Thesis (MSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: With a cure for HIV and AIDS still absent, non-nucleoside reverse transcriptase inhibitors (NNRTIs) play a major role in the current antiretroviral treatments used, which have shown to improve and prolong the lives of HIV patients significantly. However, with rapid mutations of the HI virus, the use of these drugs is becoming limited, thereby highlighting the need for the development of new NNRTIs. Previous work by our research team has led to the development of a cyclopropyl-containing indole-based compound with an inhibition activity (IC50 value) of 0.1 μM, as determined in an in vitro single-cycle, non-replicative phenotypic assay. Therefore, in this project, we focussed on enhancing the intermolecular interactions of our compound to three major areas in the NNRTI binding pocket, namely the Tyr181, the Val179, and the Lys101 binding pockets. Hereby we were able to obtain both improved and lower potencies, with our most active compound having an inhibition activity (IC50 value) of 1 nM. For the interaction to the Tyr181 binding pocket, we were thus unable to synthesise a heterocyclic ring system onto our molecule as opposed to the previously used phenyl ring. Secondly, for the interaction to the Lys101 binding pocket we were able to synthesise a tetrazole ring system and an amide functionality onto the 2-position of the indole. Lastly, in our quest to synthesise the cyclopropyl moiety onto our compound for the interaction in the Val179 binding pocket, we were able to investigate the full inhibition effect of this interaction by synthesising a similar compound with no interaction in this binding pocket. Moreover, we were able to synthesise a new compound with a methoxy moiety for this interaction with an inhibition activity (IC50 value) of 1 nM. With this compound only being submitted for efficacy evaluation as a racemic compound mixture, this opened a new door for research possibilities for our team. / AFRIKAANSE OPSOMMING: In die awesigheid van 'n geneesmiddel vir MIV en VIGS, speel nie-nukleosied omkeerbare transkripsie inhibitore ("NNRTIs")'n groot rol in die huidige antiretrovirale behandeling. Ongelukkig ondergaan die MI virus mutasies, wat dus die gebruik van hierdie antiretrovirale middels beperk. Hierdie beklemtoon dus die noodsaaklikheid vir die ontwikkeling van nuwe "NNRTIs". Vorige werk wat deur ons navorsings groep verrig is, het gelei tot die ontwikkeling van "n siklopropiel bevattende indol verbinding, met "n inhibisie aktiwiteit ("IC50" waarde) van 0.1 μM. Gevolglik, het ons in hierdie projek gefokus om die intermolekulêre interaksies van hierdie verbinding in drie hoof areas in die "NNRTI" bindings ruimte te verbeter, genaamd die Tyr181, die Val179, en die Lys101 bindings ruimtes. Hierdie projek het dus beide verbeterde en ook laer inhibisie aktiwiteits resultate gelewer, waar die mees aktiewe verbinding 'n inhibisie aktiwiteit ("IC50" waarde) van 1 nM behaal het. Vir die interaksie na die Tyr181 bindings ruimte, was ons dus onsuksesvol om 'n heteroaromatiese ring te sintetiseer as plaasvervanger vir die oorspronklike feniel ring. Tweedens, vir die interaksie na die Lys101 bindings ruimte, was ons in staat om 'n tetrazol ring en 'n amied funksionaliteit aan die 2-posisie van die indol te sintetiseer. In ons stryd om die siklopropiel ring aan ons verbinding te sintetiseer vir die interaksie in die Val179 bindings ruimte, was ons in staat om die volledige effek van hierdie interaksie te bepaal deur 'n soortgelykke verbinding te sintetiseer met geen interaksie in die Val179 bindings ruimte nie. Daarenbowe, het ons 'n verbining gesintetiseer met 'n inhibisie aktiwiet ("IC50" waarde) van 1 nM, waarvan die aktiwitiet van slegs die rasemiese mengsel van die verbinding bepaal is. Hierdie vinding het dus 'n nuwe navorsings deur vir ons groep geopen.

Thesis (PhD (Pathology. Medical Virology))--Stellenbosch University, 2006. / Host susceptibility to human immunodeficiency virus-1 (HIV-1) infection and disease progression to acquired immunodeficiency syndrome (AIDS) varies widely amongst individuals. This observation led to the identification of host genetic factors playing a vital role in HIV-1 pathogenesis. Previous studies mainly focusing on Caucasian-based populations have indicated possible associations between genetic variants and host susceptibility to HIV-1/AIDS. The limited studies performed on African-based populations have emphasised the need for extensive investigation of both previously reported and particularly novel genetic variants within the older and genetically diverse Sub-Saharan African populations. In this study, the case-control samples were represented by African individuals of Xhosa descent, all residing in the Western Cape Province of South Africa. This included 257 HIV-1 seropositive patients and 110 population-matched HIV-1 seronegative controls. Mutational screening was performed in a subset of individuals for the entire coding regions of the CC chemokine receptor 5 (CCR5) and CC chemokine receptor 2 (CCR2) genes, and the 3’ untranslated region of the CXC chemokine ligand (CXCL12) gene, as previously reported (Petersen, 2002). Further analysis of these genes in a larger study sample involved the genotyping of previously identified mutations and single nucleotide polymorphisms (SNPs), which forms part of the present study. In addition, mutational screening was performed for the entire coding region of the CXC chemokine receptor 4 (CXCR4) gene, partial coding region of the mannose binding lectin (MBL) gene, and the promoter regions of interleukin 4 (IL4), interleukin 10 (IL10) and the solute carrier 11A1 (SLC11A1) genes. This was followed by genotyping of SNPs occurring in CCR5, CCR2, CXCL12, MBL, IL4, IL10, CX3C chemokine receptor 1 (CX3CR1), CC chemokine ligand 5 (CCL5) and tumour necrosis factor alpha (TNFα) genes. Significant associations were observed with HIV-1 susceptibility in the Xhosa population of South Africa. These included the CCR5-2733A>G, CX3CR1V249I, IL10-819C>T and IL10-592C>A SNPs being associated with a reduced risk for HIV-1 infection, while the CCR5-2135C>T and SDF1-3’G>A (CXCL12-3’G>A) SNPs were associated with increased susceptibility to HIV-1 infection. Furthermore, certain haplotypes for IL4 and IL10 showed association with reduced risk for HIV-1 infection. This included the identification of a novel IL4 haplotype restricted to the HIV-1 seronegative control group. This study emphasises the importance of considering genetic diversity across all populations, as certain HIV-1/AIDS associations appear to be restricted to specific ethnic groups. These findings have also provided an understanding for further elucidating the functional roles of genetic variants in determining HIV-1/AIDS susceptibility. Ultimately, such genetic association studies will contribute to establishing HIV-1/AIDS risk profiles for African-based populations from pandemic-stricken Sub-Saharan Africa.

<p>The aim of this quasi-experimental study was to examine the impact of a health education intervention on knowledge about HIV/Hepatitis B transmission, attitudes, beliefs and intentions towards condom use. Research has shown tht small group discussion, single sex groups, age proximity of health educators, and HIV prevention integrated in the broader sexual health context, increased the effectiveness of health education with regard to safer sexual practices.</p>

<p>People's attitudes towards people living with HIV/AIDS remain a major community challenge. There is a need to generate a climate of understanding, compassion and dignity in which people living with HIV/AIDS (PLWHA) will be able to voluntarily disclose their status and receive the support and respect all people deserve. However, many people expereince discrimination because they have HIV/AIDS. In a certain area in Khayelitsha, a township in Cape Town, a young woman was killed after disclosing the HIV status after being raped by five men. While many previous studies have focused on the external stigma in the general population, there is a dearth of studies on stigma among PLWHA themselves and hence the aim of the present study was to investigate stigma attached to HIV/AIDS from the perspective of PLWHA.</p>

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science. Johannesburg, 2014. / Determining e ective treatment strategies for life-threatening illnesses such as HIV is a signi cant problem in clinical research. Currently, HIV treatment involves using combinations of anti-HIV drugs to inhibit the formation of drug-resistant strains. From a clinician's perspective, this usually requires careful selection of drugs on the basis of an individual's immune responses at a particular time. As the number of drugs available for treatment increases, this task becomes di cult. In a clinical trial setting, the task is even more challenging since experience using new drugs is limited. For these reasons, this research examines whether machine learning techniques, and more speci cally batch reinforcement learning, can be used for the purposes of determining the appropriate treatment for an HIV-infected patient at a particular time. To do so, we consider using tted Q-iteration with extremely randomized trees, neural tted Q-iteration and least squares policy iteration. The use of batch reinforcement learning means that samples of patient data are captured prior to learning to avoid imposing risks on a patient. Because samples are re-used, these methods are data-e cient and particularly suited to situations where large amounts of data are unavailable. We apply each of these learning methods to both numerically generated and real data sets. Results from this research highlight the advantages and disadvantages associated with each learning technique. Real data testing has revealed that these batch reinforcement learning techniques have the ability to suggest treatments that are reasonably consistent with those prescribed by clinicians. The inclusion of additional state variables describing more about an individual's health could further improve this learning process. Ultimately, the use of such reinforcement learning methods could be coupled with a clinician's knowledge for enhanced treatment design.

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy. 21 October, 2014. / Three decades ago, the discovery of the Human Immunodeficiency Virus (HIV) was announced. The subsequent HIV pandemic has continued to devastate the global community, and many countries have set ambitious HIV reduction targets over the years. Reliable methods for measuring incidence, the rate of new infections, are essential for monitoring the virus, allocating resources, and assessing interventions. The estimation of incidence from single cross-sectional surveys using tests that distinguish between ‘recent’ and ‘non-recent’ infection has therefore attracted much interest. The approach provides a promising alternative to traditional estimation methods which often require more complex survey designs, rely on poorly known inputs, and are prone to bias. More specifically, the prevalence of HIV and ‘recent’ HIV infection, as measured in a survey, are used together with relevant test properties to infer incidence. However, there has been a lack of methodological consensus in the field, caused by limited applicability of proposed estimators, inconsistent test characterisation (or estimation of test properties) and uncertain test performance. This work aims to address these key obstacles. A general theoretical framework for incidence estimation is developed, relaxing unrealistic assumptions used in earlier estimators. Completely general definitions of the required test properties emerge from the analysis. The characterisation of tests is then explored: a new approach, that utilises specimens from subjects observed only once after infection, is demonstrated; and currently-used approaches, that require that subjects are followed-up over time after infection, are systematically benchmarked. The first independent and consistent characterisation of multiple candidate tests is presented, and was performed on behalf of the Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA), which was established to provide guidance and foster consensus in the field. Finally, the precision of the incidence estimator is presented as an appropriate metric for evaluating, optimising and comparing tests, and the framework serves to counter existing misconceptions about test performance. The contributions together provide sound theoretical and methodological foundations for the application, characterisation and optimisation of recent infection tests for HIV incidence surveillance, allowing the focus to now shift towards practical application.

Translocation of viral integrase into nucleus is a critical precondition of integration during the life cycle of HIV, a causative agent of Acquired Immunodeficiency Syndromes (AIDS). It has been considered as an important target for the drug development to treat AIDS. In order to understand the detailed mechanisms of integrase-host cell protein complex interactions, we cloned HIV-1 integrase-EGFP into pTRE2hyg as visible tag to monitor the translocation process. When transiently transfected this vector into Tet-off ready HeLa cells, the EGFP: integrase is mainly localized in the nucleus. It has been hypothesized that any drugs that can inhibit the translocation process are novel class of drugs for AIDS treatment. More than 30000 synthetic compounds and 80000 natural products were screened by virtual screening. A total of 34 compounds were obtained and screened for their ability to block the nuclear entry of HIV-1 integrase by monitoring the EGFP fluorescence in the cells by high-throughput live cell imaging. Eight synthetic compounds (DW-IN4, DW-IN5, DW-IN6, DW-IN9, DW-IN15, DW-IN16, DW-IN17, DW-IN21) and one natural product (DW-IN719) were found to block integrase translocation significantly. According to our screening result, six compounds (INNB-1, INNB-2, INNB-3, INNB-4, INNB-5, INNB-6) were designed and synthesized. INNB-1 and INNB-2 had significant inhibition on integrase nuclear translocation. DW-IN6, DWIN719, INNB-1, INNB-2, INNB-3 and INNB-4, showed significant inhibition on P24 production in live virus assay. DW-IN6, INNB-1, INNB-2, INNB-3 and INNB-4 showed significant syncitia formation inhibition in live virus assay. Six compounds (KM7, KM8, KM14, KM30, KM37, KM79) from Kunming were screened as integrase nuclear translocation inhibitors. Using similar cell imaging techniques, we have cloned the GFP-tagged chemokine receptor CXCR4 using the lentivirus transfection system. CXCR4 receptor is a critical co-receptor in CD4 positive lymphocytes mediating the fusion of HIV into the CD4 positive cells. CXCR4-GFP was over-expressed in 293T cells and the results showed that GFP:CXCR4 receptor is expressed at the plasma membrane of the cells. These cells have been used to monitor the blockage of CXCR4 receptor internalization for drug development. Four compounds (KX128, KX166, KX171, KX180) from Kunming showed CXCR4 internalization blockage in imaging assay. The interaction of these compounds with CXCR4 was predicted by molecular docking. KX128 showed significant HIV inhibition in live virus assays. / Gu, Wangang. / Advisers: Pang Chui Shaw; David Chi Cheong Wan. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 165-179). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Orientador: Maria Inês de Moura Campos Pardini / Coorientador: Rejane Maria Tommasini Grotto / Banca: Alexandre Naime Barbosa / Banca: Atila Iamarino / Resumo: A vulnerabilidade humana à infecção pelo HIV não é uniforme, fatores virológicos e do hospedeiro são determinantes no risco da transmissão e na evolução natural da infecção. Polimorfismos (do hospedeiro) nos genes KIR estão sendo associados à evolução da infecção pelo vírus. Vários estudos vêm sendo realizados em monoinfectados pelo HIV-1, mas pouco se conhece a respeito da relação desses polimorfismos em coinfecção HIV/VHC. A finalidade deste estudo foi analisar a evolução da infecção pelo HIV em pacientes coinfectados HIV/VHC, baseada em parâmetros clínicos, laboratoriais e virológicos, correlacionando polimorfismos de genes KIR. Foram incluídas no estudo 251 amostras, as quais foram distribuídas em três grupos (Grupo 1: 100 indivíduos monoinfectados HIV-1; Grupo 2: 100 indivíduos monoinfectados VHC e Grupo 3: 51 coinfectados HIV/VHC. As determinações dos subtipos (HIV-1) e genótipos (VHC) foram realizadas por sequenciamento. As definições dos polimorfismos dos genes KIR foram determinados por PCR-SSP e do HLA, por sequenciamento. Dados referentes à evolução da infecção pelo HIV-1 e VHC foram analisados a partir dos prontuários médicos dos pacientes. Os resultados obtidos pelo presente estudo com relação aos genes KIR, 2DL2, 2DS2 e 2DL5, sugerem em caráter inédito a correlação destes polimorfismos com a evolução da infecção pelo VHC em indivíduos coinfectados. A inexistência de correlação dos polimorfismos dos genes KIR com a progressão da infecção pelo HIV-1 em coinfectados sugere que nesta condição, a presença do HIV-1 pode estar influenciando muito mais a progressão da doença pelo VHC do que o desenvolvimento de aids propriamente dito / Abstract: Human vulnerability to HIV infection is not uniform, virological and host factors are determinants on the risk of transmission and natural infection progression. KIR genes polymorphisms have been being associated with progression of HIV infection. Several studies have been performed in mono-infected by HIV-1, but few knwoledge is known about the relation of these polymorphisms in coinfection by HIV/HCV. The purpose of this study was to assess the increasing of the infection by HIV in patients coinfected HIV/HCV, based on clinical, laboratory and virological parameters and correlating KIR genes polymorphisms. The study included 251 samples which were divided into three groups (Group 1: 100 HIV mono-infected; Group 2: 100 mono-infected HCV; Group 3: 51 Co-Infected HIV/HCV). Determination of subtypes (HIV) and genotypes (HCV) was held using RNA sequencing. Polymorphisms definitions of KIR genes were determined by PCR-SSP and HLA were accomplished out by sequencing. Clinical and laboratory data, regarding the evolution of HIV and HCV infection were analyzed from the medical records of patients. The results obtained by this study concerning KIR, 2DL2, 2DL5 and 2DS2 genes demonstrate the state-of-the-art on the correlation of these polymorphisms with evolution of HCV infection in coinfected individuals. The absence of correlation between the polymorphism of KIR genes with progression of HIV-1 infection in co-infected, suggests that in this particular condition, the presence of HIV-1 may influence much more the disease progression by the HCV than the aids development in itself / Mestre

Orientador: Artênio José Isper Garbin / Banca: Renato Moreira Arcieri / Banca: Paula Caetano Araújo / Resumo: A hepatite B e a AIDS são doenças virais de grandes destaques na saúde pública, devido seus elevados índices epidemiológicos, de morbidade e mortalidade. O estigma criado às doenças virais, principalmente pelo vírus da hepatite B (VHB) e vírus da imunodeficiência humana (HIV), repercute de forma negativa e impactante à vida da pessoa infectada, gerando atitudes discriminatórias e preconceituosas, principalmente no acesso aos serviços de saúde. Entre as duas doenças, a hepatite B é a única que tem a imunoprevenção, a qual é realizada através da vacinação. A imunização contra VHB é a principal forma de prevenção da doença, além de ser uma medida de autocuidado que deve ser preconizado no exercício da odontologia. O objetivo deste estudo foi avaliar o conhecimento e a existência da discriminação, através das atitudes dos graduandos em odontologia, frente à representação da Hepatite B e HIV/AIDS; e verificar a imunização dos graduandos, contra o vírus da hepatite B utilizando o teste imunocromatográfico, para o rastreamento de anticorpos anti-HBs. No primeiro capítulo, o universo amostral do estudo foi composto de todos os alunos de graduação regularmente matriculados (n=525). Foi criado um inquérito semiestruturado e autoaplicável, exclusivamente para este estudo, que versava sobre HIV/AIDS e Hepatite B. No segundo capítulo, foram convidados a participar da pesquisa, todos os alunos que desenvolviam atividades clínicas (n=263). Como instrumento de pesquisa, foi utilizado ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: To assess the knowledge, and the existence of discrimination by the attitudes of academic dentistry when facing HIV / AIDS and hepatitis B. Method ology: This is an exploratory cross - sectional study conducted in a public college of dentistry. The sample consisted of 462 (88%) academics who agreed to participate. In data collection, we used a semi - structured questionnaire, created exclusively for this study, addressing the theme HIV / AIDS and hepatitis B. In the data analysis, we used the chi - square test of proportions, in order to verify the associations between the study variabilities and the academic level. The significance level was 5% (0.050). Re sults: It was found that although 85.5% and 88.7% of the students affirm that they knew or have had some information about AIDS and hepatitis B, only 58.9% and 55.8% respectively, had some knowledge on etiological agents. The statistical differences found in relation to the knowledge of the disease and the success of the etiological agent of AIDS, was evident as in undergraduate students it's been noticed a relevant raise on statistical data but the knowledge of the etiology of hepatitis B was significant at the beginnin g of the course. On the attitudes of students in dental treatment of patients infected with HIV and HBV, 85.3% and 91.8% respectively they said that would accept performing it, however, a considerable part of the students believed that there are difference s in clinical procedures to be followed, with statistical values significant for those who attend the first year of graduation. When asked to participants if they would accept to be treated by a dental surgeon with AIDS or hepatitis B, only 31.4% and 38.7% would consent to do the treatment. Conclusion: We conclude that there are gaps in knowledge of students in relation to AIDS and Hepatitis B. The attitudes of students, compared ... (Complete abstract electronic access below) / Mestre

Fishermen are a high-risk group for HIV, having higher HIV rates than typically high-risk groups like truck drivers and military personnel (Kissling, et al., 2005a). Despite this, fishing communities have consistently fallen through the net of HIV research initiatives and in Southeast Asia, there are few such projects targeting fishermen and their communities. In Malaysia, there is particular cause for concern as estimates suggest that fishing communities have an HIV prevalence rate 10 times that of the general population (Kissling, et al., 2005a). Although only 1.3% of the working population are employed in the fishing industry (Department of Statistics Malaysia, 2005), fishermen constitute 3.8% of the total reported HIV cases in the country (Ministry of Health Malaysia, 2008). The dearth of research initiatives targeting HIV within Malaysian fishing communities, and the criminalization of drug users, more broadly, underscores the need for a greater understanding of why fishermen are at increased risk for HIV, but also what approaches might be most effective at curbing the HIV epidemic for these men. This research examines HIV among fishermen by focusing on the social drivers of drug use and drug-related risk behavior in this community. Drawing on theories of risk, this research employs an approach that situates HIV risk behavior within the larger social context. Specifically, I ask: what social factors support an environment conducive to risk behavior and the transmission of HIV among this population of fishermen? Using a mixed-methods approach, this dissertation examines multi-level determinants of HIV among fishermen in Malaysia, assessing how occupational characteristics, social networks, and conceptions of masculinity shape drug use and HIV risk behaviors. The focus on occupational characteristics contributes to the literature on occupational cultures and workplaces as sites for the production of health vulnerabilities, particularly HIV. The focus on masculinity speaks to the to need to better understand the cultural meanings and gender norms associated with HIV risk behaviors among men and the attention to social networks complements a growing body of research that recognizes the role of informal networks in amplifying or attenuating health-related risk. The data for this dissertation comes from Project WAVES, a study conducted by the University of Malaya in collaboration with the Social Intervention Group at Columbia University. The study was conducted in and around the Kuantan jetty, one of the busiest fishing jetties in the country, located in Pahang State on the east coast of peninsular Malaysia. The data consist of 28 in-depth semi-structured interviews with drug-using fishermen and survey data from 406 fishermen who were recruited using respondent-driven sampling. The findings of this research suggest that multilevel factors tied to occupational structure shaped drug use and risk behavior contexts. The mechanization of the fishing industry created shifts in the local labor market that shaped fishermen's daily work and lives. In this new occupational context, the social and economic organization of the occupation of fishing supported drug use in this community. In particular, boat captains loaned money to buy drugs and some supplied drugs for the purpose of work, which resulted in unsafe injection practices and more limited access to clean needles/syringes. The integration of drug use and drug users into the occupational culture of fishing also shaped social and drug-using networks. I find that multidimensional aspects of social network relationships, including social support, trust, participation, and isolation were significantly associated, both positively and negatively, with recent injection and sharing needles/syringes. The results also demonstrate connections between masculinity and injection-related HIV risk behavior. Of note, drug using men were marginalized in their communities and drug use posed a threat to masculinity as men who used drugs were seen as "less of a man" or lacking in "reason." When this marginalization was internalized, men were more likely to engage in receptive sharing of a needle/syringe. Collectively, these results indicate that occupational characteristics, networks and masculinity intersect in complex ways to increase drug use and HIV among fishermen in Kuantan. Although the findings highlight a number challenges to reducing HIV in this population, they also point to a number of possible interventions, which are discussed in the final chapter.