Analysis of integrated, diverse, Human Immunodeficiency Virus (HIV)-associated datasets can increase knowledge and guide the development of novel and effective interventions for disease prevention and treatment by increasing breadth of variables and statistical power, particularly for sub-group analyses. This topic has been identified as a National Institutes of Health research priority, but few efforts have been made to integrate data across HIV studies. Our aims were to: 1) Characterize the semantic heterogeneity (SH) in the HIV research domain; 2) Identify HIV-associated common data elements (CDEs) in empirically generated and knowledge-based resources; 3) Create a formal representation of HIV-associated CDEs in the form of an HIV-associated Entities in Research Ontology (HERO); 4) Assess the feasibility of using HERO to semantically harmonize HIV research data. Our approach was guided by information/knowledge theory and the DIKW (Data Information Knowledge Wisdom) hierarchical model. Our systematized review of the literature revealed that synergistic use of both ontologies and CDEs included integration, interoperability, data exchange, and data standardization. Moreover, methods and tools included use of experts for CDE identification, the Unified Medical Language System, natural language processing, Extensible Markup Language, Health Level 7, and ontology development tools (e.g., Protégé). Additionally, evaluation methods included expert assessment, quantification of mapping tasks between raters, assessment of interrater reliability, and comparison to established standards. We used these findings to inform our process for achieving the study aims. For Aim 1, we analyzed eight disparate HIV-associated data dictionaries and developed a String Metric-assisted Assessment of Semantic Heterogeneity (SMASH) method, which aided identification of 127 (13%) homogeneous data element (DE) pairs and 1,048 (87%) semantically heterogeneous DE pairs. Most heterogeneous pairs (97%) were semantically-equivalent/syntactically-different, allowing us to determine that SH in the HIV research domain was high. To achieve Aim 2, we used Clinicaltrials.gov, Google Search, and text mining in R to identify HIV-associated CDEs in HIV journal articles, HIV-associated datasets, AIDSinfo HIV/AIDS Glossary, AIDSinfo Drug Database, Logical Observation Identifiers Names and Codes (LOINC), Systematized Nomenclature of Medicine (SNOMED), and RxNORM (understood as prescription normalization). Two HIV experts then manually reviewed DEs from the journal articles and data dictionaries to confirm DE commonality and resolved semantic discrepancies through discussion. Ultimately, we identified 2,179 unique CDEs. Of all CDEs, data-driven approaches identified 2,055 (94%) (999 from the HIV/AIDS Glossary, 398 from the Drug Database, 91 from journal articles, and a total of 567 from LOINC, SNOMED, and RxNorm cumulatively). Expert-based approaches identified 124 (6%) unique CDEs from data dictionaries and confirmed the 91 CDEs from journal articles. In Aim 3, we used the Protégé suite of ontology development tools and the 2,179 CDEs to develop the HERO. We modeled the ontology using the semantic structure of the Medical Entities Dictionary, available hierarchical information from the CDE knowledge resources, and expert knowledge. The ontology fulfilled most relevant criteria from Cimino’s desiderata and OntoClean ontology engineering principles, and it successfully answered eight competency questions. Finally, for Aim 4, we assessed the feasibility of using HERO to semantically harmonize and integrate the data dictionaries from two diverse HIV-associated datasets. Two HIV experts involved in the development of HERO independently assessed each data dictionary. Of the 367 DEs in data dictionary 1 (D1), 181 (49.32%) were identified as CDEs and 186 (50.68%) were not CDEs, and of the 72 DEs in data dictionary 2 (D2), 37 (51.39%) were CDEs and 35 (48.61%) were not CDEs. The HIV experts then traversed HERO’s hierarchy to map CDEs from D1 and D2 to CDEs in HERO. Of the 181 CDEs in D1, 156 (86.19%) were found in HERO, and 25 (13.81%) were not. Similarly, of the 37 CDEs in D2 32 (86.48%) were found in HERO, and 5 (13.51%) were not. Interrater reliability for CDE identification as measured by Cohen’s Kappa was 0.900 for D1 and 0.892 for D2. Cohen’s Kappas for CDEs in D1 and D2 that were also identified in HERO were 0.885 and 0.688, respectively. Subsequently, to demonstrate the integration of the two HIV-associated datasets, a sample of semantically harmonized CDEs in both datasets was categorically selected (e.g. administrative, demographic, and behavioral), and D2 sample size increases were calculated for race (e.g., White, African American/Black, Asian/Pacific Islander, Native American/Indian, and Hispanic/Latino) and for “intravenous drug use” from the integrated datasets. The average increase of D2 CDEs for six selected CDEs was 1,928%. Despite the limitation of HERO developers also serving as evaluators, the contributions of the study to the fields of informatics and HIV research were substantial. Confirmatory contributions include: identification of effective CDE/ontology tools, and use of data-driven and expert-based methods. Novel contributions include: development of SMASH and HERO; and new contributions include documenting that SH is high in HIV-associated datasets, identifying 2,179 HIV-associated CDEs, creating two additional classifications of SH, and showing that using HERO for semantic harmonization of HIV-associated data dictionaries is feasible. Our future work will build upon this research by expanding the numbers and types of datasets, refining our methods and tools, and conducting an external evaluation.

Submiltted in fulfillment of the requirements for the degree of Master of Science in the faculty of Science, University of the Witwatersrand, Johannesburg • Johannesburg 1993. / The roles of the highly conserved aspartic acid residues found at positions 443 and 498 within the RNase H domain of Human Immunodeficiency Virus type-1 reverse transcription were investigated by the defined substitution of these residues using site-directed mutagenesis. [Abbreviated Abstract. Open document to view full version] / MT2016

HIV/AIDS is a global pandemic that poses a great threat especially in Sub-Saharan Africa where the highest population of those infected with the virus is found. It has far reaching medical, socio-economic and scientific implications. The HIV-1 protease enzyme is a prime therapeutic target that has been exploited in an effort to reduce morbidity and mortality. However problems arise from drug toxicity and drug-resistant mutations of the protease which is a motivation for research for new, safer and effective therapies. Evidence exists to show that there are significant genomic differences in Subtype B and C that have a negative effect on the intrinsic binding of inhibitors. It is imperative to look at all perspectives from epidemiological, molecular to the pharmacological ones so as to achieve rational design of therapeutic agents. This study involved the use of in silico structural analysis of the effects of mutations in the active site. The data was provided by the National Institute of Communicable Diseases consisting of HIV-1 Subtype C protease sequences of 29 infants exhibiting drug-resistance to ritonavir and lopinavir. The major active site mutations causing drug resistance identified in this study were M46I, I54V and V82A using the Stanford HIV database tool. Homology modeling without extra restraints produced models with improved quality in comparison to those with restraints. MetaMQAPII results differed when models were visualized as dimers giving erroneous modeled regions in comparison to monomers. A broader study with a larger dataset of HIV-1 subtype C protease sequences is required to increase statistical confidence and in order to identify the pattern of drug resistant mutations. Homology modeling without extra restraints is preferred for calculating homology models for the HIV-1 subtype C. Further investigations needs to be done to ascertain the accuracy of validation results for dimers from MetaMQAPII as it is designed for evaluation of monomers.

Thesis (MScMedSc) -- University of Stellenbosch, 2002. / ENGLISH ABSTRACT: The gag gene of HIV-1 encodes for one of the major structural proteins, which contains several conserved cytotoxic T cell (CTL) epitopes. Gag specific CTL responses are important in controlling viral load during acute infection and asymptomatic stages of the infection. Currently, only one complete South African HIV-1 subtype C gag sequence has been published. The first aim of this study was to characterise the complete gag gene of 15 HIV-1 subtype C isolates, to be used as a set of reference sequences in the design of a South African HIV-1 subtype C vaccine. Fifteen HIV-1 subtype C isolates selected for this study, were isolated during 1998 and 1999 from the HIV-1 positive patients attending the Infectious Disease Clinic at Tygerberg Hospital. The gag gene of these isolates was amplified by PCR, cloned into mammalian expression vectors and sequenced. Restriction digest analyses as well as phylogenetic analyses were performed on the sequencing data. Previously published mutational analyses and CTL epitopes were compared to the predicted amino acid sequences of the gag clones. Sequences of 23 complete gag genes representing the 15 HIV-1 subtype C isolates as well as one complete sequence of an HIV-1 subtype B isolate were compiled. Subtyping by restriction fragment length polymorphism (RFLP) would have correctly identified 14 of the 15 subtype C isolates as subtype C and one as unidentifiable. The subtype B isolate would have also been correctly identified. Phylogenetic analyses showed that our subtype C isolates clustered with reference subtype C strains from various countries, including Botswana, India, Israel, Tanzania and Zambia. Strains from Ethiopia and Brazil formed a separate subtype C cluster. The diversity between our isolates was comparable to the diversity seen between all the HIV-1 subtype C strains. Comparisons of previously published mutational analyses and CTL epitopes to the predicted amino acid sequences of the gag clones, showed conservation in most of the clones throughout the sequence. A second aim was to establish transfection and Western Blot techniques in our laboratory for use in future studies. An in vitro transcription! translation assay was performed on the gag clones and the protein producing clones were used to transfect mammalian cells using electroporation. A Western blot was then used to screen for Gag protein expression in the transfected cell Iysates. The in vitro transcription! translation assay showed that seven of the 23 clones could produce a protein of -55 kDa in size. Four out of the seven of these clones gave a weak expression of a-55 kDa protein after transfection in a mammalian cell line. Since the completion of the experimental work of this study, other cloned HIV-1 genes have successfully been transfected into mammalian cells using the electroporation technique and the proteins produced were screened for by Western blot. To conclude with; the native form of the gag gene does not elicit strong expression of the protein, but studies have shown that expression can be improved by sequence-modification of the gag nucleotide sequence. Due to the conservation of gag, the sequence of any subtype C strain can be used for the development of a Southern African vaccine. / AFRIKAANSE OPSOMMING: Die HIV-1 gag geen kodeer vir een van die hoof strukturele proterene en bevat verskeie sitotoksiese T-limfosiet epitope. Gag spesifieke sellulere immuun respons is belangrik vir die beheer van virale lading tydens akute infeksies en tydens asimptomatiese fases van die infeksie. Tans is slegs een volledige Suid Afrikaanse HIV-1 subtipe C nuklerensuur volgorde gepubliseer. Die eerste doel van hierdie studie was om die volledige gag geen van 15 HIV-1 subtipe C isolate te karakteriseer, om gebruik te word as In stel verwysings nukleiensuur volgordes, vir die ontwerp van In Suid Afrikaanse HIV-1 subtipe C entstof. Die 15 HIV-1 subtipe C isolate wat vir hierdie studie geselekteer is, is tydens 1998 en 1999 ge·lsoleer vanaf HIV-1 positiewe pasiente wat die Infeksiesiekte Kliniek, Tygerberg Hospitaal bygewoon het. Die gag geen van hierdie isolate is geamplifiseer deur PKR, gekloneer in soogdier ekspressie vektore en die nukleiensuur volgorde is bepaal. Die nuklerensuur volgorde is gebruik in restriksie ensiem analises asook filogenetiese analises. Reeds gepubliseerde mutasie analises en limfosiet epitope is met die voorspelde aminosuur volgorde van die gag klone vergelyk. Die nukleiensuur volgordes van die 23 volledige gag gene wat die 15 HIV-1 subtipe C isolate verteenwoordig, asook een volledige nukleiensuur volgorde van een HIV-1 subtipe B isolaat, is saamgestel. Subtipering deur middel van restriksie fragment lengte polimorfisme (RFLP) sou 14 uit die 15 subtipe C isolate korrek qerdentifiseer het, maar sou een nie kon identifiseer nie. RFLP sou ook die subtipe B isolaat korrek qerdentifiseer het. Filogenetiese analises het gewys dat ons subtipe C isolate met die verwysings subtipe C stamme van verskeie lande, insluitend Botswana, lndie, Israel, Tanzania en Zambie groepeer. Stamme van Ethiopie en Brasilie het In aparte subtipe C groep gevorm. Die diversiteit tussen ons isolate was vergelykbaar met die diversiteit tussen al die subtipe C stamme. Vergelykings van gepubliseerde mutasie analises en limfosiet epitope met die voorspelde aminosuur volgorde van die gag klone, het konservasie in meeste van die klone, deur die hele nukleiensuur volgorde, getoon. Die tweede doel was om die metodes van transfeksie en Westerse klad in ons laboratorium tot stand te bring. In vitro transkripsie/ translasie toetse is gedoen op die gag klone en die proteten produserende klone is gebruik om soogdierselle te transfekteer deur gebruik te maak van elektroporasie. In Westerse klad is toe gebruik om vir Gag proterenuitdrukkinq in die sellisate te toets. Die in vitro transkripsie/ translasie toets het getoon dat sewe uit 23 klone, In proteren van -55 kDa kon produseer. Vier uit die sewe van hierdie klone het In -55 kDa proteren swak uitgedruk na transfektering van soogdier selle. Sedert die voltooiing van die eksperimentele werk van hierdie stud ie, is ander gekloneerde HIV-1 gene suksesvol in soogdierselle getransfekteer met die gebruik van elektroporasie en die proterene is met In Westerse klad aangetoon. Ten slotte: die natuurlike vorm van die gag geen ontlok nie In sterk ekspressie van die proteren nie, maar ander studies het wei aangetoon dat die ekspressie verbeter kan word met modifikasie van die gag nukleiensuur volgorde. As gevolg van die konservasie van gag, kan die nuklerensuur volgorde van enige subtipe C stam gebruik word vir die ontwikkeling van In Suider Afrikaanse entstof. / The Poliomyelitis Research Foundation / The South African AIDS Vaccine Initiative / Harry Crossley Foundation

Thesis (MSc)--Stellenbosch University, 2000. / ENGLISH ABSTRACT: At the end of 2002, human immunodeficiency virus (HIV) had infected 42 million people worldwide. The morbidity and mortality rate, as well as the epidemic proportions of the disease have led to concentrated scientific efforts to reveal the disease's pathogenesis and develop effective preventative and treatment measures. Advances have been made to inhibit viral replication by suppressing the virus' ability to replicate by developing antiretroviral treatments, although development of a save and effective vaccine is the only way to stem the pandemic. Advances in vaccine design, animal models and clinical research have led to the creation of promising candidate vaccines to counter this rampage, but most of these vaccines entering phase I-III clinical trials are based mainly only subtype B genomes. HIV-1 subtype C is the most commonly transmitted subtype worldwide, and is the predominant subtype in India, China, East and Southern Africa. A subtype C vaccine is critical for the developing nations such as South Africa, where antiretroviral therapies are largely unaffordable. The envelope gene (env) is an attractive target as immunogen to be included in a HIV vaccine. The envelope protein (Env) elicits neutralising antibodies and cytotoxic T-Iymphocyte (CTl) responses. This protein will therefore be useful in creating a humoral and cellular immune response in the host. A shortage in characterised subtype C env gene sequences from South Africa was recognised, and this study focussed on the characterisation of generated sequences, as well as the expression of selected env genes. These immunogens were created for possible use in a prime-boost vaccine modality. The env genes from recent circulating strains in South Africa were amplified by polymerase chain reaction (PCR). The genes were then cloned for sequencing and expression purposes. Phylogenetic relationships were determined by comparing the sequences to reference subtype strains and subtype C strains. Expression of the genes was assessed by Western Blot in 293 cells with HIV- 1 positive patient sera. Sequence analysis showed a more conserved third variable (V3) loop in South African subtype C sequences, with a more variable region downstream from the loop. The crown sequence (GPGQ) and positions of uncharged or negatively charged residues in the V3 loop indicated a non-syncytium-inducing (NSI) phenotype for the isolates. Phylogenetic analysis showed the sequences to all belong to the C subtype, and further that the sequences were not recombinant, which was confirmed by recombination analysis. The intersample diversity observed for strains from South Africa was significantly higher than distances observed to the subtype C consensus sequence. The South African sequences were distributed across several subclusters in a subtype C phylogenetic tree, highlighting the concept that these infections represent a more longstanding epidemic with multiple introductions from different geographic areas. Western Blot with HIV-1 positive patient sera showed the expression of uncleaved gp160 Env proteins, which were Rev dependent. This study has generated much needed subtype C South African env gene sequences that can be used as basis for modification for use as immunogens in a South African vaccine. / AFRIKAANSE OPSOMMING: Teen die einde van 2002 was 42 miljoen mense wêreldwyd geïnfekteer met die menslike immuniteitsgebrekvirus (MIV). Die dode- en sterfte syfers, asook die skaal van die epidemie, het gelei tot 'n wetenskaplike poging om die siekte se patogenese te openbaar en om effektiewe voorkomende en terapeutiese middels te ontwikkel. Vordering is reeds gemaak om die virus se replikasie te hinder deur die ontwerp van antivirale middels, alhoewel die ontwikkeling van 'n doeltreffende en veilige entstof die enigste manier is om die pandemie te stuit. As gevolg van die vordering in entstof ontwerp, diere modelle en kliniese navorsing is belowende kandidaat entstowwe wat die infeksie kan teenwerk ontwikkel, maar die meeste van hierdie enstowwe wat vir fase I-III kliniese proewe gebruik word is gebaseer op subtipe B genome. MIV-subtipe C is wêreldwide die algemeenste subtipe wat oorgedra word en is die oorheersende subtipe in lande soos Indië, China, oostelike en suidelike Afrika. 'n Subtipe C entstof word dringend benodig in ontwikkelende lande soos Suid-Afrika waar antivirale middels onbekostigbaar is. Die membraangeen is 'n aanloklike teiken om as immunogeen in 'n MIV entstof te dien. Die membraanproteïen lok neutraliserende teenliggame en sitotoksiese T-limfosiet reaksies uit. Die proteïen sal dus 'n humorale en sellulêre immuunrespons in die gasheer ontlok. 'n Tekort aan gekarakteriseerde subtipe C membraangeen volgordes van Suid-Afrika is opgemerk, en dus fokus hierdie studie op die karakterisering van gegenereerde volgordes, asook die uitdrukking van geselekteerde membraangene. Die immunogene is geskep om moontlik gebruik te word in 'n stimuleer-versterkingsenstof toedieningstrategie. Die membraangene van onlangs sirkulerende virusstamme in Suid-Afrika was geamplifiseer deur polimerase kettingreaksie (PKR). Die gene is daarna gekloneer vir beide volgordebepalings en uitdrukkingdoeleindes. Filogenetiese verhoudings is uitgewerk deur die volgordes met verwysingsstamme en subtipe C stamme te vergelyk. Uitdrukking van die gene is waargeneem in 293 selle deur die Westerse kladtegniek te gebruik met MIV-1 positiewe pasiëntsera as teenliggaam. Volgorde-analise het aangetoon dat die derde varieerbare (V3) lus meer gekonserveer is, en dat die gedeelte wat op die lus volg meer varieerbaar is. Die kroonvolgorde (GPGQ) asook posisies van ongelaaide of negatief gelaaide aminosure in die V3 lus het aangedui dat die isolate 'n nie-syncytia induserende fenotipe het. Filogenetiese analise het aangedui dat al die volgordes subtipe C is en dat die volgordes nie rekombinant is nie. Dit is ook deur rekombinasie analise bewys. Die inter-monster diversiteit van die Suid-Afrikaanse volgordes was hoër as die waargenome afstand vanaf die subtipe C konsensus volgorde. Die Suid-Afrikaanse volgordes is versprei oor verskeie subgroepe in 'n subtipe C boom, wat die konsep dat hierdie infeksies 'n meer gevestigde epidemie voorstel waar veelvuldige infeksies met verskillende geografiese oorspronge plaasgevind het beklemtoon. Die Westerse klad het ongeprosesseerde gp160 membraanproteïne aangetoon wat Rev afhanklik was. Hierdie studie het hoogs benodigde subtipe C Suid-Afrikaanse volgordes van membraangene geproduseer. Die volgordes kan as basis dien om die gene te modifiseer sodat dit gebruik kan word as immunogene in 'n entstof vir Suid-Afrika.

Despite the current interventions to avert contagions and AIDS-related deaths, sub-Saharan Africa is still the region most severely affected by the HIV/AIDS pandemic, where clade C is the dominant circulating HIV-1 strain. The pol-encoded HIV-1 protease enzyme has been extensively exploited as a drug target. Protease inhibitors have been engineered within the framework of clade B, the commonest in America, Europe and Australia. Recent studies have attested the existence of sequence and catalytic disparities between clades B and C proteases that could upset drug susceptibilities. Emergence of drug-resistant associated mutations and combinatorial explosions due to recombination thwarts the attempt to stabilize the current highly active antiretroviral therapy (HAART) baseline. The project aimed at identifying the structural and molecular mechanisms hired by mutants to affect the efficacies of both FDA approved and Rhodes University (RU)-synthesized inhibitors, in order to define how current and or future drugs ought to be modified or synthesized with the intent of combating drug resistance. The rationale involved the generation of homology models of the HIV-1 sequences from the South African infants failing treatment with two protease inhibitors: lopinavir and ritonavir (as monitored by alterations in surrogate markers: CD4 cell count decline and viral load upsurge). Consistent with previous studies, we established nine polymorphisms: 12S, 15V, 19I, 36I, 41K, 63P, 69K, 89M, and 93L, linked to subtype C wild-type; some of which are associated with protease treatment in clade B. Even though we predicted two occurrence patterns of M46I, I54V and V82A mutations as V82A→I54V→M46I and I54V→V82A→M46V, other possibilities might exist. Mutations either caused a protracted or contracted active site cleft, which enforced differential drug responses. The in silico docking indicated susceptibility discordances between clades B and C in certain polymorphisms and non-polymorphisms. The RU-synthesized ligands displayed varied efficacies that were below those of the FDA approved protease inhibitors. The flaps underwent a wide range of structural motions to accommodate and stabilize the ligands. Computational analyses unravelled the need for these potential drugs to be restructured by (de novo) drug engineers to improve their binding fits, affinities, energies and interactions with multiple key protease residues in order to target resilient HIV-1 assemblages. Accumulating evidences on contrasting drug-choice interpretations from the Stanford HIVdb should act as an impetus for the customization of a HIVdb for the sub-Saharan subcontinent.

Thesis (MBA (Business Management))--Stellenbosch University, 2008. / The government has identified the need to transform the South African economy from one that is primarily resource based to one that is knowledge-based and has formulated a 10 year plan in order to accomplish this objective. The plan involves the creation and funding of five theme-specific consortium-based centres of competence that focus on the five top national health priorities, linked to the growth of the local pharmaceutical industry. This research study proposed that if collaboration and communication between academic researchers and the biotechnology industry in South Africa was improved it would lead to an increase in the development of innovative products for HIV/AIDS prevention and treatment. The objective of the study was the development of a strategy for a centre of competence for HIV research and development that brings together academic researchers and industry in a public private partnership and that will enable the proposal to be tested. Centre of competence programmes in both developed and developing countries, including Sweden, Austria and Estonia, were reviewed. The success factors for the various programmes were discussed. The strategic planning analysis began by considering the mandate of the CoC for HIV R&D. The requirements and expectations of the DST in establishment of the centres of competence were examined. An analysis of the external environment relevant to the South African biotechnology industry was then performed. This involved a detailed macro-environmental analysis in which political, economic, social, technological and environmental factors were considered. It was followed by an analysis of the current biotechnology industry in South Africa. The industry’s dominant economic features were identified as were its future driving forces. In a competitive environment analysis the South African biotechnology industry was found to be extremely competitive. Two industry issues, price controls and access to capital, were identified and discussed. The industry key success factors identified included access to large and sustained capital, attracting and retaining talented employees, an efficient and high quality regulatory authority, continued government support, productive and appropriate partnerships and skilled intellectual property management. An internal environment analysis was performed which identified competencies and resource strengths of the CoC for HIV R&D, including the high level of academic research in the HIV/AIDS field and expertise in clinical trials of HIV/AIDS products. Competitive deficiencies and resource weaknesses identified included shortages of skills and talent and the lack of co-ordination for funding of HIV/AIDS research. The analysis of the internal environment continued with the examination of the internal value chain of the CoC for HIV R&D. This consisted of discovery, pre-clinical development and clinical development stages. Gaps in the value chain were identified, including the lack of facilities for high-throughput screening of compounds for anti-HIV activity, lack of pre-clinical testing facilities and lack of manufacturing plants capable of producing products for use in clinical trials. The results of the external and internal environment analysis were used in a SWOC analysis and a number of strategies were identified to capitalise on opportunities and to address challenges. A subsequent competitive strength assessment identified a competitive advantage in the formation of the CoC for HIV R&D. In addition a number of strategic issues facing the centre were identified and ways to address or manage the issues were proposed. The strategic planning process was completed by the selection of a strategic approach for the CoC for HIV R&D. The study concluded that a PPP of public and private organisations operating under a corporate strategy of related diversification developed and implemented by the CoC for HIV R&D, would be suitable for testing the Proposal. The study’s conclusion also highlighted the need to ensure that the CoC for HIV R&D receives a long term commitment of funding from public sources, and that is managed by an experienced team with strong leadership skills. Important strategies emerging from the study and specifically from the SWOC analysis were development of a national HIV research plan and funding of the highest priority projects; focusing research funding on research with greatest potential for generation of HIV/AIDS products; and establishment of new technology platforms to fill gaps in the value chain. Finally, a number of recommendations were made for implementation of the results of this study or as the basis for further study.

This thesis sought to develop an agent-based model that replicates the formation of social and sexual partnerships in real-world settings with an eventual aim of revealing the main drivers of the HIV pandemic in a closed mixed society. Agent-based modelling is a computational modelling approach that allows for the simulation of the actions and interactions of autonomous agents, with the eventual objective of disovering global effects on the system. This modelling technique is less dependent on generalisations and does not average out the behaviour of individuals. Sexual partnerships formed in the model goes through the process of dating, courting and has a chance of developing into marriage as well as the possibility of breaking up or undergo divorce. Sexual partnership formation is based on a likeability index calculated using aspiration, attractiveness and age. Over and above the the sexual relationships we include commercial sex work. Commercial sex work depends mainly on the availability of female sex workers and their clients. We superimpose the spread of HIV on the social and sexual network model. Results from the model reveal that saturation of HIV prevalence is driven by the social and sexual network structure, behaviour change as well as biologic factors. Excluding commercial sex work in the model resulted in a decrease in HIV prevalence and incidence. Dense social networks resulted in a dense sexual network which consequently increased HIV incidence. A change in the infection probability per coital act contributed significantly to a change in incidence and prevalence levels. Model results also show that enrolling all HIV positive agents on antiretroviral therapy (ART) as from 2016 simulation year will help in curbing HIV transmission if zero dropout rate from ART is assumed. Therefore, on concomitant action to avoid dropouts from ART is necessary if full benefits of introducing ART to all HIV positive individuals are to be realised. / Operations Management / D.Phil. (Operations Research)

Indiana University-Purdue University Indianapolis (IUPUI) / Magnetic resonance (MR) spectroscopy is a neuroimaging technique. It is widely used to quantify the concentration of important metabolites in a brain tissue. Imbalance in concentration of brain metabolites has been found to be associated with development of neurological impairment. There has been increasing trend of using MR spectroscopy as a diagnosis tool for neurological disorders. We established statistical methodology to analyze data obtained from the MR spectroscopy in the context of the HIV associated neurological disorder. First, we have developed novel methodology to study the association of marker of neurological disorder with MR spectrum from brain and how this association evolves with time. The entire problem fits into the framework of scalar-on-function regression model with individual spectrum being the functional predictor. We have extended one of the existing cross-sectional scalar-on-function regression techniques to longitudinal set-up. Advantage of proposed method includes: 1) ability to model flexible time-varying association between response and functional predictor and (2) ability to incorporate prior information. Second part of research attempts to study the influence of the clinical and demographic factors on the progression of brain metabolites over time. In order to understand the influence of these factors in fully non-parametric way, we proposed LongCART algorithm to construct regression tree with longitudinal data. Such a regression tree helps to identify smaller subpopulations (characterized by baseline factors) with differential longitudinal profile and hence helps us to identify influence of baseline factors. Advantage of LongCART algorithm includes: (1) it maintains of type-I error in determining best split, (2) substantially reduces computation time and (2) applicable even observations are taken at subject-specific time-points. Finally, we carried out an in-depth analysis of longitudinal changes in the brain metabolite concentrations in three brain regions, namely, white matter, gray matter and basal ganglia in chronically infected HIV patients enrolled in HIV Neuroimaging Consortium study. We studied the influence of important baseline factors (clinical and demographic) on these longitudinal profiles of brain metabolites using LongCART algorithm in order to identify subgroup of patients at higher risk of neurological impairment. / Partial research support was provided by the National Institutes of Health grants U01-MH083545, R01-CA126205 and U01-CA086368