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M.Sc. / Background: The continuous emergence of drug resistant strains of HIV as a result of errors made by reverse transcriptase coupled with undesirable side effects of available drugs, latency problems, cost etc, warrants the continuous search for new drug candidates. Chrysotherapy which is the use of gold compounds for the treatment of various ailments has been practiced since 2500 BC. The use of gold compounds such as auranofin for the treatment of rheumatoid arthritis has lead to remission of this disease. Gold compounds such as auranofin not only prevented the progression of arthritis but also increased the CD4+ count of an HIV positive patient who was not on antiretrovirals. These compounds have been implicated in the treatment of cancers, autoimmune diseases and microorganism infections. Objectives: In this work, novel gold compounds were evaluated with the aim of identifying lead compound(s) that can eventually serve as anti-HIV agents. Materials and Methods: Eleven gold (I) phosphine complexes, four of their corresponding ligands (compound without gold atom), and a gold (III) complex were tested for the ability to inhibit reverse transcriptase (RT) and protease (PR) in direct enzyme assays. Uptake of the compounds by host cells was evaluated with inductively coupled plasma atomic emission spectrometry (ICP-AES). Potential toxicity of the gold compounds was screened for by viability dyes and flow cytometry assays. To determine inhibition of whole virus by other mechanisms in addition to RT or PR, p24 production by infected cells was evaluated. Prior to all these analysis, stability of compounds in solution was determined by 31P nuclear magnetic resonance (NMR) and UV-visible spectroscopy. Results: The compounds were shown to be stable in solution over a one week period and were taken up by both continuous cell lines and primary cells. Eight of the gold compounds significantly inhibited HIV-1 reverse transcriptase at concentrations of 25 and 250 μM while four compounds and the four ligands did not. In a fluorogenic assay against HIV-1 PR, four of the gold compounds demonstrated inhibitory activity. The gold compounds were toxic to cells lines but not to primary cells. One of the complexes (EK231) significantly reduced p24 (p=0.0042) production at a concentration of 25 μM. Conclusion: Data provided here suggests that the therapeutic benefits of these gold containing compounds as potential HIV-1 reverse transcriptase and protease inhibitors should be considered.

D.Phil. / This enquiry represents an attempt to understand the ways in which the ecology of ideas surrounding HIV and Aids in post-apartheid South Africa functions discursively to silence people living with the dis-ease. In this regard, it seeks to understand how the range of subject positions available to people with HIV and Aids influences their opportunities for treatment and disclosure. The meanings emerging from this enquiry have implications for interventions aimed at people living with HIV and Aids, in that they challenge the liberal humanism underpinning a Western individualist paradigm which constructs people as ‘rational’ and ‘responsible’ on the basis that such constructions tend to attribute guilt or moral culpability to people living with HIV and Aids. The conversations and narratives elicited in the process of this enquiry suggest that such discourses constitute a form of disciplinary power in a Foucauldian sense, positioning people living with HIV and Aids defensively and limiting their options for ‘positive’ self-definition by foreclosing available subject positions, thereby contributing to the spread of HIV and Aids. Hence, this enquiry focuses on social constructions of morality and the impact of these on participants’ attempts to maintain key relationships that afford them a ‘positive’ sense of them-selves. Thus, it looks at experiences of connection and dis-connection and explores the ways in which efforts to retain ‘relatedness’ in order to maximise possibilities for the co-construction of a ‘moral self’ mediate opportunities for disclosure and treatment options. The enquiry aimed to assist participants in deconstructing dominant social constructions of HIV and Aids implicit in cultural and political discourse by applying a critical, poststructuralist and discourse-analytic lens in order that they might resist moral attributions based on liberal humanism and access their own voices in narrating the experience of living with HIV and Aids in keeping with their lived experience. My aim in this regard was to resurrect alternative or previously silenced accounts and to open up spaces for a multiplicity of meanings associated with HIV and Aids to emerge and be heard, toward the end of breaking the silence and creating a conversational space in which people’s meanings could simultaneously be heard and challenged through dialogue.Ultimately, this enquiry highlights the importance of attempting to understand the local and idiosyncratic nature of people’s constructions of HIV and Aids, which are often a hybrid mix of ideas and meanings circulating within social, cultural and political discourse. It also underscores the salience of considering people’s lives in context and particularly their need to maintain relationships that afford a positive sense of self. This is reflected in the tendency for participants to construct their identities in relation to significant others and for these relationships to mediate decision making in relation to HIV and Aids by availing or foreclosing certain subject positions, depending on the discourses within which they are situated.

Twenty-five gay men, 20 with Acquired Immune Deficiency Syndrome (AIDS) and 5 with either AIDS Related Complex (ARC) or who tested positive for the AIDS virus, were asked in semi-structured interviews whether they felt supported or isolated. Areas covered included society in general, employment, housing, health care, insurance, religion, families of origin, ex-wives, children, friends and lovers. Subjects indicated that fear of AIDS, homophobia, and death anxiety were all present in certain circumstances, but there was no attempt to differentiate between these three possible causes of social isolation in this exploratory study. / Master of Science

The aim of this research was to implement and evaluate guidelines that will be used by treatment support counsellors in an attempt to increase client adherence to antiretroviral treatment.

HIV-associated lipodystrophy (HIVLD) syndrome is a condition comprising abnormalities in distribution of body fat and metabolism of lipids and glucose that arises in HIV-infected patients on long-term antiretroviral therapy. This thesis describes clinical research into aspects of the natural history and treatment of HIVLD, as well as molecular research into its pathogenesis centred on subcutaneous adipose tissue. Results demonstrate HIVLD to be a treatment-induced syndrome characterised by initial gains in body fat followed by selective, progressive loss of limb fat. Exposure to thymidineanalogue nucleoside reverse transcriptase inhibitors (tNRTI) induces lipoatrophy through mitochondrial dysfunction of which inhibition of mitochondrial RNA expression, rather than mitochondrial DNA depletion, is an early feature. Mitochondrial dysfunction is associated with decreases in expression of peroxisome proliferatoractivated receptor gamma (PPAR??), an adipocyte transcription factor, which helps explain how tNRTI exposure leads to the loss of adipocyte function. Once established, lipoatrophy is characterised by mitochondrial DNA depletion, although this depletion occurs throughout the mitochondrial genome, suggesting an underlying cause other than inhibition of DNA polymerase gamma. HIVLD is a difficult syndrome to treat. Lipoatrophy is resistant to treatment with rosiglitazone, an agonist of PPAR??, which is ineffective in the setting of ongoing tNRTI therapy and mitochondrial dysfunction. Dyslipidaemia is also difficult to treat as use of pravastatin in the setting of ongoing exposure to protease inhibitors results in only modest declines in fasting cholesterol concentrations. Gains in central fat, such as that seen in patients with buffalo hump, are associated with insulin resistance and diabetes, but only occur in a relatively small percentage of treated patients, suggesting a role for genetic factors in its development. Use of strategies such as avoidance of tNRTI in firstline ART, genetic screening to identify those at risk of toxicities and targeted selection of interventions in subgroups of affected patients, may help prevent this syndrome occurring and better treat those patients in which it has already occurred.

South Africa and the province of KwaZulu-Natal (KZN) has one of the greatest HIV burdens in the world with an estimated 5.7 mHIion people living with HIV/AIDS. One of the interventions that the government introduced to address this situation was the provision of antiretroviral treatment (ART) to those individuals that are eligible for HIV treatment in order to reduce the morbidity and mortality. Despite widespread availability of ART in KZN, children do not access ART to the extent that adults do, and therefore continue to die because of HIV and AIDS. This qualitative study explored the psychosocial and health system factors that influence paediatric access to ART in KZN from parents and caregivers perspectives. The ecological theory and the social cognitive theory was used to formulate an interview schedule used in conducting the in-depth interviews with adults (parents or guardians) who were bringing their children for ARTservices and those attending these services themselves and not their children at Edendale and King Edward Hospitals in KZN. Purposive sampling was used to select clients for interviews and thematic was done in accordance with the aims and objectives of the study. A total of 42 participants were interviewed in this study. The low uptake of child ART was found to be influenced by several psychosocial and economic factors such as the poor knowledge about ART, stigma and disclosure associated with HIV, extent of support provided by parents/caregivers, parent's own ART was a determinant for bringing children for ART, use of traditional / alternative medicines, disintegrated families, especially the issue of multiple caregivers, complexity of paediatric ART, poor referrals of children from community institutions, unsatisfactory service at clinics, and some health policy and legislation with respect to health care for HIV-infected children that had an unintended effect of restricting child access to ART as well as poverty related Issues. Improving knowledge and self-efficacy related to ART, prevention of mother to child transmission ofHIV, re-training of health workers on child issues and addressing stigma and discrimination and other psychosocial and institutional problems and logistics could help to improve the low paediatric uptake of ART. / Thesis (M.A.)-University of KwaZulu-Natal, Durban, 2009.

The purpose of the study was to determine if perceived severity of the consequences of physical inactivity is an important component for exercise motivation in college students. The participants of the study were 581 college students who had enrolled in HSC 160, Fundamentals of Human Health, at Ball State University during the spring semester of 2001. Using a cross-sectional data collection process, participants completed a survey instrument consisting of the stages of change for exercise scale, the perceived severity of the consequences of physical inactivity scale, and demographic questions.The data were analyzed using both univariate and bivariate analyses. Specific descriptive and inferential statistic analyses were used to: 1) determine the degree of association between the participants' perceived severity and their identified stages of change for exercise, 2) examine the relationship between the stages of change for exercise and the participants' demographic characteristics, and 3) determine the difference between perceived severity of consequences of physical inactivity and the Participants' demographic characteristics.The results indicated that those who perceived the threat of a health condition as a result of not being physically active to be high were more likely to exercise regularly. Males and females differed in their exercise stage of change with males being more likely in the maintenance stage whereas females were more likely to be in the preparation stage. Also, perceived severity of the consequences from the lack of physical activity was greater in females than males, suggesting that those men who exercise regularly do so, but not exclusively for preventing negative health conditions.The results of this study should be useful to health and physical education instructors to assist them with organizing and tailoring appropriate physical activity lecture topics and emphasizing the severity of the consequences to those who are not physically active.Finally, additional research should be conducted in order to determine what factors affect perceived severity of a health threat as it relates to physical inactivity such as demographics, sociopsychological, and structural variables, to help identify all the possible factors that could impact future program planning efforts. / Department of Biology

The aim of this research was to implement and evaluate guidelines that will be used by treatment support counsellors in an attempt to increase client adherence to antiretroviral treatment.

HIV-associated lipodystrophy (HIVLD) syndrome is a condition comprising abnormalities in distribution of body fat and metabolism of lipids and glucose that arises in HIV-infected patients on long-term antiretroviral therapy. This thesis describes clinical research into aspects of the natural history and treatment of HIVLD, as well as molecular research into its pathogenesis centred on subcutaneous adipose tissue. Results demonstrate HIVLD to be a treatment-induced syndrome characterised by initial gains in body fat followed by selective, progressive loss of limb fat. Exposure to thymidineanalogue nucleoside reverse transcriptase inhibitors (tNRTI) induces lipoatrophy through mitochondrial dysfunction of which inhibition of mitochondrial RNA expression, rather than mitochondrial DNA depletion, is an early feature. Mitochondrial dysfunction is associated with decreases in expression of peroxisome proliferatoractivated receptor gamma (PPAR??), an adipocyte transcription factor, which helps explain how tNRTI exposure leads to the loss of adipocyte function. Once established, lipoatrophy is characterised by mitochondrial DNA depletion, although this depletion occurs throughout the mitochondrial genome, suggesting an underlying cause other than inhibition of DNA polymerase gamma. HIVLD is a difficult syndrome to treat. Lipoatrophy is resistant to treatment with rosiglitazone, an agonist of PPAR??, which is ineffective in the setting of ongoing tNRTI therapy and mitochondrial dysfunction. Dyslipidaemia is also difficult to treat as use of pravastatin in the setting of ongoing exposure to protease inhibitors results in only modest declines in fasting cholesterol concentrations. Gains in central fat, such as that seen in patients with buffalo hump, are associated with insulin resistance and diabetes, but only occur in a relatively small percentage of treated patients, suggesting a role for genetic factors in its development. Use of strategies such as avoidance of tNRTI in firstline ART, genetic screening to identify those at risk of toxicities and targeted selection of interventions in subgroups of affected patients, may help prevent this syndrome occurring and better treat those patients in which it has already occurred.