Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

CD4⁺ T cells are a critical component of the adaptive immune compartment. Each T cell expresses a clonotypic T cell receptor (TCR) that must discriminate between self and foreign peptides presented in major histocompatibility molecules (pMHC) on the surface of antigen presenting cells to direct T cell fate decisions. Information regarding TCR-pMHC interactions must then be transmitted to the TCR-associated CD3 signaling modules, which contain ITAMs that serve as signaling substrates for Src kinases. The Src kinase, Lck, is recruited to the pMHC-bound TCR-CD3 complex via association with the CD4 coreceptor that binds MHCII. It is therefore through the coordinated interactions within the TCR-CD3-pMHC-CD4 macro-complex that productive TCR signaling can occur to inform T cell activation and fate decisions. While much is known regarding the structure of the individual subunits that make up the TCR-CD3-pMHC-CD4 macro-complex, there is little information regarding how these components come together to initiate TCR signaling and determine functional outcomes. Here, we have interrogated how interaction of these individual components leads to productive T cell activation. Specifically, we interrogated the nature of TCR-MHC interactions and provide evidence that there is intrinsic specificity of the TCR for MHCII. We have also built mouse models to determine the role of TCR-CD3 interactions and TCR dimerization in the transmission of information from the TCR to the CD3 subunits following TCR-pMHC engagement. Finally, we show that both the CD4 transmembrane and extracellular domains contribute to T cell activation in vitro. Overall, this work provides insight into how the constituents of the TCR-CD3-pMHC-CD4 macro-complex interact to initiate T cell fate and function.

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Objetivo: Evaluar factores de riesgo asociados con un diagnóstico tardío de infección por VIH en pacientes atendidos en el hospital San José del Callao, en el período 2009-2014. Material y métodos: Se realizó un estudio observacional-analítico, casos y Controles, empleándose historias clínicas confidenciales de los pacientes con VIH de PROCETSS del hospital San José, obteniéndose 1030 historias de las cuales 310, podían ingresaron al estudio, cumpliendo con los criterios de inclusión y de exclusión. De esta población, 207 tuvieron diagnóstico tardío (casos) y 103 (controles), no. Luego, de forma aleatoria se tomó de muestra de casos, obteniéndose al final 103 casos y 103 controles. Se estudiaron 3 factores de riesgo: Sexo, edad, orientación sexual. Para el análisis de variables se utilizó el programa SPSS y pruebas de chi cuadrado y OR. Resultado: El 53,5% del sexo masculino presentó diagnóstico tardío de VIH, pero, no tuvo relación estadística (OR=0.55). En cuanto a la edad, los pacientes mayores de 40 años presentaron mayor riesgo (OR=1.68). Y Los pacientes con una orientación distinta a la heterosexual obtuvo un mayor porcentaje de diagnóstico tardío (54,1 %), sin embargo esta variable no se encuentra relacionada (OR=0,66). Conclusiones: Se evaluaron 3 posibles factores de riesgo para el diagnóstico tardío de VIH, de los cuales solo la edad resultó ser un factor de riesgo, mientras que el sexo y la orientación sexual no guardaron relación significativa, por lo tanto no constituyeron un factor de riesgo.

Objetivo general: Determinar las características clínicas epidemiológicas asociados con la supervivencia en pacientes portadores de VIH – SIDA en el Hospital Militar Central en el periodo 2007-2014 Metodología: observacional, analítico y retrospectivo, la unidad de análisis fue todo los pacientes con el diagnostico confirmado de VIH SIDA durante el periodo 2007 al 2014 en el hospital militar que tiene controles esta población fue conformado por un total de 101 pacientes, se recolecto los datos de las historias clínicas y se analizaron en el programa SPPS resultados Resultados: Podemos observar que de los 101 pacientes diagnosticados con VIH SIDA tan solo han fallecido 10 donde las características clínicas son las que más están relacionados con la supervivencia Con respecto al nivel de CD4 tenemos: 25 pacientes presentaron un nivel de CD < 100, en comparación de 76 pacientes que presentaron CD4> a 100. Posteriormente se realizó la valoración del nivel de CD4 como condición asociada a la sobrevida, observando la distribución en función a la tabla tetracorica, haciendo posteriormente el cálculo de los parámetros estadísticos correspondientes empezando por el odds ratio cuyo valor resulto de 4,7 y que expresa que aquellos pacientes con un nivel de CD4 <100 está asociado a una sobrevida menor en 3,17 veces más que aquellas pacientes con nivel CD4 >100. En el análisis estadístico de estadio clínico bajo el valor de chi cuadrado fue de 7.2, siendo estadísticamente significativo (p<0,05), interpretándose que el estadio clínico está asociado a la sobrevida. Luego se realizó si el estadio clínico es una condición asociada a mayor sobrevida. Se realizó la tabla tetracorica haciendo el cálculo del odds ratio y se obtuvo un valor de 2,3, pero el intervalo de confianza encontrado es IC 1,7 - 5,3, lo cual es significativo. Conclusiones Las características clínicas epidemiológicas están asociado a la supervivencia en los pacientes con VIH – SIDA en especial estadio clínico y el CD4

MSc (Med), Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, 2009 / This study assessed the effect that certain logistical and methodological factors in the laboratory could have on influencing precision and accuracy of enumeration of CD4+ cells. The efficacy of a new blood stabiliser to extend the window of CD4 testing, was also evaluated. CD4+ counts were derived using the 2-colour Pan-leucogating, 4-colour TetraONE and MultiTEST/TruCount protocols on the EPICS-XL, FC-500 or FACSCalibur flow cytometers. Statistical analyses included the paired-t-test, Spearman’s correlation and Bland Altman comparisons. The results showed that the reliability of CD4+ count results was heavily dependent on how blood samples were handled prior to and after receipt into the laboratory and on how samples were processed and analysed. The factors, motion, operator pipetting and analysis skills, storage temperature, use of different protocols, different gating strategies and the use of different flow cytometers, were found to influence accurate and precise enumeration of CD4+ counts.

M.Med.(Anaesthesia), Faculty of Health Sciences, University of the Witwatersrand, 2008 / BACKGROUND HIV infection is common in South Africa. The disease often remains clinically latent, despite the patient having severe immune compromise. Clinical preoperative assessment may result in patients with this severe systemic disease going unnoticed. OBJECTIVES The primary objective was to determine the relationship between the preoperative physical status of HIV-positive patients presenting for anaesthesia and the CD4- count. The secondary objectives were to determine the prevalence of HIV infection in this group of patients, to determine the prevalence of HIV infection in selected subgroups, to ascertain what proportion of patients presenting for anaesthesia know their HIV status, and to ascertain what proportion of HIVpositive patients are receiving highly active antiretroviral therapy (HAART). METHOD A sample of 350 adult patients presenting for anaesthesia at Chris Hani Baragwanath Hospital was selected. Patients were interviewed preoperatively and were examined, and in doing so their ASA physical status grading was determined. Blood was sampled, and in those who were confirmed HIV-positive, vi a CD4-count was checked. Further data were collected: age, gender, the type, nature, urgency and time of day of surgery, the patient’s knowledge of their HIV status, and whether the patient was receiving HAART or not. RESULTS HIV-positive patients were more likely to be classified as ASA 1 or 2 than ASA 3 or 4 (OR 2.1). HIV-positive patients with CD4-counts above 200 cells.mm-3 were also more likely to be ASA 1 or 2 than ASA 3 or 4 (OR 3.88). However, within the group of HIV-positive patients with CD4-counts below 200 cells.mm-3, significantly more patients were classified as ASA 1 or 2 than ASA 3 or 4 (p<0.0001). Three patients with CD4-counts below 50 cells.mm-3 were classified as ASA 1 or 2. The overall prevalence of HIV infection was 29.4%. Within the various subgroups, the groups with higher disease prevalence rates were females, patients presenting for obstetric surgery, and the younger age groups. The highest prevalence of HIV infection was found in patients aged 30-39 years (43.0%), and the lowest prevalence was found in patients aged 60 years or older (7.7%). CONCLUSIONS Routine clinical preoperative assessment in patients from a population with a high HIV prevalence rate may result in asymptomatic, severe immune compromise secondary to HIV infection being missed in a significant number of patients. Further study into the perioperative outcomes of these patients is warranted.

Introduction: This study is a secondary data analysis of HIV/AIDS patients on Anti-retroviral Therapy (ART), at Themba Lethu HIV/AIDS clinic, who have had the first break in the continuity of taking their Antiretrovirals (ARVs) of more than 10 days, measured by patient missing the refill appointment for more than 10 days. The clinic started in 2004. HIV/AIDS is high in South Africa with about 400,000 AIDS patients on ARVs. For ARVs to be most effective they must be taken continuously without breaks, and for life. Without this, there is risk of ARVS drug resistance development and consequent failure of the ART program. Some patients may break this continuity and this seems to be a problem in South Africa. Where the patients develops side-effects or is not responding well to treatment, clinicians may also cause a break in the therapy. This study described the first break as when it occurred and for how long it lasted, investigated the factors associated with this break and the association of the first break and the last CD4 count. Materials and methods: 7,930 adults (≥18 years, either gender) on ART and baseline CD4 <250 cells/μl were included in the study. The study group were patients who had first break in continuity of therapy of more than 10 days. The first break was described as when it occurred after months of ART initiation and how long(days) the first break lasted. Patients on Post- Exposure Prophylaxis, single-dose Nevirapine, Prevention-of mother-To-Child- transmission therapy, and those with breaks in therapy of more than 364 days were excluded. Outcome variables was the last CD4 count. Analyses were in STATA 10, at 95% confidence interval. Median and quartile ranges were used to describe participants in the study. T-test, Fishers exact test and chi-square were used to compare groups. Regression was used to determine demographic and clinical factors associated with first break in therapy and also to determine the association of first break in therapy and the last CD4 count. Results: The median duration on ART for the patients was 764 days. 63% of patients had a break in ART. 47.5% of patients had their first break in therapy within the first 2 years of being on the ART program, with the largest proportion within the first 6 months of therapy. Most patient came with advanced disease(CD4 <100cells/μl, WHO clinical staging IV). Women were twice more than men. They tended to come earlier for therapy, took longer to improve and delayed in having the first break compared to men (254 vs. 205 days). Baseline hemoglobin and unemployment were factors associated with when the first break occurred. The median length of first break was 21 (Q1-Q3 7-43) Unemployment and baseline hemoglobin were associated with length of first break. The first break in therapy was associated with the last CD4 count. The longer the patient stayed on ART without the first break, the higher the last CD4 would be. Peripheral neuropathy had a statistically significant positive association with the last CD4 count. However, baseline CD4, Age, baseline BMI, WHO stage IV, baseline hemoglobin and unemployment had a statistically significant but negative association with the last CD4 count. The weakness of using the missing appointment system is that it does not inform clinician whether patients is really taking or not taking ARVs at home. Its strength over the self reported adherence system is that it is free of recall bias. Conclusion: Though Themba Lethu clinic has a follow-up system in place for patients missing refill appointment, up to 63% patient missed their appointment to collect medicine on time and this had a negative effect on the last CD4. There is need to strengthen existing follow-up method besides decentralising the ART services in Johannesburg.

RATIONALE: Tuberculosis and HIV infection together form a highly mortal combination. Even after the advent of highly active antiretroviral therapy (HAART) medications, management for Tuberculosis and HIV/AIDS still remains a challenge. Poor outcomes (in both morbidity and mortality) are still being witnessed throughout the world, and especially in the poorly developed countries that bear the bulk of the burden of the cases. It is assumed that one of the major contributors to the poor outcomes is poor nutritional status resulting from the disease process itself, poverty and toxicity from medications being used to treat these diseases that substantially reduce appetite. An assessment of the role that nutritional status has on change in CD4 as a surrogate marker of disease progression is therefore of importance. OBJECTIVES: To evaluate the role that nutritional supplementation has on change in CD4 in TB patients co-infected with HIV who are receiving standard care of treatment. METHODS: Data from a randomized controlled trial of a Protein Calorie Supplement (PCS) were used. To assess the effect of randomization to a nutritional supplement, baseline characteristics were compared among the intervention and the control groups and confounder variables, such as age, BMI, baseline CD4, socioeconomic status, previous exposure to TB and compliance with HAART medication were analyzed and adjusted for in a model using multivariate linear regression. RESULTS: 151 HIV-infected women with TB disease were enrolled; 72 received PCS while 79 did not. We found that the PCS intervention had no significant effect on change in CD4 between baseline and 8 months. Average change in CD4 count was similar for intervention and control groups (204 vs. 207 units). This similarity persisted after adjusting for baseline BMI and previous TB disease. CONCLUSION: Randomization (i.e. nutritional supplement) did not have a significant effect on change in CD4 count among study participants. However, an effect could have been masked by high compliance with ART.