Bibliography / Thesis (MScMedSc (Pathology. Medical Virology))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: In just 25 years since the first reported cases in 1981, the number of Human
Immunodeficiency virus (HIV) infected people has risen to 65 million, and over 25
million have died of acquired immunodeficiency syndrome (AIDS). Sub-Saharan Africa
accounts for 67% of all people living with HIV and 72% of deaths in this region were
AIDS related. Tuberculosis (TB) is one of the most common opportunistic infections in
AIDS patients, particularly in developing countries, where 60 - 70% of TB cases occur
in HIV-1-infected persons. HIV-1 is a high risk factor for the development of TB, the
reactivation of a latent Mycobacterium tuberculosis infection and also progressive TB.
CD8+ Cytotoxic T Lymphocytes (CTL) are pivotal in the host immune response to HIV
infection. CTL are associated with resolution of acute infection and with reduction in
viral load. Studies in macaques and humans indicate the importance of CTL in the
control of HIV infection, where reduction in CD8+ T cell number has been correlated
with progression to AIDS.
The current study was a cross-sectional descriptive study of CD8+ T cells of HIV+ adult
South Africans with and without TB co-infection (TB disease). The cohort consisted of
anti-retroviral therapy (ART) naive patients and all CTL analyses were carried out on
peripheral blood mononuclear cells (PBMCs). A total of 60 South African adults from the
Western Cape were utilized in this study, including 15 healthy controls; 30 HIV+TB-individuals
and 15 HIV+TB+ individuals. Expression of phenotypic, activation and
functional markers were investigated by flow cytometry with the use of fluorochomeconjugated
antibodies. The markers examined included the novel activation marker
CD137, the CTL associated markers Perforin, Granzyme A, CD107a/b, Fas (CD95),
and FasL (CD95L), intracellular cytokines IFN-y and TNF-a and the chronic HIV CTL
dysfunction marker PD-1. HIV infection alone was associated with increased baseline expression of TNF-a,
Perforin, Granzyme A, PD-1, Fas (CD95), and FasL (CD95L), but not CD137(4-1BB) or
IFN-y as compared to uninfected controls. TB co-infection resulted in further increased
baseline expression of TNF-a, perforin, PD-1, FasL (CD95L), as well as increased IFN-y. HIV-1 antigen (gag)-specific stimulation in vitro indicated that in HIV infection was
associated with antigen-specific upregulation of activation and cytotoxicity markers
CD137, IFN-y, TNF-a, Fas, FasL and CD107a/b. In TB co-infection a reduction in
antigen-specific degranulation (CD107a/b up-regulation) and also Fas and FasL
expression was observed.
TB co-infection (in the form of active pulmonary TB) reduced antigen-specific CTL
functional activity, but simultaneously there was an association with increased baseline
PD-1 expression and also cytolytic marker expression (Fas, FasL, TNF-a). These
cytolytic markers could be involved in non-antigen-specific bystander target cell death.
The expression of the co-stimulatory molecule CD137 appeared to correlate with
interferon-y production and levels of degranulation, confirming its usefulness as a
putative surrogate marker of functional responsiveness. These data indicate that in
addition to impacting on CD4 T cell function, TB co-infection leads to higher baseline
expression of CTL-associated markers, but to dysfunctional antigen-specific CTL
responses. / AFRIKAANSE OPSOMMING: Slegs vyf en twintig jaar na die eerste berigte van die menslike immuniteitsgebrekvirus
(MIV) in 1981, het die getal MIV-geinfekteerde individue gestyg tot 65 miljoen en het
meer as 25 miljoen mense alreeds gesterf aan die verworwe immuniteitsgebrek
sindroom (VIGS). Sub Sahara Afrika maak 67% uit van alle HIV gevalle en het `n MIVverwante
doodsyfer van 72%. Een van die algemeenste opportunistiese infeksies in
VIGS pasiente is Tuberkulose (TB). In ontwikkelende lande, veral, kom 60-70% van TB
gevalle voor in MIV-1 geinfekteerde individue. MIV-1 is `n hoe risiko faktor vir die
ontwikkeling van TB, die heraktivering van latente Mycobacterium tuberculosis infeksie
en progressiewe TB.
Die CD8+ sitotoksiese T Limfosiete (STL) se immuun reaksie teen `n MIV infeksie is
noodsaaklik en word geassosieer met `n resolusie van die akute infeksie en `n afname
in viruslading. Studies in die mens en macaque het getoon dat sitotoksiese T limfosiete
belangrik is vir die beheer van MIV infeksies aangesien die afname in CD8+ sel getalle
korreleer met die verloop tot VIGS.
Hierdie deursnit-beskrywende studie het die CD8+ T selle van MIV+ volwasse Suid-Afrikaners, met of sonder`n TB mede-infeksie, ondersoek. STL analise is gedoen op die
perifere bloed mono-nuklere selle (PBMS) van pasiente wat geen teen-retrovirale
terapie (TRT) ontvang het nie. `n Totaal van sestig Suid-Afrikaanse volwassenes van
die Wes-Kaap het deelgeneem aan die studie wat 15 gesonde kontroles; 30 MIV+TBen
15 MIV+TB+ individue ingesluit het. Die uitdrukking van fenotipiese, aktiverings en
funksionele merkers is ondersoek deur middel van vloeisitometrie en fluorochroomgekonjugeerde
teenliggaampies. Laasgenoemde het ingesluit die nuwe
aktiversingsmerker CD 137, die STL geassosieerde merkers Perforien en Gransiem A,
CD 107a/b, Fas (CD95) en FasL (CD95L), intrasellulere sitokiene IFN-y en TNF-a en
PD-1, die merker vir chroniese MIV CTL disfunksie. Daar is gevind dat `n TB mede-infeksie (in die vorm van aktiewe pulmonere TB) die
antigeen-spesifieke STL funksie verlaag en terselftertyd `n verhoging in die uitdrukking
van PD-1 en sitolitiese merkers (Fas, FasL, TNF-a) bewerkstellig. Hierdie sitolitiese
basislyn merkers is moontlik betrokke by die dood van nie-antigeen-spesifieke
omstander teiken selle. Die uitdrukking van die mede-stimulatoriese molekule CD 137
blyk om te korreleer met die produksie van STL IFN-y en die vlakke van degranulasie.
Dit bevestig die merker se bruikbaarheid as `n gewaande surrogaat merker vir
funksionele reaksies. Die data toon verder dat `n TB mede-infeksie nie net `n effek het
op die CD4 T sel funksie nie, dit lei ook tot `n verhoogde basislyn uitdrukking van STLgeassosieerde
merkers, maar met disfunksionele antigeen-spesifieke STL reaksies.
Hierdie studie het bepaal dat `n MIV infeksie verbind word met `n toename in die
basislyn uitdrukking van TNF-a, Perforien, Gransiem A, PD-1, Fas (CD95) en FasL
(CD95L). Dit is egter nie die geval wanneer die uitdrukking van CD 137 (4-1BB) of IFN-y
vergelyk word met nie-geinfekteerde kontroles. `n TB mede-infeksie het `n verdere
toename in die uitdrukking van TNF-a, Perforien, PD-1, FasL (CD95L) getoon, asook `n
verhoging in IFN-y vanaf die basislyn. In vitro MIV-1 antigeen (gag)-spesifieke
stimulasies het aangedui dat `n MIV infeksie met die antigeen-spesifieke op-regulasie
van aktiverings en sitotoksiese merkers CD137, IFN-y, TNF-a, Fas, FasL en CD107a/b
geassosieer word. In `n TB mede-infeksie, is `n verlaging van antigeen-spesifieke
degranulasie (CD 107a/b op-regulasie) asook die uitdrukking van Fas en FasL
waargeneem. / The Poliomyelitis Research Foundation / The National Health Laboratory Service
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/5182 |
| Date | 12 1900 |
| Creators | Pillay, Santhoshan Thiagaraj |
| Contributors | Glashoff, Richard, University of Stellenbosch. Faculty of Health Sciences. Dept. of Pathology. Medical Virology. |
| Publisher | Stellenbosch : University of Stellenbosch |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | xvii, 135 p. : col. ill. |
| Rights | University of Stellenbosch |
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