Circulating monocytes have the capacity to mature into either macrophages or dendritic cells in tissue, both of which play important roles in the induction and effector phase of immune response. In TB, the macrophages are the central player in the host-bacteria interaction as the main mycobacterial reservoir. In HIV disease, monocyte lineage cells are one of the two main cell types (along with CD4+ T-cells) in sustaining intracellular HIV infection. Monocytes are heterogeneous population with three functionally distinct subsets namely classical, intermediate and non-classical monocytes. The three subsets exist in a continuum, and have a certain plasticity or flexibility to develop into multiple roles depending on the local and tissue environment. In the current study we sought to evaluate the frequencies of these three subsets in participants with TB, HIV and TB/HIV co-infection. While previous studies had shown that the intermediate and non-classical monocyte subsets were elevated relative to classical monocytes, very little had been done in these disease groups regarding more comprehensive characterization of these subsets. In particular, we wished to quantitate the expression of multiple sets of cell surface and intracellular molecules of high relevance using multi-parameter flow cytometry from a functional point of view. In publication I, we evaluated Toll-like receptors (TLRs) expression in each of the study cohorts. TLRs are vital pattern recognition receptors by monocyte lineage cells and signal the induction of crucial functions. We focused on three such TLRs (TLR2, TLR4 and TLR9) which have been shown to be involved in many monocyte lineage cell interactions with mycobacterial and HIV infections. We observed enhanced expression of TLR2 and TLR4, but not TLR9 in TB and HIV. TLR4 was particularly high in patients with TB, but also in HIV. We observed comparable increase of TLR4 irrespective of monocyte subset. However, TLR2 expression exhibited a different pattern. Levels among the most prominent classical monocyte subsets were identical in all four cohorts, healthy controls (HC), HIV, TB, and TB/HIV co-infection. In contrast, TLR2 expression was significantly elevated in both participants with HIV and TB, but not with participants with TB/HIV co-infection in the intermediate monocyte subset. We also observed correlations between TLRs and plasma cytokines that were disease and TLR specific. In publication II, we observed elevated chemokine receptors (CRs) expression which above healthy controls and exhibit a pattern of disease preference. Thus, CCR2 and CX3CR1 were the highest in participants with TB, followed by HIV and TB/HIV co-infection, whereas CCR4 and CCR5 were highest in participants with HIV, and less elevated in TB. CCR2 and CX3CR1 are critical for migration of monocytes to sites of TB infection, as determined by murine models. CCR4 and especially CCR5 have been implicated in migration of cells to distant organs but more as co-receptors for HIV infection. Thus, the observed pattern of CRs expression in these monocytes in different disease states would predict greater availability of these cells or their receptors for interaction with either TB or HIV organisms. From the perspective of the pathogen this would lead to enhanced “substrate”, whereas from the perspective of the host, this could lead to greater immune potential. As a final point, we also observed that the pattern of disease association of CRs was independent of the monocyte subset. In publication III, we explored the expression of Programmed cell death-ligand 1 (PDL1) on the three monocyte subsets. Like many of the other molecules we have addressed in this thesis, PDL1 expression was enhanced in participants with HIV, TB, and TB/HIV co-infection. Among participants with HIV, PDL1 was correlated with HIV-1 viral load. The enhanced expression was apparent in all three subsets, but it was particularly prominent in the intermediate monocyte subset. Moreover, PDL1 expression was the highest in participants with TB/HIV co-infection. The implications behind these observations is that the subset thought to have the greatest potential for T cell antigen presentation had the highest levels of the T cell down-regulatory PDL1 molecule in the cohort of patients particularly participants with TB/HIV co-infection. Participants with TB/HIV co-infection have the greatest potential to be immuno-compromised and as a result the very need for enhanced not depressed APCs function. In addition, we also observed the PDL1 levels were correlated with multiple plasma, mostly pro-inflammatory,cytokines. We analyzed cytokine mRNA levels of total monocytes to address the source of the cytokines but mRNA levels did correlate with neither plasma cytokine nor PDL1 levels. Considering all the phenotype analysis in each of the three studies together we could see two patterns emerging. In one scenario,surface molecules expression patterns were disease specific but independent of monocyte subset expression. In other words, whatever the underlying mechanism(s) involved in their regulation, those mechanisms apparently acted similarly in all three subsets. In another scenario, expression of surface molecules showed disease specific patterns, but molecules were particularly enhanced in the intermediate monocyte subsets. These findings imply that there exist mechanisms to modulate surface phenotypes and functions that are unique to a given subset. In conclusion, we have comprehensively defined the density of multiple molecules expressed by different subsets of monocytes and explored their differences in participants with TB, HIV and TB/HIV co-infection, as well as their correlations with microbial indices and plasma cytokines. Many molecules levels were elevated to some extent in all disease cohorts, but we observed patterns of expression which were particularly elevated in TB (CCR2, CX3CR1, and TLR2), those in HIV (CCR4, CCR5) and those on both (TLR4, PDL1). Molecule-disease associations were either independent of monocyte subset, or most readily revealed in a single monocyte subset. TB/HIV co-infection did not follow a consistent pattern in association with monocytes markers, in some cases more resembling TB, in others HIV, in others neither. Finally, to proof one possible mechanism of association between disease and monocyte phenotype, we explored correlations between monocyte markers and plasma cytokines. We observed significant positive and negative associations, frequently unique to a single monocyte subset or disease cohort, such as TB/HIV co-infected cohort. Collectively, the results imply that there are likely multiple mechanisms involved at many levels regulating the phenotype and function of monocytes, and these differ in different disease states.:Abbreviations ............................................................................................................ 3 Abstract ..................................................................................................................... 4 1. Introduction ........................................................................................................... 6 1.1 Epidemiology of Tuberculosis and Human Immunodeficiency virus ................... 6 1.2 The immunological response to TB and HIV ....................................................... 7 1.2.1 Innate immunity of TB ...................................................................................... 7 1.2.2 Innate immunity of HIV .................................................................................... 11 1.2.3 Immune checkpoint regulation in TB and HIV.................................................. 13 1.3 The role of monocytes in TB, HIV and TB/HIV ................................................... 14 1.3.1 Monocytes ....................................................................................................... 14 1.3.2 Abnormalities of monocytes in TB ................................................................... 15 1.3.3 Abnormalities of monocytes in HIV ................................................................. 16 1.3.4 Abnormalities on monocytes in TB/HIV co-infection ....................................... 17 1.4 The rationale for the thesis ................................................................................ 17 2. Objectives ............................................................................................................ 19 3. Publications .......................................................................................................... 20 4. Summary .............................................................................................................. 65 References ............................................................................................................... 69 Annex I: Author contribution ..................................................................................... 76 Annex II: Declaration of independent writing of the work ......................................... 77 Annex III: Curriculum Vitea ....................................................................................... 78 Annex V: Acknowledgment........................................................................................ 82 Annex VI ................................................................................................................... 84

Thesis (MCurr)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Taking into consideration the long duration of standard treatment for Mycobacterium tuberculosis (TB), the high prevalence of HIV co-infection and the growing prevalence of drug-resistant TB, there is an urgent need for improved treatment approaches for TB and HIV. However, there is inadequate information regarding the burden being placed on the Department of Health (DOH) systems by the current treatment of patients established on Antiretroviral Therapy (ART) who are newly diagnosed with TB, and by their clinical management. The aim of the study was to determine what proportion of patients established on ART were newly diagnosed with TB, and what their clinical and treatment outcomes were in different public sector settings in the eThekwini Region, KwaZulu-Natal (KZN). Approval for the study was obtained from the Human Research Committee of Stellenbosch University and from the Biomedical Research Committee, KZN. The study used a retrospective, quantitative, cohort technique at both TB and ART clinics at three sites in the eThekwini region, KZN. These sites were DOH clinics and were selected as they all had a TB clinic and a DOH-registered ART clinic. The study focused on a period of one year prior to a patient established on ART developed TB. The study population comprised all TB patients who attended the selected DOH clinics. A data collection tool was developed and pilot-tested. A small sample of patient files (n=15, representing 2% of the study population) was randomly selected; five from each site. The files and data were excluded from the main study. A total of 1824 files (579 from the TB clinics and 1245 from the ART clinics) were reviewed. The data were captured into an electronic database (EpiData Version 3.3) and analyzed using STATA (Version 11.0) with the assistance of a statistician. The findings show that of the study sample from the TB clinics (N=579), 78% (454/579) were newly diagnosed with TB. Of the new TB cases, 90% (409/454) had pulmonary TB and 71% (413/579) were HIV-positive. Nearly 50% (68/137) of the patients had commenced ART prior to TB diagnosis and treatment, and 14% (19/137) had commenced ART after TB. Of those who commenced ART prior to TB diagnosis and treatment, 29% (20/68) had commenced ART more than three months prior to acquiring TB. The findings from the ART clinics show that of the files (N=1245) reviewed, 40% (501/1245) had TB, and of these 8% (42/501) developed TB after three months or more of ART. Missing data in the patient medical files was a major challenge. The lack of recorded data about ART in the TB clinics and about TB in the ART clinics suggests suboptimal clinical management and poor integration of HIV and TB services. It was therefore not possible to derive a combined HIV-TB outcome measure. Recommendations to promote and implement the integration of TB and HIV services included policy changes and implementation, management and practice suggestions, education and training to integrate TB/HIV services and increase research to identify gaps in clinical management and to improve integration of services. / AFRIKAANSE OPSOMMING: Met inagneming van die lang duur van die standaard behandeling vir Mycobacterium tuberkulose (TB), hoë voorkoms van MIV-infeksie en die groeiende voorkoms van dwelmweerstandige TB, is daar ’n dringende behoefte aan verbeterde behandelingbenaderings vir TB en MIV. Daar is egter ’n gebrek aan inligting oor die las geplaas op die Departement van Gesondheid (DvG) se stelsels deur die huidige behandeling van pasiënte op antiretrovirale terapie (ART) wat gediagnoseer is met TB en deur hul kliniese bestuur. Die doel van die studie was om vas te stel watter persentasie van pasiënte wat op ART gevestig is, wel met TB gediagnoseer is, en wat hul kliniese en behandeling-uitkomste was in verskillende openbare-sektorinstellings in die eThekwini-streek, KwaZulu-Natal (KZN). Goedkeuring vir die studie is verkry van die Menslike Navorsingskomitee van die Universiteit van Stellenbosch en van die Biomediese Navorsingskomitee, KZN. Die studie het gebruik gemaak van ’n retrospektiewe, kwantitatiewe ‘cohort’-tegniek by beide TB en ARB-klinieke op drie plekke in die eThekwini-streek, KZN. Hierdie terreine was DvG-klinieke en is gekies omdat hulle almal oor ’n TB-kliniek en 'n DvGgeregistreerde ART-kliniek beskik. Die studie het gefokus op ’n tydperk van een jaar voor ’n pasiënt wat op ART is, TB ontwikkel het. Die studiepopulasie bestaan uit alle TBpasiënte wat die geselekteerde DvG-klinieke bygewoon het. ’n Data-insamelinginstrument is ontwikkel en getoets. ’n Klein voorbeeld van die pasiëntlêers (n = 15, 2% van die studie bevolking verteenwoordig) is ewekansig gekies: vyf uit elke plek, en die data is vervat in ’n elektroniese databasis (EpiData Version 3,3). ’n Totaal van 1824 lêers (579 in die TB-klinieke en 1245 lêers in die ART-klinieke) is ondersoek. Die data is ontleed deur gebruik te maak van Stata (weergawe 11,0) met die hulp van ’n statistikus. Die bevindinge toon dat van die studiemonster in die TB-klinieke (N = 579), 78% (454/579) met TB gediagnoseer is. Van die nuwe TB-gevalle, het 90% (409/454) pulmonêre TB gehad en was 71% (413/579) MIV-positief. Byna 50% (68/137) van die pasiënte het ART begin vóór hulle TB-diagnose en -behandeling, en 14% (19/137) ART ná TB. Van dié wat ART voor TB-diagnose en -behandeling begin het, het 29% (20/68) meer as drie maande voor die opdoen van TB met ART begin. Die bevindinge van die ART-klinieke toon dat van die lêers (N = 1245) wat bestudeer is, 40% (501/1245) TB het, en hiervan het 8% (42/501) TB na drie of meer maande van ART ontwikkel. Ontbrekende data in die pasiënt se mediese lêers was ’n groot uitdaging. Die gebrek aan aangetekende data oor ART in die TB-klinieke en oor TB in die ART-klinieke dui op suboptimale kliniese bestuur en swak integrasie van MIV- en TB-dienste. Dit was dus nie moontlik om ’n gesamentlike MIV-TB uitkomsmaatreël af te lei nie. Aanbevelings om die integrasie van TB- en MIV-dienste te bevorder en te implementer, het beleidveranderinge en -implementering ingesluit, asook bestuur- en praktykvoorstelle, onderwys en opleiding om TB-/MIV-dienste by DvG-vlak te integreer en meer navorsing om gapings in die kliniese bestuur te identifiseer en die integrasie van dienste te verbeter.

This dissertation focuses on the modelling, identification and the parameter estimation for the co-infection of HIV-1 and M. tuberculosis. Many research papers in this field focus primarily on HIV, but multiple infections are explored here, as it is common in many individuals infected by HIV. Tuberculosis is also responsible for the highest number of casualties per year in the group of HIV-infected individuals. A model is proposed to indicate the populations of both pathogen as well as key information factors, such as the overall infected cell population and antigen-presenting cells. Simulations are made to indicate the growth and decline in cell-type numbers for a specific individual. Such simulations would provide a means for further, well-founded investigation into appropriate treatment strategies. One previous such model developed by Kirschner is used to obtain a nominal parameter set. Furthermore, the nominal set is then used in conjunction with real-world samples provided by the National Institute for Communicable Diseases in South Africa, to solidify the credibility of the model in the practical case. This is achieved via simulations and employs parameter estimation techniques, namely the Nelder-Mead cost-function method. An identifiability study of the model is also done. Conclusions drawn from this study include the result that the treatment of M. tuberculosis does not affect the course of HIV-1 progression in a notable way, and that the model can indeed be used in the process of better understanding the disease profile over time of infected individuals. / Dissertation (MEng)--University of Pretoria, 2008. / Electrical, Electronic and Computer Engineering / MEng / unrestricted

Using data collected in 2007 for Addis Ababa Mortality Surveillance, the paper examines the effect of cause of death/type of illness on choice of health care in adults 12 years and above. The multinomial logit model using bootstrapped standard errors is used to investigate the relationship between dominant type of treatment and the covariates: cause of death, gender, age, education, occupation, ethnicity and religion. Availability of water, television and telephone in the household are used as a proxy for economic status. After controlling for duration of illness (exposure), type of illness, gender and marital status are significant. Those who die of HIV/TB and cancer behave similar in way they seek help, and have high likelihood of using traditional healers as the first point for help compared to those who died as a result of other illnesses. Thus the study concludes that cause of death; gender and marital status affect choice of health service.

Tuberculosis (TB) and human immunodeficiency virus (HIV) are difficult conditions to manage, in tandem they pose even more challenges to public health programs in identifying coinfection to ensure that all TB cases are treated to completion of therapy (COT). The purpose of this study was to test variables that predicted COT among the HIV/TB coinfected population of non-Hispanic, U.S.-born Blacks alive at the time of diagnosis. Social determinants of health were the theoretical foundation used to guide the study based on data from the Report of Verified Cases of TB (RVCT) between 2009 and 2014. Relationships were tested between ethnic/racial group membership and the likelihood of COT, and whether any association to COT was moderated by COT eligibility; a Centers for Disease Control and Prevention calculated algorithm considering disease severity, site, age, and disease complexity. The research design was a longitudinal quantitative approach using binary logistic regression to identify correlated variables associated with COT in the final model. The results showed no statistically significant differences among racial/ethnic groups, age, and gender for COT. COT was moderated by COT eligibility; odds ratio (5.4 - 11.6) times more likely to complete therapy. This study supports positive social change for programs by providing data driven outcomes to providers that support outreach, patient education, and disease prevention. In addition, this research describes an evaluation metric based on performance to set a foundation for collaboration among partners who manage other comorbidities in the United States.

<p>The global impact of the converging dual epidemics of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major public health challenges of our time, because in many countries, human immunodeficiency virus (HIV) and mycobacterium tuberculosis (TB) are among the leading causes of morbidity and mortality. It is found that infection with HIV increases the risk of reactivating latent TB infection, and HIV-infected individuals who acquire new TB infections have high rates of disease progression. Research has shown that these two diseases are enormous public health burden, and unfortunately, not much has been done in terms of modeling the dynamics of HIV-TB co-infection at a population level. In this thesis, we study these models and design and analyze robust numerical methods to solve them. To proceed in this direction, first we study the sub-models and then the full model. The first sub-model describes the transmission dynamics of HIV that accounts for behavior change. The impact of HIV educational campaigns is also studied. Further, we explore the effects of behavior change and different responses of individuals to educational campaigns in a situation where individuals may not react immediately to these campaigns. This is done by considering a distributed time delay in the HIV sub-model. This leads to Hopf bifurcations around the endemic equilibria of the model. These bifurcations correspond to the existence of periodic solutions that oscillate around the equilibria at given thresholds. Further, we show how the delay can result in more HIV infections causing more increase in the HIV prevalence. Part of this study is then extended to study a co-infection model of HIV-TB. A thorough bifurcation analysis is carried out for this model. Robust numerical methods are then designed and analyzed for these models.&nbsp / Comparative numerical results are also provided for each model.</p>

<p>The global impact of the converging dual epidemics of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major public health challenges of our time, because in many countries, human immunodeficiency virus (HIV) and mycobacterium tuberculosis (TB) are among the leading causes of morbidity and mortality. It is found that infection with HIV increases the risk of reactivating latent TB infection, and HIV-infected individuals who acquire new TB infections have high rates of disease progression. Research has shown that these two diseases are enormous public health burden, and unfortunately, not much has been done in terms of modeling the dynamics of HIV-TB co-infection at a population level. In this thesis, we study these models and design and analyze robust numerical methods to solve them. To proceed in this direction, first we study the sub-models and then the full model. The first sub-model describes the transmission dynamics of HIV that accounts for behavior change. The impact of HIV educational campaigns is also studied. Further, we explore the effects of behavior change and different responses of individuals to educational campaigns in a situation where individuals may not react immediately to these campaigns. This is done by considering a distributed time delay in the HIV sub-model. This leads to Hopf bifurcations around the endemic equilibria of the model. These bifurcations correspond to the existence of periodic solutions that oscillate around the equilibria at given thresholds. Further, we show how the delay can result in more HIV infections causing more increase in the HIV prevalence. Part of this study is then extended to study a co-infection model of HIV-TB. A thorough bifurcation analysis is carried out for this model. Robust numerical methods are then designed and analyzed for these models.&nbsp / Comparative numerical results are also provided for each model.</p>

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