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MSc., Faculty of Science, School of Statistics and Actuarial Science, University of the Witwatersrand, 2011 / The Human Immunodeficiency Virus (HIV) epidemic is currently one of the greatest challenges and most important health issues in the world. South Africa has one of the fastest growing epidemics in the world therefore reliable estimates of prevalence and incidence are required for understanding the magnitude of the epidemic and improving the methods of prevention. This study examines the estimation of HIV incidence from a cross-section of people, using one of the laboratory methods that discover recent HIV infection in blood samples. The incidence estimate is obtained at a single point in time, thereby saving time and cost expended in following a cohort over a period of time. It also examines incidence from pooled blood samples, and evaluates the assumptions of the different methods of estimating HIV incidence, comparing each of them; and checking the sensitivity of the estimates to the assumptions. Results from the simulation study shows that accurate estimates of incidence can be obtained by pooling blood samples; and these estimates are obtained at a fraction of the cost of individual testing.

Ph. D, Faculty of Science, University of Witwatersrand, 2011 / The evolution of drug resistance in human immunodeficiency virus (HIV) infection has been a focus of research in many fields, as it continues to pose a problem to disease prevention and HIV patient management. In addition to techniques of molecular biology, studies in mathematical modelling have contributed to the knowledge here, but many questions remain unanswered. This thesis explores the application of a number of hybrid stochastic/deterministic models of viral replication to scenarios where viral evolution may be clinically or epidemiologically important. The choice of appropriate measures of viral evolution/diversity is non-trivial, and this impacts on the choice of mathematical techniques deployed. The use of probability generating functions to describe mutations occurring during early infection scenarios suggest that very early interventions such as pre-exposure prophylaxis (PrEP) or vaccines may substantially reduce viral diversity in cases of breakthrough infection. A modified survival analysis coupled to a deterministic model of viral replication during transient and chronic treatment helps identify clinically measurable indicators of the time it takes for deleterious rare mutations to appear. Lastly, persistence of problematic mutations is studied through the use of deterministic models with stochastic averaging over initial conditions.

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Thesis (MSc Virology)--University of Limpopo, 2010. / OBJECTIVES: To date there is no effective and safe vaccine to stop the spread of human immunodeficiency virus (HIV) and provide cross protection among different subtypes. HIV accessory genes were overlooked for many years and recently they are becoming candidates for development of new anti-HIV drugs and vaccines. This is supported by their ability to elicit cytotoxic T lymphocyte response. To date, there are limited studies on accessory genes (nef, vif, vpr and vpu) on South African HIV strains. This study sought to amplify and analyse the sequences of HIV-1 subtype C accessory genes (vif, vpr and vpu) to assess the genetic diversity as well as the motifs and residues associated with key biological functions of these genes. This study further sought to compare the degree of genetic diversity between the accessory and structural genes. METHODS: The study was an exploratory study using stored (-70ºC) HIV positive plasma samples. The study population comprised of 25 HIV positive plasma samples which were already sequenced in the gag and env genes in another study. The samples were drawn from the neighbouring townships of Pretoria: Ga-Rankuwa, Soshanguve, Mamelodi, Laudium, Kalafong, Jubilee and Mabopane. For the purpose of this study, the same samples were amplified, sequenced and characterised in the pol and accessory (vif, vpr and vpu) genes in order to obtain near full length sequences of the HIV isolates from Pretoria region. Six samples were cloned for accessory genes. Five clones from each sample were selected. Sequence analysis was performed for all the PCR amplicons and clones. Base calling for the sequences generated was performed on Chromas Pro program. Computing of phylogenetic tree was performed with MEGA 4 program. ClustalW software was used for sequence alignment and translation of nucleotides to amino acids was performed with BioEdit. The amino acid alignments were analysed on graphic view. RESULTS: All 25 samples were successfully amplified for accessory genes (vif, vpr and vpu) and pol gene. All the 25 pol PCR amplicons were successfully sequenced, while all but one accessory PCR amplicons were successfully sequenced. A number of conserved motifs and residues were observed in all the four genes (vif, vpr, vpu and pol). Vif and vpr showed to harbour most of these conserved motifs and residues; 144-SLQYLA-149 and H71 respectively. In addition, the R77Q mutation associated with long term non-progressors was observed in the vpr gene of 15 sequences. Drug resistant mutations were evaluated in both protease and RT regions. Nine samples had one or two drug resistant mutations i.e T74S, L10I, V179D, E138A/D, Y318F,Y181C and K108N. Phylogenetic analysis confirmed the 25 HIV positive samples to be HIV-1 subtype C in both structural and accessory genes. The genetic diversity of HIV-1 subtype C was compared between accessory (vif, vpr and vpu) and structural (pol, gag and env) genes. The gag and env sequences were available from a previous project (Musyoki, 2009). The gag and vif gene sequences were highly conserved (89% to 96% and 88% to 96%, respectively), as compared to vpr gene (84% to 94%), the pol gene (79% to 95%), the env gene (83% to 93%) and finally the vpu gene (73% to 92%). CONCLUSION: This study found that amplification of clones was more sensitive as compared to direct samples and analysis of clone sequences was more clear than analysis of direct PCR products. Functional motifs and residues observed in all accessory genes were highly conserved. Vif was more conserved, followed by vpr and vpu, respectively. Genetic analysis of pol gene revealed that there were drug resistant strains in circulation. This indicates that the patients were infected with drug resistant viruses; this cannot be verified from the study population. And that most of the strains in this study had mutations associated with long term non-progressors (LTNP’s). However, it is not known whether these patients were indeed LTNP’s. Comparison of genetic diversity between structural and accessory genes demonstrated that, gag, vif and vpr were more conserved than pol, env and vpu.

Thesis (M Cur)-- University of Limpopo, 2012. / ABSTRACT Background and problem statement The increase in AIDS related deaths of parents leave many children orphaned and some of these children live with HIV. These children are cared for by primary caregivers who are mostly elderly women. The primary caregivers experiences challenges when caring for the children living with HIV. These challenges may be physical, spiritual, psychological and social. The researcher conducted a study in order to explore the experiences of primary caregivers caring for children living with HIV. Aim and objectives The aim of the study was to promote the mental health of primary caregivers who provide care for children living with HIV attending the Wellness Clinic at the Jubilee Hospital in Hammanskraal. The objectives of this study were to: i) describe the biographical data of primary caregivers who provide care for children living with HIV; ii) explore and describe the experiences of primary caregivers who provide care for children living - with HIV; and iii) make recommendations which are based on the findings of this study in order to assist the nursing personnel at the Wellness Clinic in the promotion of the mental health of primary caregivers based on the findings of this study. Research Design and method A qualitative, exploratory, descriptive and contextual design was utilised to enable the primary caregivers to share with the researchers their experiences of caring for children living with HIV. The setting was the Wellness Clinic at the Jubilee hospital, Hammanskraal. Ethical principles were adhered to in order to protect the rights of the primary caregivers. Throughout the process, the methods to ensyre trustworthiness of the study were foll9wed. A purposive sample of eight primary caregivers was chosen for the unstructured interviews. Data were analysed by the researcher and an independent coder using the Tescn method. Research Findings Consensus was reached after consultation with an independent coder,- about the following categories i) primary caregivers' experiences in caring for a child living with HIV related to the self of the caregiver; ii) primary caregivers' experiences related to the decision to disclose the child's HIV status to various role-players were influenced by stigmatisation and discrimination related to HIV and AIDS; iii) primary caregivers' challenges when caring for a child living with HIV; and iv) the mobilisation of resources by primary caregivers to assist them in caring for a child living with HIV. Findings were contexualised by implementing a literature control and recommendations were made to promote their mental health. Conclusions Primary caregivers who cared for children living with HIV in this study were mostly elderly women who were related to the children. They took over the care of the children living with HIV after the children's parents had died. Although they were faced with many challenges, their concern for the children's wellbeing made them to give the children loving care. They found strength and support from prayer, faith and hope in God. The primary caregivers also appreciated the support they received from the health care workers at the Well"ness Clinic. Key words: caring, mental health, HIV, children, primary caregiver

Background: The human immunodeficiency virus (HIV) is the cause of the acquired immunodeficiency syndrome (AIDS). AIDS is fatal if not treated appropriately. Although there are treatment options for the infection, there are many problems associated with it, including non-compliance to prescribed treatments due to toxicity and side effects, leading to drug resistance. There is therefore a need to develop novel drugs that are less toxic. This study contributes to the fight against HIV/AIDS by recommending new metallodrugs able to address the shortcomings of existing treatments. Metals have previously demonstrated potential in targeting HIV-1, mostly with activity against the enzymes reverse transcriptase and protease. The current study investigated the effects of metal-based complexes against viral entry into host cells. Methods: Three metal-based complexes; Aryl-1H-1,2,3- triazole-based cyclometalated Ruthenium (II) complex (A), Aryl-1H-1,2,3- triazole-based cyclometalated Iridium (III) complex (B) and Aryl-1H-1,2,3- triazole-based cyclometalated Osmium (II) complexes (C) were investigated for potential HIV entry inhibition and their activity was compared to that of the ligand which did not contain the metal component. The study analysed the toxicity of the complexes in TZM-bl cells and Peripheral blood mononuclear cells (PBMCs). Three pseudo-viruses (CAP 210, Du 156 and Q 23) were created using transformation and transfection methods and a luciferase reporter gene assay was used to analyse the inhibitory effects of the complexes on the pseudo-virus infection of TZM bl cells. Active complexes were further analysed for a potential mechanism of action through in silico docking. Results and discussion: The complexes were found to have lower CC50 values in PBMCs compared to TZM-bl cells. In both cell lines, B had the lowest CC50 value, which can be attributed to the increased hydrolysis of the chloride atom bound to the iridium as well as the increased uptake into the cells. Based on the luciferase reporter gene assay all three of the metal-based complexes had inhibition of viral infection with IC50 values ranging from 5.34 – 7.41 µM for A, 2.35 – 8.09 µM for B and 2.59 to 4.18 µM for C. The ligand was only analysed for any inhibitory activity on one of the pseudo-viruses (Du 156) and was found to have no significant inhibition. Selectivity index (SI) values indicated the complexes were effective at non-toxic concentrations with values ranging from 1.61 – 4.56 for B, 3.29 – 4.56 for A and 7.03 – 11.26 for C. In silico docking analysis of the proteins involved in viral entry indicated that inhibition possibly occurred through interaction with the CCR5 co-receptor, as the docking scores for this protein were the most negative indicative of favourable interactions between proteins and ligands. Conclusion: The metal-based complexes showed inhibition with IC50 values in the low micromolar range, while the ligand had no statistically significant inhibition. This suggests that the presence of the metal ion enhances viral inhibition. Furthermore, inhibition was through the interaction of the complexes with CCR5, in a manner similar to that of Maraviroc, a clinically utilized CCR5 inhibitor. This study identified novel metal-based HIV-1 entry inhibitors which were effective against HIV-1 subtype A and C at non-toxic concentrations. / Dissertation (MSc (Biochemistry))--University of Pretoria, 2021. / Biochemistry / MSc (Biochemistry) / Unrestricted