Thesis (MSc (Psychology))--University of Stellenbosch, 2006. / HIV vaccines are currently being developed and tested worldwide. This thesis reports on a qualitative study that was conducted to determine the concerns and problems regarding participation in future HIV vaccine trials. The sample for the study was selected from a peri-urban township, Masiphumelele, in Cape Town, Western Cape province, South Africa. The HIV-prevalence rate in Masiphumelele is 25%. A total of 10 participants between the ages of 19 and 30 were recruited for the present study. All participants’ first language was Xhosa and seven of them had English as a second language. Owing to a language barrier, an interpreter assisted the interviewer in conducting the interviews in the preferred language of the participants. Participants were recruited by convenience sampling and were asked to participate in two semi-structured interviews, under confidential conditions. The first interview addressed knowledge regarding HIV/AIDS, HIV vaccines and HIV clinical trials. The second interview identified the concerns and problems participants had regarding participation in future HIV vaccine trials. The interviews were recorded, transcribed and entered into Atlas ti., a computer program that assists in the analysis of textual data. The analysis of the data focused on the content of participants’ concerns about barriers to participation and their perspectives on facilitators to participation. The data collected on concerns and problems which, may influence participants’ willingness to participate in future HIV vaccine trials, was divided into two overarching themes, namely, barriers to participation and facilitators to participation. The barriers to participation included physical symptoms, stigma and discrimination, trypanophobia, distrust, psychological distress, sexual disinhibition and family responsibilities. The facilitators to participation included altruism, own protection from HIV infection, hopefulness, medical incentives, determining of HIV status, acquisition of knowledge, and equal treatment of participants in the experimental group and the placebo control group resulting from a double-blinded randomised trial. The question of participants’, recruited in the present study, willingness to participate in a future HIV vaccine trial are discussed in terms of Bronfenbrenner’s (1979) theoretical work on ecological systems, the social learning theory and the Health Belief Model (HBM). These theoretical frameworks deal with individuals, their behaviour and their environment, and how these influence one another. The significance and future direction of this line of research helps to overcome the barriers to participation and enhance the facilitators to participation. Thus, the intended result of such efforts is to maximise individuals’ participation in future HIV vaccine trials.

Thesis (PhD)--Stellenbosch University, 2008. / ENGLISH ABSTRACT: Background South Africa is the country with the largest number of HIV infections in the world. As behaviour change initiatives have been suboptimal in curbing the spread of the pandemic, an HIV vaccine is likely to be an important development as a biological agent may circumvent some of the challenges of initiating widespread behaviour change. The development of an HIV vaccine will require several thousands of HIV negative participants who are at high risk of HIV infection to participate in HIV vaccine clinical trials. Before recruitment for such trials may begin, various scientific, ethical, and sociobehavioural issues need to be considered. One of the key sociobehavioural issues concerns the willingness of individuals at high risk of HIV infection to participate in HIV vaccine trials. However, a psychometric measure of willingness to participate (WTP) has not been constructed, and there is a paucity of theory to guide studies of WTP. Objectives The first objective of this study was to construct a psychometric measure of WTP in an HIV vaccine trial, and to derive the exploratory factor structure of the measure. The second objective was to examine the extent to which the Theory of Planned Behavior (TPB) could predict variance in WTP, and to determine whether the TPB was strengthened by the inclusion of mistrust of researchers, knowledge of HIV vaccines and HIV vaccine trials, altruism, and perceived risk of HIV infection as additional predictor variables. Methodology This study was a research survey with a cross-sectional design. A convenience sample of 399 participants was recruited from an urban-informal settlement near Cape Town. As 79 of the questionnaires were poorly completed, the final sample size was 320. To develop a measure of WTP in an HIV vaccine trial, an item pool was developed whereby items directly reflected inhibitors and facilitators of WTP. After an iterative process of refinement, the final scale consisted of 35 items and was named the Willingness to Participate Scale (WTPS). A principal component Kaiser normalised exploratory factor analysis (EFA) was conducted on the items that constituted the WTPS. This procedure was performed to identify latent factors which were informed by the items of the scale. To test the predictive capacity of the TPB and the additional predictor variables, a two-step linear hierarchical multiple regression analysis was performed. At step 1, the TPB variables were entered simultaneously. At step 2, the TPB variables along with the additional predictor variables were entered simultaneously. Results The WTPS demonstrated excellent internal consistency (α = 0.90) and initial construct validity, as evidenced by the presence of seven latent factors. The factors accounted for 53.15% of the variance in WTP and were: (i) Social approval and trust; (ii) Stigmatisation; (iii) Personal costs; (iv) Personal gains; (v) Personal risks; (vi) Convenience; and (vii) Safety. The TPB significantly accounted for 6.4% (R² = 0.06) of the variance in WTP [F(3, 316) = 7.16, p < 0.001], yielding a small effect size (ƒ2 = 0.06). The TPB, together with mistrust, knowledge of HIV vaccines and HIV vaccine trials, altruism, and perceived risk of HIV infection as additional predictor variables significantly accounted for 10.2% (R² = 0.10) of the variance in WTP [F(7, 312) = 5.06, p < 0.001], yielding a small to medium effect size (ƒ2 = 0.11). Subjective norms, mistrust of researchers, altruism, and perceived risk of HIV infection were significant independent predictors of WTP. Conclusion Against the backdrop of the study limitations, the results of this study provide initial support for the reliability and construct validity of the WTPS among the most eligible trial participants in the Western Cape of South Africa. The findings also suggest that the TPB may not be an appropriate theoretical framework for predicting WTP in an HIV vaccine trial in this context. Nonetheless, normative pressure by others, mistrust of researchers, altruism, and perceived risk of HIV infection may influence WTP in this population. Implications for future research are discussed. / AFRIKAANSE OPSOMMING: Agtergrond Suid afrika is die land met die hoogste getal HIV infeksies in die wêreld. Vir die ontwikkeling van 'n HIV entstof, sal daar vereis word dat duisende HIV negatiewe deelnemers, wat 'n hoë risko kans staan om HIV infeksie op te doen, moet deelneem aan 'n kliniese HIV vaksine proeftog. Verskeie, wetenskaplike, etiese en sosiale gedrags punte moet oorweeg word, voor die werwing van sulke proefnemings. Een van die hoof aspekte van sosiale gedrags punte is die bereidwillgheid van 'n individu om blootgestel te word aan die HIV infeksie tydens die proeftog. 'n Psigometriese skatting van bereidwiligheid om deel te neem (BODTN) is egter nog nie gekonstruktureer nie en daar is 'n skaarste/geringheid in studies om as gids te dien vir die BODTN. Doel Die eerste doel van hierdie studie was om 'n psigometriese skatting van BODTN in ’n HIV vaksiene proefneming te konstruktureer, en om die ondersoekings oorsaak/faktor struktuur daarvan te meet en af te lei. Die tweede doel was om ondersoek in te stel of die omvang van die Teorie van Beplande Gedrag (TBG) verskille kan voorspel in die BODTN, en om vas te stel of die TBG versterk word deur die insluiting van wantroue in navorsers, kennis van HIV vaksienes en HIV vaksiene proefnemings, altruïsme, en die begrypbare risko van HIV infeksie as adisionele voorspellers. Metode Hierdie studie is 'n navorsings ondersoek met 'n deursneeproef ontwerp. ’n Grieflike aantal van 399 deelnemers was gewerf van 'n informele nedersetting naby Kaapstad. Die finale getal was 320 omdat 79 nie die vraelys korrek on volledig ingevul het nie. Na 'n interaktiewe proses van suiwering/verfyning, het die finale skaal uit 35 items bestaan en word die skaal benoem na die Willingness to Participate Scale (WTPS). Die prinsipale komponent Kaiser normaliseer EFA wat gedoen was op die items wat die WTPS konstitueer. Hierdie prosedure was gedoen om die latente faktore te identifiseer wat beskikbaar gestel was deur die items van die skaal. Om die voorspelbare kapasiteit van die TBG en die adisionele voorspelbare verskille te toets, het ons 'n twee stap hiërargiese veelvoudige agteruitgaan analise gebruik. By stap 1 was die TBG veranderlikes gelyktydig ingedruk. By stap 2 is die TBG veranderlikes tesame met die adisionele voorspellers in gedruk. Resultate Die WTPS het uitstekende interne konsistensie en 'n aanvanklike geldigheid gedemonstreer, soos bewys deur die teenwoordigheid van die 7 latente faktore. Die faktore verantwoord 53.15% van die verskil in WTP en was: (i) Sosiale aanvaarding en vertroue; (ii) Stigma; (iii) Persoonlike koste; (iv) Persoonlike wins/profyt; (v) Persoonlike risiko's; (vi) Gerieflikheid; en (vii) Veiligheid. Die TBG verantwoord 6.4% (R²=0.06) van die verskil in BODTN [F(3.316) = 7.16, p<0.001] met 'n toegewende klein groote uitwerking/uitslag. Die TBG tesame met wantroue, kennis van HIV vaksienes en HIV vaksiene proefnemings, altruïsme, en begrypbare risko van HIV infeksie as adisionele voorspellers, verwantwoord 10.2% (R²=0.10) van die verskil in BODTN [F(7.312 = 5.06, p<0.001], met 'n toegewende klein tot medium groote uitwerking/uitslag (f²=0.11). Subjektiewe norme, wantroue in navorsers, altruïsme, en 'n beprypbare risko van HIV infeksie was betekenisvolle, onafhanklike voorspellers van die BODTN. Gevolgtrekking Teen die agtergrond van die studie beperkinge, het die resultate van hierdie studie ondersteuning voorsien aan die vertroubaarheid en konstruktiewe geldigheid van die WTPS onder die mees geskikste proef deelnemers in die Wes Kaap van Suid Afrika. Die bevinding stel ook voor dat die TBG nie altyd 'n geskikte teoretiese raamwerk is vir die voorspelling van die BODTN in 'n HIV vaksiene proefneming in hierdie konteks is nie. Des nie teen staande, normale druk van ander, wanrtroue in navorsers, altruïsme en die begrypbare infeksie van HIV kan die populasie deur die BODTN beinvloed word. Implikasies vir toekomstige navorsing is bespreek.

In the history of public health vaccines have proven to be among the most effective disease prevention tools. It is clear that in the fight against HIV that new and powerful preventive technology such as a vaccine is badly needed. Ethically, however the processes of developing a vaccine against HIV have been distinctly different from that of any previous pharmaceutical products. HIV vaccine trials can be ethically complex for a number of reasons. In 2004 the HIV I AIDS Vaccine Ethics Group undertook a research initiative that aimed to collect data from various South African stake holders of HIV vaccine trials to ascertain what they perceived as the ethical challenges related to HIV vaccine trials. A quantitative content analysis on the data from 31 semistructured interviews revealed that the ethical issue listed spontaneously by most of the respondents was that of informed consent. Further probing and discussion on informed consent identified a number of sub issues which the respondents thought would pose important challenges to HIV vaccine trials in the South African context. This study undertook to do a more in-depth qualitative analysis of the data to ascertain whether the challenges and concerns the stakeholders have are consistent with or different to those already identified in the literature and ethical guidelines on informed consent in medical research. What variables may be impacting on the position stakeholders take was also of interest. Results indicated that many concerns relating to the substantive and procedural elements of informed consent were consistent with those debated in the literature. These issues related to first person consent, the voluntariness of participants' consent, practicing cultural sensitivity, dealing with language issues, promoting and assessing understanding of material disclosed, issues around the vulnerability of .. participants, children and adolescents' capacity to consent and the role of the media. More specific to the South African context, stakeholders were concerned about the legal framework under which the trials take place, the general lack of education and training about HIV vaccine trials, a lack of communication and coordination between stakeholder groups, and the historical influences of apartheid on black South African participants' capacity to consent. The main variables that appeared to impact on the position stakeholders took related to the role the stakeholders play within the trials, the philosophical position underpinning their ethical viewpoints, stakeholders' understanding of vulnerability and capacity to consent, and how they view the universality or relativity of ethical issues. / Thesis (M.A.)-University of KwaZulu-Natal, Pietermaritzburg, 2008.

Indiana University-Purdue University Indianapolis (IUPUI) / The transcriptional repressor BCL6 has been shown to be essential for the differentiation of germinal center (GC) B cells and follicular T helper (TFH) cells. The interaction of TFH and GC B cells is necessary for the development of high affinity antibodies specific for an invading pathogen. Germline BCL6-deficient mouse models limit our ability to study BCL6 function in T cells due to the strong inflammatory responses seen in these mice. To overcome this, our lab has developed a new BCL6 conditional knockout (cKO) mouse using the cre/lox system, wherein the zinc finger region of the BCL6 gene is flanked by loxP sites. Mating to a CD4-Cre mouse allowed us to study the effects of BCL6 loss specifically in T cells, without the confounding effects seen in germline knockout models. Using this cKO model, we have reaffirmed the necessity of BCL6 for TFH differentiation, including its role in sustained CXCR5 surface expression, a signature marker for TFH cells. This model also allowed us to recognize the role of BCL6 in promoting the expression of PD-1, another key surface marker for TFH cells. Without BCL6, CD4+ T cells cannot express PD-1 at the high levels seen on TFH cells. Our discovery of DNMT3b as a target for BCL6 suggests BCL6-deficient T cells have increased DNA methyltransferase activity at the PD-1 promoter. This data establishes a novel pathway for explaining how BCL6, a transcriptional repressor, can activate genes. Experiments with the BCL6 cKO model have also established a role for BCL6 in naïve CD4+ T cell activation. Furthermore, we did not observe increased differentiation of other helper T cell subsets, in contrast to what has been reported elsewhere with germline BCL6-deficient models. Unexpectedly, we found decreased T helper type 2 (Th2) cells, whereas mouse models with a germline mutation of BCL6 have increased Th2 cells. These results indicate that BCL6 activity in non-T cells is critical for controlling T cell differentiation. Finally, using an HIV-1 gp120 immunization model, we have, for the first time, shown BCL6-dependent GCs to be limiting for antibody development and affinity maturation in a prime-boost vaccine scheme.