Thesis (PhD)--University of Stellenbosch, 2003. / 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. / AFRIKAANSE OPSOMMING: Die risiko vir menslike immuniteitsgebrek virus tipe-1 (MIV-1) infeksie en die progressietempo
vir ontwikkeling van die verworwe immuniteits gebrek sindroom (VIGS) word
hoofsaaklik deur fn kombinasie van virale eienskappe, immuunfunksie en gasheer
genetiese variasie bepaal. Alhoewel mutasies van die chemokien en chemokien koreseptor
gene en alleliese variasie van die major weefsel-verenigbaarheidskompleks
(MWVK) reeds omvattend bestudeer is, verklaar variasie van hierdie gasheer genetiese
faktore nie noodwendig verskille in vatbaarheid vir MIVNIGS in alle gevalle nie. Hierdie
studie verteenwoordig die eerste analise van nuwe kandidaatgene, geïmpliseer in yster
metabolisme en immuunfunksie in die konteks van MIV-1 siekte in Swart
bevolkingsgroepe. Beide gevalle-kontrole assosiasie-studies en genotipe-fenotipe
korrelasies is uitgevoer om moontlik betekenisvolle verwantskappe met genetiese variante
te bepaal, wat moontlik direk of indirek betrokke mag wees in vatbaarheid vir MIV-1 siekte
in die Suid Afrikaanse populasie.
Genotipering van die solute draer familie 11 lid 1 (SLC11A1), hemochromatose (HFE) en
protein-tirosien fosfatase reseptor-tipe C (PTFRC/CD45) gene is uitgevoer in beide MIVseropositiewe
en MIV-seronegatiewe individue. Daaropvolgend is genotipering van die
menslike leukosien antigeen-B27 (MLA-B27) uitgevoer in MIV-1 geïnfekteerde individue
met bekende siekte-status, om die potensiële impak van gekombineerde genotipes te
bepaal vir verskillende mutasies wat in dieselfde studie populasie geïdentifiseer is.
Voorkeur-assosiasie is nie waargeneem vir enige van die mutasies waarvoor geanaliseer
is in die CCR5, SLC11A1, HFE of CD45 gene nie. Hierdie bevinding is in ooreenstemming
met die onafhanklike rol van MLA-B27 in verwantskap met siekte progressie in MIV-1
geïnfekteerde individue.
Alhoewel die alleelverspreiding van In Afrika-spesifieke mutasie 32A~GI wat in In
eksoniese splytingsdemper-element (ESS-1) van die CD45 geen geïdentifiseer is, nie
statisties betekenisvolle verskille getoon het tussen studiegroepe nie, is die mutasie
oorheersend waargeneem in MIV-1 geïnfekteerde individue met WGO Klas I siektestatus
en stadige progressie na VIGS. Hierdie mutasie was teenwoordig in 35.7% (5/14)
van HIV-seropositiewe individue met WGO Klas I siekte-status, terwyl dit afwesig was in
22 HIV-seropositiewe pasiënte met vinnige siekteprogressie. Hierdie bevinding mag moontlik verband hou met verskille in verhoudings van beide die
CD4+ en CD8+ substelle, soos waargeneem gedurende vloei sitometriese (VAS, FACs)
analise in twee HIV-seropositiewe individue met mutasie 32A---+G, in vergelyking met en
HIV-seropositiewe individu sonder hierdie mutasie.
Analise van die yster-verwante SLC11A 1 en HFE gene het nie betekenisvolle assosiasies
opgelewer met gemodifiseerde risiko vir MIV-1 siekte of progressie na VIGS in die
hoofsaaklik Swart studie-populasie nie. Die effek van die virus op ystermetabolisme is wel
vir die eerste keer op DNS vlak gedemonstreer. Hemoglobien vlakke was betekenisvol
verlaag in beide MIV-seropositiewe (P=O.004) en MIV-seronegatiewe (P=O.02) Swart
individue met die HFE geen IVS3-48C---+G mutasie, in vergelyking met mutasie-negatiewe
individue in beide groepe. Aangesien hierdie effek meer uitgesproke was in MIVgeïnfekteerde
individue as in kontroles, blyk dit dat die teenwoordigheid van die HFE
mutasie die hemoglobienvlakke tot engroter mate beïnvloed weens die akute fase respons
wat verband hou met die virusinfeksie. Hierdie effek kan moontlik toegeskryf word aan
genetiese variasie in ennaasliggende geen wat in aangebore immuniteit betrokke is, heel
moontlik in die MLA gebied van chromosoom 6. Dit wil dus voorkom asof genetiese
variasie in enige van die gasheer molekules betrokke by respons op infeksie kan bydra tot
die kliniese uitkoms.
Die belangrike rol van die veelvuldige gasheer genetiese faktore wat in hierdie studie
bestudeer is, of wat voorheen geïmpliseer is in vatbaarheid vir MIV-1 infeksie en siekte
progressie, het enkomplekse inter-verwantskap tussen gasheer en MIV-1 geopenbaar. In
sommige gevalle is die siekte-proses na MIV-1 infeksie afhanklik van gekombineerde
effekte van verskillende mutasies in dieselfde individu, terwylonafhanklike effekte van
spesifieke gene tesame met omgewings-invloede uiteenlopende kliniese uitkomste in
ander mag verklaar.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/53502 |
| Date | 12 1900 |
| Creators | Pretorius, Gideon Stephan |
| Contributors | Kotze, Maritha J., De Jong, Geertje, Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Obstetrics and Gynaecology . |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | Unknown |
| Type | Thesis |
| Format | 184 p. : ill. |
| Rights | Stellenbosch University |
Page generated in 0.0028 seconds