Molecular-genetic investigation into host susceptibility and variability to HIV/AIDS in the South African population

[摘要] ENGLISH ABSTRACT:The risk of human immunodeficiency virus type-1 (HIV-1) infection and rate of progressiontowards development of the acquired immunodeficiency syndrome (AIDS) is determinedby a combination of viral characteristics, immune function and host genetic variation.Although mutations of the chemokine and chemokine co-receptor genes and allelicvariation of the major histocompatibility complex (MHC) have been studied extensively,variation in these host genetic factors does not explain the differences in HIV/AIDSsusceptibility in all cases. This study represents the first analysis of new candidate genesimplicated in iron metabolism and immune function in relation to HIV-1 disease in theAfrican context. Both case-control association studies and genotype-phenotypecorrelations were performed to determine the potential functional significance of geneticvariants that may be involved, either directly or indirectly, in susceptibility to HIV-1 diseasein the South African population.Genotyping was performed to identify potentially important polymorphisms in the solutecarrier family 11 member 1 (SLC11A 1), haemochromatosis (HFE) and protein-tyrosinephosphatase receptor-type C (PTPRC/CD45) genes in HIV-seropositive versus HIVseronegativeindividuals. This was followed by HLA-B27 genotyping in HIV-1 infectedindividuals with known disease status to determine the potential impact of combinedgenotypes for different mutations identified in the same study cohort. Preferentialassociation with any of the mutations screened for in the CCR5, SLC 11A1, HFE or CD45genes were not detected in HLA-B27 positive individuals identified. These findings were inaccordance with the independent protective role of HLA-B27 in relation to diseaseprogression 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 silencerelement (ESS-1) of the CD45 gene, appeared to predominate in HIV-1 infected subjectswith WHO Class I disease status and slow progression to AIDS. This mutation waspresent 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 findingmay be related to differences in proportions of both CD4+ and CD8+ subsets observedfollowing flow cytometry (FACs) analys.s in two HIV-seropositive individuals with mutation32A~G, compared with an HIV-seropositive individual without this mutation.Analysis of the iron-related SLC11A1 and HFE genes did not reveal significantassociations with modified risk of HIV-1 infection or progression to AIDS in ourpredominantly African study population. However, the effect of the virus on ironmetabolism was demonstrated for the first time at the DNA level. Haemoglobin levels weresignificantly 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 mutationnegativeindividuals in both groups. Since this effect was more pronounced in HIV-infectedindividuals compared with controls, presence of the HFE mutation seems to result in aneven stronger effect on haemoglobin levels, which may be related to the acute phaseresponse following virus infection. This effect possibly results from genetic variation in anearby 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 inresponse to infection could contribute to clinical outcome.The significance of the multitude of host genetic factors investigated in this study, orpreviously implicated in susceptibility to HIV-1 infection and disease progression, revealeda complex interrelationship between the host and HIV-1. In some instances the diseaseprocess following HIV-1 infection depends on combined effects of different mutationsoccurring in the same individual, while independent effects of specific genes in conjunctionwith environmental influences may explain diverse clinical outcomes in others.

[发布机构] Stellenbosch University