The human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) response is important in the control of HIV-1 infection. Due to the virus having a high rate of mutation, immune pressure can select for variants that are no longer recognised by CTLs to dominate the viral quasispecies. This is similar to how antiretroviral resistance emerges. HIV-1 is therefore adapting to both human leukocyte antigen (HLA)-restricted immune responses and antiretroviral therapy. This thesis initially focused on the natural CTL response to an HLA-B*51-restricted epitope in integrase. This HLA class I allele is associated with slow progression to AIDS; however, as no CTL-driven escape mutation has been fully defined within this integrase epitope, we cannot determine what contributes to the association of HLA-B*51 and natural control of infection. By longitudinally studying a cohort of early HIV-infected individuals, we observed the emergence of polymorphisms that abrogate a CTL response to this epitope. CTL escape may also prove to be the downfall of current immunotherapy strategies attempting to combat HIV infection. T cell receptors (TCRs) have been genetically modified to enhance their binding affinity to an HLA-A*02-peptide complex and transduced into CD8+ cells to create an HIV adoptive therapy. We demonstrate through in vitro selection pressure assays that escape from these cells may be a difficult task for the virus given that the TCR is able to recognise the majority of variants of this epitope. Antigen processing mutations may represent the only option for escape. How this may translate clinically will only be determined through in vivo studies, which must be meticulously monitored. Finally, when this high affinity TCR was fused to an anti-CD3 single chain variable fragment to create proteins capable of redirecting non-HIV-specific CTLs to HIV-infected cells, we found that the result was specific lysis. These proteins may supersede the use of TCR-transduced cells when used in synergy with antiretroviral therapy.

Bibliography: leaves 127-161. / x, 161, [94] leaves, [30] leaves of plates : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Direct transmission from infected cells to uninfected cells, otherwise known as cell-to-cell infection, is one mode of viral spread adopted by HIV-1. Transcriptional aspects of HIV-1 replication were examined following cell-to-cell infection. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1997

This study compare immunological and virological outcomes in antiretroviral therapy naïve patients exposed to Isoniazid prevention treatment.Medical records of antiretroviral naïve patients managed in the public sector from 1st January 2006 to 31st December 2006 were analysed.Multivariate analysis of variance showed that each treatment group achieved statistically significant increases in CD4+ cell count and viral load decay at each follow-up time point. Pairwise post hoc contrast tests showed patients in NVPipt-past group and EFVipt-past group to have superior immunological and virological outcomes respectively. / Health Studies / M.A. (Public health)

Since being identified as the cause of AIDS in 1983, HIV-1 infection has reached pandemic proportions. Despite public awareness about prevention, the growing incidence of HIV-1 infection and the limitations of current antiretroviral therapy underscore the imperative need for a vaccine. Understanding the basis of an immune response that controls infection or provides sterilizing immunity remains a major goal in the search for effective vaccines or immunotherapies. Research into correlates of immunity to HIV-1 have largely focused on CD8⁺ T cells or neutralising antibodies (NAbs) but to date these responses have not proved effective in containing viral replication in vaccinees who become infected. Natural killer cells (NKs), monocytes (MCs), and neutrophils (PMNs) are cells of the innate immune system with intrinsic cytotoxic function that can be enhanced by antibodies (Abs) in what is termed antibody-dependent cellular cytotoxicity (ADCC). In my studies I investigated the production of PMNs from human stem cells, the elimination of HIV-1 infected cells by these effector cells, the modulation of cellular cytotoxicity by Ab, and characterized how Abs facilitate a potent ADCC response. I developed a novel flow cytometry assay to measure cytotoxic activity against HIV-1 infected CD4⁺ T cells. Using this, effector cells were shown to have different cytotoxic capacities which were enhanced by Ab. Comparing ADCC mediated by patient serum revealed that higher levels correlated with IgG binding to infected cells. I observed no correlation between serum-mediated ADCC and markers of disease progression including patient status, viral RNA load, CD4⁺ T cell count, or NAb titers. The data presented here have implications for acquisition and control of early HIV-1 infection by NKs, MCs, and PMNs prior to activation of an adaptive immune response, at later stages in the presence of HIV-1-specific Abs, and are relevant to vaccine-induced anti- HIV-1 Ab-based effector mechanisms.

This study compare immunological and virological outcomes in antiretroviral therapy naïve patients exposed to Isoniazid prevention treatment.Medical records of antiretroviral naïve patients managed in the public sector from 1st January 2006 to 31st December 2006 were analysed.Multivariate analysis of variance showed that each treatment group achieved statistically significant increases in CD4+ cell count and viral load decay at each follow-up time point. Pairwise post hoc contrast tests showed patients in NVPipt-past group and EFVipt-past group to have superior immunological and virological outcomes respectively. / Health Studies / M.A. (Public health)

This study using a quantitative, descriptive design with a questionnaire investigated cultural, religious and social factors that might impact on ARV treatment in HIV/AIDS-infected women in Botswana. The study found that the majority never missed any doses, a few missed doses once or twice, and a small minority missed more than three times. The respondents’ perception of cultural influence on treatment of HIV/AIDS in women revealed that the majority (70%) believe culture has an influence on the treatment. Social factors also impacted on ARV adherence. A few of the respondents indicated that side effects and the number of pills prevented ARV medication adherence. The main reason for non-adherence, however, was forgetfulness. There had been an improvement in the majority of the respondents’ health status and quality of life. Maximizing adherence is essential. Providers and patients both have responsibilities in this regard. / Health Studies / M.A.(Health Studies)

This study using a quantitative, descriptive design with a questionnaire investigated cultural, religious and social factors that might impact on ARV treatment in HIV/AIDS-infected women in Botswana. The study found that the majority never missed any doses, a few missed doses once or twice, and a small minority missed more than three times. The respondents’ perception of cultural influence on treatment of HIV/AIDS in women revealed that the majority (70%) believe culture has an influence on the treatment. Social factors also impacted on ARV adherence. A few of the respondents indicated that side effects and the number of pills prevented ARV medication adherence. The main reason for non-adherence, however, was forgetfulness. There had been an improvement in the majority of the respondents’ health status and quality of life. Maximizing adherence is essential. Providers and patients both have responsibilities in this regard. / Health Studies / M.A.(Health Studies)

The aim of the study was to determine the factors that influence adherence to ART among adolescents who contracted HIV through vertical transmission. Qualitative research using descriptive phenomenology was conducted at Botswana-Baylor Children’s Clinical Centre of Excellence. Data was collected using in-depth individual semi-structured interviews. Eight (8) adolescents between 14 and 19 years who had been on ART for minimum of 4 years were interviewed. Thematic analysis of data was done and five (5) themes emerged from the participants' description of the experience of taking ART over a long period of time. The themes that emerged indicated the factors that influence adherence to ART, and they included knowledge and positive beliefs about ART, need for support, ART difficult treatment regimen, having a regular doctor and psychosocial emotional needs. The findings suggested that the adolescents who contracted HIV through vertical transmission require support while continuing on a simplified long-term ART regimen after an assessment of their psychological well beings and periodic checks. / Health Studies / M.A. (Public Health)

The aim of the study was to determine the factors that influence adherence to ART among adolescents who contracted HIV through vertical transmission. Qualitative research using descriptive phenomenology was conducted at Botswana-Baylor Children’s Clinical Centre of Excellence. Data was collected using in-depth individual semi-structured interviews. Eight (8) adolescents between 14 and 19 years who had been on ART for minimum of 4 years were interviewed. Thematic analysis of data was done and five (5) themes emerged from the participants' description of the experience of taking ART over a long period of time. The themes that emerged indicated the factors that influence adherence to ART, and they included knowledge and positive beliefs about ART, need for support, ART difficult treatment regimen, having a regular doctor and psychosocial emotional needs. The findings suggested that the adolescents who contracted HIV through vertical transmission require support while continuing on a simplified long-term ART regimen after an assessment of their psychological well beings and periodic checks. / Health Studies / M.A. (Public Health)

Notre thèse de pharmacie clinique est une contribution à l’optimisation de l’efficience du traitement antirétroviral (TAR) par des méthodes de modélisation en Côte d’Ivoire. La première étude a été consacrée à une modélisation de la réponse antirétrovirale par taxonomie des trajectoires de taux de CD4 en utilisant un modèle de méta-apprentissage des trajectoires d’indicateurs biomédicaux. Ce modèle appliqué à la taxonomie des trajectoires des taux de CD4 a montré son intérêt dans la mise en évidence de classes distinctes de patients avec des caractéristiques particulières justifiant et/ou déterminant le profil particulier de méta-trajectoires de leur marqueur immunologique au cours du traitement. La deuxième tâche a consisté en une évaluation de l’impact de principaux déterminants des méta-trajectoires de taux de CD4 sur divers types de réponse immunologique à partir d’un modèle explicatif avec une équation de régression logistique. Les réponses immunologiques considérées ont été exprimées en termes d’absence de gain de CD4, de gain sub-optimal et de gain optimal de CD4 à différentes périodes de suivi du TAR. Enfin l’évaluation de l’efficience des stratégies antirétrovirales de première ligne en Côte d’Ivoire, a été abordée dans la dernière partie avec un modèle pharmaco-économique. Nous avons effectué une étude préliminaire ouvrant des perspectives pour encourager la mise en oeuvre d’évaluations pharmaco-économiques complètes par modélisation en Côte d’Ivoire. Elle a permis de mettre en exergue les parties méthodologiques pouvant être sujettes à caution dans une étude de modélisation pharmaco-économique des TAR de première ligne dans un contexte de ressources limitées / Our thesis of Clinical pharmacy is a contribution to optimize the efficiency of antiretroviral therapy (ART) by modeling methods in Côte d'Ivoire. The first study was devoted to modeling the antiretroviral response from taxonomy of CD4 counts trajectories, using a meta-learning model of biomedical markers trajectories. This model applied to the taxonomy of the CD4 counts trajectories showed its interest in the identification of distinct classes of patients with particular characteristics justifying and/or determining the specific profile of meta-trajectories of the immunological marker during treatment. The second task was an assessment of the impact of key determinants of CD4 counts meta-trajectories on various types of immune response from an explanatory model with a logistic regression equation. Antiretroviral immune responses considered were expressed in terms of absence of CD4 gain, sub-optimal gain and optimal gain of CD4 at different periods of follow-up of ART. Finally the evaluation of the efficiency of first-line antiretroviral strategies in Côte d'Ivoire, was discussed in the last part with a projective pharmaco-economic model. We conducted a preliminary exploratory study opening up prospects to encourage the implementation of comprehensive pharmaco-economic assessments by modeling in Côte d'Ivoire. This study helped to highlight the unreliable methodological sections in a pharmaco-economic modeling of first-line ART in resource-limited settings