No description available.

No description available.

No description available.

No description available.

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.

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

No description available.

No description available.

No description available.