuals identified. These findings were in accordance with the independent protective role of HLA-B27 in relation to disease progression in HIV-1 infected individuals. Although differences in allelic distribution were not significant between the study groups, an apparently African-specific mutation 32A~G, identified in an exonic splicing silencer element (ESS-1) of the CD45 gene, appeared to predominate in HIV-1 infected subjects with WHO Class I disease status and slow progression to AIDS. This mutation was present in 35.7% (5/14) of HIV-seropositive individuals with WHO Class I disease status, whilst absent in 22 HIV-seropositive patients with rapid disease progression. This finding may be related to differences in proportions of both CD4+ and CD8+ subsets observed following flow cytometry (FACs) analys.s in two HIV-seropositive individuals with mutation 32A~G, compared with an HIV-seropositive individual without this mutation. Analysis of the iron-related SLC11A1 and HFE genes did not reveal significant associations with modified risk of HIV-1 infection or progression to AIDS in our predominantly African study population. However, the effect of the virus on iron metabolism was demonstrated for the first time at the DNA level. Haemoglobin levels were significantly reduced in both HIV-seropositive (P=O.004) and HIV-seronegative (P=O.02) Black Africans with mutation IVS3-48c~g in the HFE gene, compared with mutationnegative individuals in both groups. Since this effect was more pronounced in HIV-infected individuals compared with controls, presence of the HFE mutation seems to result in an even stronger effect on haemoglobin levels, which may be related to the acute phase response following virus infection. This effect possibly results from genetic variation in a nearby gene involved in innate immunity, most likely in the HLA region on chromosome 6. It therefore seems possible that genetic variation in any of the host molecules involved in response to infection could contribute to clinical outcome. The significance of the multitude of host genetic factors investigated in this study, or previously implicated in susceptibility to HIV-1 infection and disease progression, revealed a complex interrelationship between the host and HIV-1. In some instances the disease process following HIV-1 infection depends on combined effects of different mutations occurring in the same individual, while independent effects of specific genes in conjunction with environmental influences may explain diverse clinical outcomes in others.