Spelling suggestions: "subject:"HIV (aboviruses)."" "subject:"HIV (arboviruses).""
81 |
Estimates and projections of HIV and Hepatitis C virus in Australia and the Asia-Pacific regionRazali, Karina, National Centre in HIV Epidemiology & Clinical Research, Faculty of Medicine, UNSW January 2008 (has links)
The use of mathematical models in studying disease epidemics can be diverse, from the focused study of the role of a single determinant of the epidemic, or to the overall estimation of morbidity and mortality. In using simple deterministic models, a balance is struck between biological and social complexities, and the high data input demands of mathematical models. This thesis aims to apply the use of deterministic mathematical models to the studies of HIV and hepatitis C epidemiology in the Asia-Pacific region. In Australia, about 85% of reported HIV cases are among homosexual men. Casual homosexual partnerships made up 40% of incident HIV cases in 1995 increasing to 65% in 2004. In the state of New South Wales, it was estimated that over 7,500 people were living with HIV/AIDS in 2005, increasing to over 10,000 by 2016 with existing levels of intervention. Intervention measures were estimated to have prevented some 44,500 cases, the majority being among injecting drug users through the Needle and Syringe Programmes. Models for the HIV epidemics in developing countries were also developed incorporating multiple routes of HIV transmission. For Papua New Guinea, it was estimated 64,000 people were living with HIV/AIDS in 2005, rising to over 500,000 by 2025 with current levels of intervention. High levels of interventions, in particular increased condom use, will be required to achieve a stabilisation or reduction in HIV prevalence. In East Timor, the HIV epidemic is still in the early stages with 138 people estimated to be living with HIV/AIDS, rising to 5,000 by 2025 with minimal intervention. For HCV, models of the epidemic in Australia showed HCV incidence peaking in 1999, followed by a decline reaching 9,700 incident cases in 2005. Of 197,000 estimated chronic HCV cases in 2005, 58% had stage F 0/1 liver disease, 15% F 2/3 liver disease, and 2% HCV-related cirrhosis. Models estimated 210 and 105 people developed HCV-related liver failure and hepatocellular carcinoma, respectively. Comparisons of modelled HCV long-term sequelae projections with linkage data showed relatively good agreement, despite discrepancies in liver-related deaths. To decrease the number of chronic HCV, at least a tripling of treatment coverage would be required. These models provide estimates of the current levels of epidemics as well as projections of future scenarios under different intervention strategies, which have an important role in the planning of strategies, as well as assessment of previous epidemic conditions.
|
82 |
Biology and molecular biology of new HIV-1 recombinant forms from MalaysiaLau, Katherine Aik Hee. January 2008 (has links)
Thesis (Ph. D.)--University of Sydney, 2009. / Title from title screen (viewed 31 March 2009). Submitted in fulfilment of the of the requirements for the degree of Doctor of Philosophy to the Discipline of Medicine, Faculty of Medicine. Degree awarded 2009; thesis submitted 2008. Includes bibliographical references. Also available in print form.
|
83 |
The structure of susceptibility : a multi-scalar investigation of linkages between economic development, social organization and HIV susceptibility in Sub-Saharan Africa /Shipman, Aimee. January 1900 (has links)
Thesis (Ph. D., Geography)--University of Idaho, December 2008. / Major professor: Harley Johansen. Includes bibliographical references (leaves 193-202). Also available online (PDF file) by subscription or by purchasing the individual file.
|
84 |
Human immunodeficiency virus and public health measures in Thailand and India new and emerging models /Wanglund, Christian Arielle. Unknown Date (has links)
Thesis (M.A.)--State University of New York at Binghamton, Dept. of Anthropology, 2006. / Includes bibliographical references.
|
85 |
Access to HIV treatment for refugees : case study of South Africa and UgandaNjiba, Jessica Tshiosha January 2015 (has links)
Magister Legum - LLM
|
86 |
B lymphocyte activation and exhaustion in chronic HIV : novel surrogate markers of generalised immune activation and selective modulation of aberrant B cell responses using vasoactive intestinal peptide (VIP)Reid, Timothy Dawson 04 1900 (has links)
Thesis (MScMedSc)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Introduction:
Chronic HIV-1 infection is characterized by immune activation and dysregulation of immune
homeostasis, which impacts on multiple immune cell types. The B-cell compartment, which
plays an important role in the producing neutralizing antibodies, is also dysregulated in HIV-
1 infection. In this study we investigated peripheral blood B-cell subset distribution, and
changes in expression of cellular activation, inhibition, and apoptosis signaling markers in
both untreated chronic HIV-1 infected individuals and healthy uninfected controls. The
neuropeptide immune modulator, vasoactive intestinal peptide (VIP) is known to selectively
down-regulate activation of CD4+ T-cells in various disease settings including HIV-1,
however to our knowledge, no studies have investigated the effect of VIP inhibition on B-cell
activation.
Materials & Methods:
A total of 21 HIV+ve (CD4 count >250 cells/µl), and 19 HIV-ve individuals were recruited from
the Emavundleni voluntary testing and counseling clinic in Crossroads, Western Province,
South Africa. Whole blood was stained to distinguish B-cell subsets (activated memory (AM:
CD21-CD27+), resting memory (RM: CD21+CD27+), mature naïve (MN: CD21+CD27-), or
tissue-like memory (TLM: CD21loCD27lo). In addition expression of markers of B-cell
activation (CD126, CD86, CD38, CD284, CD287), inhibition (CD72, CD85j, CD300a,
CD305, CD307d), and apoptosis signaling (CD95), was assessed ex vivo by flow cytometry
(BD FACSCanto II). For determination of functional responsiveness isolated B-cells
(RosetteSep, Stemcell Technologies) were cultured for 18h (37°C, 5%CO2) without
stimulation or stimulated with TLR ligands (LPS or R848). Stimulation experiments were also
performed in the presence or absence of VIP.
Results:
Chronic HIV-1 infection affected B-cell subset distribution. The percentage (%) of TLM was
increased by 59.24%, and %RM was decreased by 22.73% (both p<0.01). Total expression
of the VIP receptor VPAC2 was decreased by 47.35% (p=0.0296). Subsets had a mixed
phenotype ex vivo; HIV infection upregulated CD38 (by 59.56%, p=0.0004), CD72 (by
60.70%, p=0.0396), CD307d (by 68.63%, p=0.0015) on AM, while RM B-cells had increased
expression of TLR4 (by 107.04%, p=0.0057) and TLR7 (by 208.14%, p=0.0199). TLM B
cells (i.e. exhausted phenotype) displayed upregulated TLR7 (by 550%, p=0.0128) and
CD307d (by 72.40% p=0.045) expression. MN B-cells had increased CD72 expression (by
70.98%, p=0.0026). R848 upregulated CD86 expression by 42.20% on AM (p<0.01), and by
56.06% on RM B-cells (p<0.01), which was significantly downregulated with VIP inhibition
(both p<0.05). Similarly, CD95 expression on RM, TLM, and MN B-cells increased by
31.10% (p<0.001), 21.46% (p<0.01), and 39.92% (p<0.01) with R848 stimulation
respectively, which was also significantly downregulated with VIP inhibition.
Conclusion:
These data indicate that B-cells in untreated HIV infection display increased levels of
activation, and also the potential for increased susceptibility to apoptosis as evidenced by
increased FAS (CD95) expression. VIP significantly down-regulated markers of activation,
inhibition, and apoptosis signaling. Dysregulation of B-cells is thus apparent in asymptomatic
stable chronic HIV-1 infection, which may impact on both inefficient neutralizing antibody
production and hypergammaglobulinemia. The ability of VIP to prevent stimulationassociated
marker upregulation may indicate that VIP is a potential therapeutic agent. Its
immuno-modulatory properties were demonstrated to limit B-cell hyperactivation, and
selectively down-regulate apoptosis and mark it out for further investigation. / AFRIKAANSE OPSOMMING: Inleiding:
Immunaktivering en ongekoppelde immuun-homeostase is kenmerke van chroniese MIVinfeksie.
Ons het perifere bloed B-sel subgroep-verspreiding, en veranderinge in die
uitdrukking van merkers van aktivering, inhibisie, en apoptose in 'n onbehandelde MIV-1
besmettende groep ondersoek (in vergelyk met 'n gesonde onbesmettende kontrole). Die
immuun-moduleerder, vasoaktiewe intestinale peptied (VIP) is bekend om aktivasie van
geaktiveerde CD4+ T-selle te verminder, maar tot ons kennis, is daar geen studies wat die
effek van VIP-inhibisie op B-sel aktivering ondersoek het, in die konteks van MIV-1 infeksie.
Materiaal & Metodes:
MIV+we individue (CD4-telling >250 selle/µl) , en MIVwe
kontroles is gewerf uit die vrywillige
toetsing en berading Emavundleni kliniek, Crossroads, Westelike Provinsie, Suid-Afrika. Bsel
subgroepe is gedefinieer as geaktiveerde geheue (AM: CD21-
CD27+
), rusende geheue (RM: CD21+
CD27+
), volwasse naïef (MN: CD21+
CD27-
), of weefsel-agtige geheue (TLM:
CD21loCD27lo). Merkers van aktivering (CD126, CD86, CD38, CD284, CD287), inhibisie
(CD72, CD85j, CD300a, CD305, CD307d), en apoptose signalering (CD95) is via
vloeisitometrie (BD FACSCanto II) op B-selle ex vivo en ook op geïsoleerde B-selle
(RosetteSep, Cell Technologies) ondersoek. Vir die bepaling van funksionele responsiwiteit,
geïsoleerde B-selle (RosetteSep, StemCell Technologies) was vir 18h (37°C, 5%CO2)
gekweek, sonder stimulasie of gestimuleer met TLR ligande (LPS of R848). Stimulasie
eksperimente het ook in die teenwoordigheid of afwesigheid van VIP plaasgevind.
Resultate:
Chroniese MIV-1 infeksie het B-sel subset verspreiding geraak. Die persentasie (%) van
TLM is verhoog deur 59,24%, en% RM het met 22.73% afgeneem (beide p <0,01). Totale
uitdrukking van die VIP reseptor VPAC2 het met 47,35% afgeneem (p = 0,0296). Subgroepe
het 'n gemengde ex vivo fenotipe; MIV-infeksie het CD38 (deur 59,56%, p=0,0004), CD72
(deur 60,70%, p=0,0396), CD307d (deur 68,63%, p=0,0015) op AM verhoog, terwyl RM Bselle
het verhoogde uitdrukking van TLR4 (deur 107,04%, p=0,0057) en TLR7 (deur
208,14%, p=0,0199). TLM B-selle (die uitgeputtende fenotiep) het verhoogde TLR7 (deur
550%, p=0,0128) en CD307d (deur 72,40% p=0.045) uitdrukking gewys. MN B-selle het
verhoogde uitdrukking van CD72 (deur 70,98%, p = 0,0026). R848 het CD86 uitdrukking op
AM deur 42,20%, en op RM deur 56,06% toegeneem (beide p <0,01). Dit het met VIP
inhibisie beduidend afgeneem (beide p <0.05). CD95 uitdrukking was soortgelyk verhoog op
RM, TLM, en MN B-selle met 31.10% (p <0.001), 21,46% (p <0,01), en 39,92% (p <0,01)
met R848 stimulasie. Al drie het beduidend afgeneem met VIP inhibisie.
Gevolgtrekking:
Hierdie data dui daarop dat B-selle in onbehandelde MIV-infeksie vertoon verhoogde
aktiveringsvlakke, en ook die potensiaal vir verhoogde vatbaarheid vir apoptose soos bewys
deur verhoogde uitdrukking van FAS (CD95). VIP het beduidend merkers van aktivering,
inhibisie, en apoptose af-gereguleer. Wanfunksie van B-selle is dus in asimptomatiese
stabiele chroniese MIV-1 infeksie duidelik, wat impak kan hê op beide oneffektiewe
neutraliserende teenliggaampie produksie, en hiepergammaglobulinimie. Die vermoë van
VIP stimulasie-verwante merker opregulasie te voorkom kan aandui dat VIP 'n potensiële
terapeutiese agent is. VIP se immuno-moduleerende eiendomme is gedemonstreer om Bsel
hieperaktiveering te beperk, en selektief apoptose afreguleer, en merk dit vir verdere
ondersoek.
|
87 |
A comparative analysis of mathematical models for HIV epidemiologyDe la Harpe, Alana 04 1900 (has links)
Thesis (MSc)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: HIV infection is one of the world’s biggest health problems, with millions of
people infected worldwide. HIV infects cells in the immune system, where it
primarily targets CD4+ T helper cells and without treatment, the disease leads
to the collapse of the host immune system and ultimately death. Mathematical
models have been used extensively to study the epidemiology of HIV/AIDS.
They have proven to be effective tools in studying the transmission dynamics of
HIV. These models provide predictions that can help better our understanding
of the epidemiological patterns of HIV, especially the mechanism associated
with the spread of the disease.
In this thesis we made a functional comparison between existing epidemiological
models for HIV, with the focus of the comparison on the force of infection
(FOI). The spread of infection is a crucial part of any infectious disease, as
the dynamics of the disease depends greatly on the rate of transmission from
an infectious individual to a susceptible individual.
First, a review was done to see what deterministic epidemiological models
exist. We found that many manuscripts do not provide the necessary information
to recreate the authors’ results and only a small amount of the models
could be simulated. The reason for this is mainly due to a lack of information
or due to mistakes in the article.
The models were divided into four categories for the analysis. On the basis of
the FOI, we distinguished between frequency- or density-dependent transmission,
and as a second criterion we distinguished models on the sexual activity
of the AIDS group. Subsequently, the models were compared in terms of their
FOI, within and between these classes. We showed that for larger populations,
frequency-dependent transmission should be used. This is the case for HIV,
where the disease is mainly spread through sexual contact.
Inclusion of AIDS patients in the group of infectious individuals is important
for the accuracy of transmission dynamics. More than half of the studies
that were selected in the review assumed that AIDS patients are too sick to
engage in risky sexual behaviour. We see that including AIDS patients in the
infectious individuals class has a significant effect on the FOI when the value
for the probability of transmission for an individual with AIDS is bigger than
that of the other classes.
The analysis shows that the FOI can vary depending on the parameter values
and the assumptions made. Many models compress various parameter values
into one, most often the transmission probability. Not showing the parameter
values separately makes it difficult to understand how the FOI works, since
there are unknown factors that have an influence. Improving the accuracy
of the FOI can help us to better understand what factors influence it, and
also produce more realistic results. Writing the probability of transmission
as a function of the viral load can help to make the FOI more accurate and
also help in the understanding of the effects that viral dynamics have on the
population transmission dynamics. / AFRIKAANSE OPSOMMING: MIV-infeksie is een van die wêreld se grootste gesondheidsprobleme, met miljoene
mense wat wêreldwyd geïnfekteer is. MIV infekteer selle in die immuunstelsel,
waar dit hoofsaaklik CD4+ T-helperselle teiken. Sonder behandeling lei die
siekte tot die ineenstorting van die gasheer se immuunstelsel en uiteindelik sy
dood. Wiskundige modelle word breedvoerig gebruik om die epidemiologie van
MIV/vigs te bestudeer. Die modelle is doeltreffende instrumente in die studie
van die oordrag-dinamika van MIV. Hulle lewer voorspellings wat kan help
om ons begrip van epidemiologiese patrone van MIV, veral die meganisme wat
verband hou met die verspreiding van die siekte, te verbeter.
In hierdie tesis het ons ‘n funksionele vergelyking tussen bestaande epidemiologiese
modelle vir MIV gedoen, met die fokus van die vergelyking op die
tempo van infeksie (TVI). Die verspreiding van infeksie is ‘n belangrike deel
van enige aansteeklike siekte, aangesien die dinamika van die siekte grootliks
afhang van die tempo van oordrag van ‘n aansteeklike persoon na ‘n vatbare
persoon.
‘n Oorsig is gedoen om te sien watter kompartementele epidemiologiese modelle
alreeds bestaan. Ons het gevind dat baie van die manuskripte nie die nodige
inligting voorsien wat nodig is om die resultate van die skrywers te repliseer
nie, en slegs ‘n klein hoeveelheid van die modelle kon gesimuleer word. Die
rede hiervoor is hoofsaaklik as gevolg van ‘n gebrek aan inligting of van foute
in die artikel.
Die modelle is in vier kategorieë vir die analise verdeel. Op grond van die
TVI het ons tussen frekwensie- of digtheidsafhanklike oordrag onderskei, en
as ‘n tweede kriterium het ons die modelle op die seksuele aktiwiteit van die
vigs-groep onderskei. Daarna is die modelle binne en tussen die klasse vergelyk
in terme van hul TVIs. Daar is gewys dat frekwensie-afhanklike oordrag
gebruik moet word vir groter bevolkings. Dit is die geval van MIV, waar die
siekte hoofsaaklik versprei word deur seksuele kontak.
Die insluiting van die vigs-pasiënte in die groep van aansteeklike individue
is belangrik vir die akkuraatheid van die oordrag-dinamika van MIV. Meer
as helfte van die uitgesoekte studies aanvaar dat vigs-pasiënte te siek is om
betrokke te raak by riskante seksuele gedrag. Ons sien dat die insluiting van
vigs-pasiënte in die groep van aansteeklike individue ‘n beduidende uitwerking
op die TVI het wanneer die waarde van die waarskynlikheid van oordrag van
‘n individu met vigs groter is as dié van die ander klasse.
Die analise toon dat die TVI kan wissel afhangende van die parameter waardes
en die aannames wat gemaak is. Baie modelle voeg verskeie parameter waardes
bymekaar vir die waarskynlikheid van oordrag. Wanneer die parameter waardes
nie apart gewys word nie, is dit moeilik om die werking van die TVI te verstaan,
want daar is onbekende faktore wat ‘n invloed op die TVI het. Die
verbetering van die akkuraatheid van die TVI kan ons help om die faktore
wat dit beïnvloed beter te verstaan, en dit kan ook help om meer realistiese
resultate te produseer. Om die waarskynlikheid van oordrag as ‘n funksie van
die viruslading te skryf kan help om die TVI meer akkuraat te maak en dit kan
ook help om die effek wat virale dinamika op die bevolkingsoordrag-dinamika
het, beter te verstaan.
|
88 |
The relevance of apoptosis in the pathogenesis of human immunodeficiency virus-1 diseaseCotton, Mark Fredric 12 1900 (has links)
Thesis (PhD)--Stellenbosch University, 2004. / ENGLISH ABSTRACT: A simple and rapid scatter-based flow cytometric assay was developed to detect
apoptosis in CD4+ and CD8+ T cells from a mixed population of cells. The assay was
suitable for children.
Apoptotic PBMCs were confirmed by morphologic assessment in clinical samples
ex vivo and after overnight culture. The scatter-based assay was validated in a number of
ways. Firstly, PBMCs were irradiated with 500 rads and cultured overnight to induce
apoptosis. Thereafter, PBMCs were labeled with a CD4 MAb. CD4+ cells were sorted
into apoptotic and viable populations by scatter characteristics (diminished forward and
increased side scatter). Morphology was assessed by fluorescence microscopy. The
majority of cells with apoptotic scatter characteristics had apoptotic morphology
(chromatin condensation) (80.6%). Ninety-two percent of cells from the viable region had
normal morphology. CD4+ T cell apoptosis measured by scatter was then correlated with
the TdT assay for DNA fragmentation. Lastly, CD4+ T cell apoptosis by scatter and
annexin V uptake were also shown to correlate. In the latter experiments, PBMC
morphology and cell death by trypan blue uptake were studied simultaneously and
confirmed the two flow cytometric assays.
Apoptosis of CD4+ and CD8+ T cells has been shown in PBMCs from HIV infected
adults analyzed after overnight culture. Since cell death may be an artifact of in
vitro culture, and because there is little information on apoptosis in paediatric HIV disease,
I undertook a cross-sectional analysis in PBMCs analyzed immediately ex vivo from HIV infected
children and adults. Patients were studied in Denver, CO, USA. PBMCs from 21 children, 4 adolescents and 9 adults and seronegative age-matched controls were stained
for CD4 and CD8 surface markers. Apoptotic cells were detected in a newly characterized
flow cytometric assay by diminished forward and increased side scatter.
For the scatter assay, PBMCs had been labeled initially by an indirect method
involving an intermediary incubation in the presence of biotinylated MAbs at 37°C for 30
minutes prior to incubating with streptavidin-FITC at 4°C for 20 minutes. Thereafter, the
intermediary incubation step was removed and PBMCs were incubated with PE-conjugated
CD4+ and CD8+ MAbs. Both CD4+ and CD8+ T cell apoptosis appeared
enhanced in the indirect method. The significant differences were abolished after
subtraction of data from simultaneously studied time-matched controls.
CD4+ and CD8+ T cell apoptosis were significantly higher in HIV-infected study
subjects than in simultaneously studied seronegative controls. PBMCs were assayed
immediately ex vivo and after overnight culture after stimulation by an anti-TCR MAb as
well as spontaneously. There was a direct correlation between CD4+ and CD8+ T cell
apoptosis and CD4+ T cell depletion. A significant correlation was also shown between
apoptosis immediately ex vivo and after overnight culture.
I then studied apoptosis in a South African population comprising 18
symptomatic children and 4 seroreverters. CD4+ and CD8+ T cell apoptosis were
significantly higher in symptomatic HIV-1-infected children than in seroreverters and
seronegative controls. CD4+ T cell apoptosis correlated with depletion of CD4+ T cell
percentage in symptomatic HIV-1-infected children. I also noted elevated CD4+ T cell
apoptosis in patients recovering from intercurrent disease in comparison to those who
were either acutely ill or relatively asymptomatic outpatient attendees. Lastly, I compared CD4+ and CD8+ T cell apoptosis in cohorts from Denver, CO
and Tygerberg Children’s Hospital, South Africa. I selected only patients with moderate
or severe HIV infection from both centers. South African patients were significantly
younger, more malnourished, had higher gamma globulin levels and were less likely to
receive ART. CD8+ T cell apoptosis was higher in North American patients suggesting a
possible impairment in CD8+ activity in the South African study subjects. / AFRIKAANSE OPSOMMING: ‘n Eenvoudige en vinnige vloei sitometriese toets is ontwikkel om apoptose aan te
toon vanuit ‘n gemengde populasie selle. Dit moes geskik wees vir kinders van wie net
klein volumes bloed getrek kan word.
Die teenwoordigheid van apoptotiese perifere bloed mononuklere selle (PBMS)
was vasgestel deur morfologiese beoordeling in kliniese monsters ex vivo en na oornag
kultuur. Die ondersoek is gebasseer op die verstrooings patroon van bestraalde PBMS
wat apoptose induseer. PBMS is gemerk met a CD4 MAb. CD4+ selle is gesorteer in
apoptotiese en lewensvatbare populasies deur verstrooings karakteristieke. Morfologie is
beoordeel deur fluoreserende mikroskopie. Die meerderheid van selle met apoptotiese
verstrooings karakteristieke (verminderde voorwaartse en verhoogde sywaartse
verstrooings patroon) het apoptotiese karakteristieke gehad (80.6%). Twee-en-negentig
persent van selle van die lewensvatbare area het normale morfologie gehad. Verstrooings
patroon is ook gekorreleer met die TdT meting vir DNA fragmentasie in kliniese
monsters van MIV-geinfekteerde kinders. Daarna is Annexin V gekorreleer met verstrooings patroon, apoptotiese morfologie en trypan blou opname in selle wat
blootgestel is na verskillende konsentrasies van beauvericin.
Apoptose van CD4+ en CD8+ T-selle is bewys in PBMS van MIV-geinfekteerde
volwassenes na oornag kultuur. Omdat sel dood ‘n artefak van in vitro kultuur kan wees,
en omdat daar min inligting is oor apoptose in paediatriese MIV siekte, het ek onderneem
om ‘n deursnee analiese te doen in PBMS wat onmiddelik ex vivo geanaliseer is vanaf
MlV-geinfekteerde kinders en volwassenes. Die pasiente is bestudeer in Denver,
Colorado, VS A.
PBMS van 22 kinders, 4 adolessente en 9 volwassenes en seronegatiewe
ouderdoms-gepasde kontroles is gekleur vir CD4+ en CD8+ oppervlaksmerkers.
Apoptotiese selle is vloeisitometries aangedui deur verandering in verstrooings patroon.
Vir die doeleindes van die verstrooings assay is die PBMS aanvanklik deur ‘n
indirekte metode gemerk, wat ‘n intermediere inkubasie in die teenwoordigheid van
biogetinileerde MAbs by 37°C vir 30 minute voor dit geinkubeer is met streptavidin-
FITC by 4°C vir 20 minute behels. Daarna is die intermediere inkubasie stap verwyder
en PBMC is geinkubeer met PE - gekonjugeerde CD4+ and CD8+ MAbs. Beide die
CD4+ en CD8+ T-sel apoptose het verhoog voorgekom met die indirekte metode. Die
betekenisvolle verskille het verdwyn na data van gelyktydige tyd - gepaarde kontroles
afgetrek is.
CD4+ en CD8+ T-sel apoptose was betekenisvol hoër in MIV-geinfekteerde
studie gevalle as in gelyktydig bestudeerde seronegatiewe kontroles. PBMS assays is
gedoen onmiddelik ex vivo en na oornag inkubasie na stimulasie deur ‘n anti-TCR MAb,
sowel as spontaan. Daar was ‘n direkte korrelasie tussen CD4+ en CD8+ T sel apoptosis en CD4+ T sel vermindering. ‘n Beduidende korrelasie is ook getoon tussen apoptose
onmiddelik ex vivo en na oornag kultuur.
Daaropvolgend het ek apoptose in ‘n Suid Afrikaanse populasie van 18
simptomatiese kinders en 4 serologies terukerende gevalle bestudeer. CD4+ en CD8+ T
sel apoptose was aansienlik hoër in siptomatiese MIV - 1-geinfekteerde kinders as in die
serologies terukerende gevalle en seronegatiewe kontroles. CD4+ T sel apoptose het
gekorrelleer met vermindering van CD4+ T sel persentasie. Ek het ook opgemerk dat daar
‘n tendens bestaan het tot verhoogde CD4+ T sel apoptose in pasiente wat besig was om
te herstel van bykomende siektes.
Ek het CD4+ en CD8+ T sel apoptose in kohorte van Denver, Colorado en
Tygerberg, Suid Afrika vergelyk. Suid Afrikaanse pasiente was jonger en meer
wangevoed as hul Noord Amerikaanse ewekniee. Suid Afrikaanse kinders het ook meer
gevorderde siekte gehad. Wanneer pasiente gepas is vir die graad van ernstigheid van
siekte en slegs die minder ernstige (B) en ernstige siekte (C) vergelyk is, was CD8+ T sel
apoptose beduidend hoër in Noord Amerikaanse pasiente. Hierdie waarneming
ondersteun die hipotese dat CD 8+ T sel aktiwiteit moontlik onderdruk mag wees in
simptomatiese Suid Afrikaanse MIV-1-geinfekteerde kinders.
|
89 |
Molecular-genetic investigation into host susceptibility and variability to HIV/AIDS in the South African populationPretorius, Gideon Stephan 12 1900 (has links)
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.
|
90 |
Immune regulation in response to mycobacterial infectionCheung, Ka-wa, Benny, 張嘉華 January 2007 (has links)
published_or_final_version / abstract / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy
|
Page generated in 0.0318 seconds