Ever since the seminal Marienthal studies during the Great Depression of the 1930s, studies have linked employment to health and well-being of individuals. However, employment participation for people living with HIV (PLHIV) may not necessarily provide positive health outcomes given negative social responses to HIV infection, particularly stigma and discrimination. Using causal steps approach, the study examines the extent to which the linkage between formal employment status and health-related quality of life is affected by both social capital and HIV-related stigma among PLHIV. Quantitative data were obtained from 554 male and female adults on HIV treatment for at least two years in South Africa. Health-related quality of life (HRQoL) was measured using the validated Medical Outcomes Short Form (SF-36) (Quality Metric, USA) and is represented by physical and mental component summary scores. Formally employed study participants experienced superior HRQoL in comparison to those not formally employed. Both employment status and physical and mental component summary scores were unrelated to objective measures of HIV disease status – CD4 count and viral load. Levels of social capital did not vary significantly by formal employment status. Perceived HIV-related stigma was significantly lower among formally employed study participants than those who were not formally employed, but only in the dimension of personalised stigma, after controlling for potential confounders. Social capital indicators were significantly positively associated with mental but were unrelated to physical component summary scores. All HIV-related stigma scale scores were inversely associated with social capital indicators and with physical and mental component summary scores, after controlling for potential confounders. These results provide little support for mediation of the relationship between formal employment status and HRQoL among PLHIV by social capital and HIV-related stigma. Both social capital and HIV-related stigma have independent relevance to, but formal employment accounts for the largest effect on the health and well-being of PLHIV.

Interleukin-l0 (IL-10) helps to limit the duration of potentially harmful inflammatory responses but has also been implicated in the persistence of a number of chronic viral infections. This thesis aimed to investigate the phenotype and function of mv -specific IL-l0-producing cells in chronic HIV-I infection, and the effect of IL-10 blockade on responses to candidate HIV -I vaccines. A cytokine capture assay was used to determine the HIV -specific cellular sources of IL- 10 in PBMC from 55 chronically infected individuals. A rare subset of CD8+ T cells was found to be the major HIV -I Gag-specific IL-10-producing population; these cells were restricted to ART-naive individuals and did not express the regulatory T cell markers CD25 or FoxP3 but could co-express IFN-y. A proportion of the population (median 48% and 9% respectively) expressed the P7 chain of the gut-homing integrin a4p7 and the chemokine receptor CXCR3, which mediates lymphocyte migration to sites of inflammation. Experimental depletion of Gag-specific IL-10+ CD8+ T cells did not affect T cell activation, or the production of cytokines such as IL-2 or IFN-y during short-term culture. However, depletion was associated with a significant increase in CD38 expression on CDI4+ monocytes, a trend towards increased HLA-DR expression on the same cells, and a significant increase in the concentration of the pro-inflammatory cytokine IL-6 in culture supernatants. There was also a significant increase in the number of HIV-infected (p24 antigen+) CD4+ T cells in cultures depleted of Gag- specific IL-10+ CD8+ T cells after 3 days, indicating that this population may contribute to control of viral replication. In order to determine the effect of IL-10 blockade on vaccine immunogenicity, IL-10R blocking antibody was administered to BALB/c mice prior to immunisation with two mV-I candidate vaccines, HIVA and HIVconsv. IL-10R blockade resulted in a trend towards increased IFN-y production by CD8+ T cells in response to the dominant H (Env) and P (Pol) epitopes of HIV A, and a significant increase in IFN-y ELISPOT responses to the subdominant Gl (Gag) epitope of HIV consv in vitro. Collectively, these data suggest that IL-10 producing cell populations may play critical but different roles in chronic infection and vaccination. Further research into how the timing of IL-10 responses affects disease outcome may allow IL-IO blockade to be explored as a therapeutic strategy in humans

Macrophages are a natural target cell for HIV-1 infection, and they contribute to the development of disease as they are important for transmission, dissemination and persistence of the virus in an infected patient. Macrophages are less well-studied than T cells and cell lines in relation to HIV-1 infection, yet macrophages are highly specialised and key aspects of the HIV-1 life cycle in these cells are already known to differ compared to other cell types. HIV-1 entry into macrophages has been suggested to occur by macropinocytosis, however the entry route in these cells has not been fully characterised. In this thesis I have tested a panel of pharmacological inhibitors of cellular proteins and uptake pathways, in order to delineate the requirements for HIV-1 entry into macrophages and to determine the nature of the entry route. My findings suggest that the following host factors are important for entry; membrane cholesterol, actin rearrangements, dynamin, sodium-hydrogen exchange, Pak1, and Rac. Other factors including clathrin, PI-3 kinase, Rho kinase and some isoforms of PKC were found to be dispensable for infection or to inhibit infection. Macrophages are a heterogeneous group of cells, and tissue macrophages from different parts of the body differ in their morphology, phenotype and function. I have used the growth factors M-CSF and GM-CSF to direct monocytes to differentiate into distinct types of macrophage. This allowed me to determine that different macrophages differ in their susceptibility to infection and in their ability to support replication. This is likely to be due to variation in HIV-1 receptor expression and the levels of key HIV-1 transcription factors, respectively. Overall this thesis contributes to existing knowledge regarding HIV-1 infection of macrophages. These findings may assist with the design of entry inhibitors, and with therapies designed to eradicate HIV-1 from infected individuals.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfillment of the Masters of Medicine in Paediatrics (MMED) / Paediatric HIV Clinic, Harriet Shezi Children's Clinic in an academic hospital, Chris Hani Baragwanath Hospital, Soweto, South Africa. OBJECTIVE: To describe and compare clinical, immunological and virological characteristics of HIV-infected children co-treated for TB, comparing those investigated microbiologically and those not, with a detailed description of microbiological TB investigation results

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, in fulfillment of the requirements for the degree of Master of Science Johannesburg, August 2012 / It is known that infectious agents elicit different responses in different individuals which strengthens the view that susceptibility and resistance to infectious diseases has a genetic component. These differences in susceptibility to disease can be observed in populations. APOBEC3G is a member of the cytidine deaminase gene family located on chromosome 22. It is crucial in non-permissive cells as it functions as part of the innate immunity system and is an inhibitor of the HIV-1 accessory protein vif. The goal of the study was to develop genotyping assays and estimate allele frequencies. Thus, genetic variation within APOBEC3G was identified and characterized in black South Africans. Indirect genotyping assays were designed to amplify regions within the upstream non-coding region, and in exon 4 of the coding region of the gene. Selected polymorphisms were then genotyped using allele-specific PCR, RFLP-PCR and Pyrosequencing™ assays. Reanalysis of sequence data from 2003 showed numerous SNPs were well represented. Comparison of sequence data at various SNPs showed that allele frequencies were similar to frequencies in other African populations. The only sequenced SNP that deviated from the frequencies in Ensembl was -590. Thus the sequencing was a useful tool for detection of variation. ASA proved to be the least reliable genotyping technique as the minor allele frequency of -571 (0.59) deviated from the published frequency of 0.894 in Africans. RFLP analysis proved more reliable for genotyping -571 and H186R. The minor allele frequency was estimated to be 0.84 and 0.32 for -571 and H186R respectively. The frequency of H186R is similar to published data from An et al (2004) and Reddy et al (2010). If SNPs are in LD they occur together on the same haplotype more often than by chance. Usually SNPs that are in LD are in close proximity. However our data suggests -571 and H186R SNPs which are 5kb apart are not in LD. A LD map of chromosome 22 shows highly variable pattern of LD (Dawson et al, 2002). Widespread regions of nearly complete LD up to 804 kb in length are intermingled with regions of little or uundetectable LD. Haplotype analysis showed the most frequent haplotype was GA. This was the most frequent haplotype when the sample types were subdivided according to spoken language. in comparison to studies from An et al, (2004) D’ of the two SNPs was estimated at 0.967. The linkage disequilibrium (LD) revealed a non-independence of allele segregation because the loci analyzed were strongly linked in the Apobec 3 G gene. The data are consistent with greater genetic diversity of African populations and can form the basis for further evaluation of the role of variation in this gene in response to HIV.

The study explores pertinent issues around a comprehensive provision of antiretroviral drugs to HIV positive pregnant women in South Africa from a human rights perspective. Although these drugs have been proven to significantly reduce the transmission of HIV from a pregnant mother to her newborn baby/babies at birth, the South African government for over five years refused to roll them out in the public health sector. Reasons that were provided in this regard were multifaceted and have included claims regarding their alleged toxicity, potential side effects, huge cost, inadequate infrastructure, etc until March 2004 when it announced to start a national rollout program. It is in light of this that the study sets out to explore some of the key positions within the government and amongst activist groups on the health rights of HIV positive pregnant women, and how these different positions have evolved in response to each other. In particular, the paper aims at examining how discourses of human rights were employed, and how they have impacted on the Social Work discipline. It further focuses on developing a Social Work perspective on the human rights of HIV positive pregnant women in South Africa, thereby contributing to the discipline’s professional value base and body of knowledge, which inform, inter alia, its advocacy role and social action approach. The research project was embedded in a theoretical framework often referred to as ‘standpoint research’. An archival study of local and international literature and policy documents was conducted. This was complemented with a limited qualitative study. Semi-structured interviews were conducted with a purposive sample of five interviewees representing a cross-section of positions on the topic. This data was analyzed using a three step coding procedure that allowed for categorizing, connecting, and systematically relating the gathered data to each other and to the reviewed literature. The research findings indicate that the South African government’s absence of consistency and apparent lack of political will to rollout the drugs have contributed to the deterioration of the right of HIV positive pregnant women to access health care services. The role of civil society organizations in helping to realize, promote and protect the health and related human rights of this group is emphasized. It was also found that the different strategies employed to this end speak well to Social Work’s value base, and some of its methods and approaches to practice. Social Work is therefore well placed to join and support those efforts of other segments of civil society that have been investigated in this paper. The paper concludes by making recommendations towards, inter alia, the need for the South African government to adhere to the values enshrined in the country’s Constitution; to work closely and transparently with different organs of civil society; and simultaneously implement the said ARV rollout program while building and strengthening its infrastructural capacity. The various roles Social Work could, and should, assume with regards to improving the human rights of HIV positive pregnant women in this regard are also highlighted.

Thesis (Ph.D. (Virology))--University of the Witwatersrand, Faculty of Health Sciences, 2012 / The majority of HIV-1 infections around the world occur via sexual intercourse and women, especially in developing countries, are disproportionately affected. Recently a number of strategies have been proposed to control the spread of HIV, among these the use of microbicides to prevent the sexual transmission of the virus. A clinical trial of 1% tenofovir gel that conferred up to 39% protection provided a proof-of-concept that an anti-HIV microbicide is feasible. Various other compounds, acting at different stages of HIV-1 life cycle, are also being investigated as potential microbicides. These include the lectins Griffithsin (GRFT), cyanovirin-N (CV-N) and scytovirin (SVN). GRFT was isolated from the red algae griffithsia sp. while CV-N and SVN were isolated from the blue green alga Nostoc ellipsosporum and the cyanobacterium Scytonema varium, respectively. These lectins bind mannose-rich glycans found on the surface of HIV-1 envelope and act as entry inhibitors. Although HIV-1 subtype C is the main cause of infections around the world, almost all studies conducted with GRFT, CV-N and SVN are based on subtype B viruses. The Chapter Two sought to establish the neutralization sensitivity of HIV-1 subtype C viruses to the three lectins, using both a cell line and primary cells, and compared this sensitivity to subtype B. This Chapter also examined mannose-rich glycans on HIV-1 that are involved in GRFT, CV-N and SVN binding. The conclusion from this study was that the neutralization of subtype C viruses by these lectins is similar to subtype B and that the 234 and 295 mannose-rich glycans were involved in their interaction with the virus. In general these data supported further studies on the use of GRFT, CV-N and SVN for prevention of HIV-1 subtype C sexual transmission. In Chapter Three, the ability of GRFT to expose the CD4 binding site (CD4bs) on HIV-1 gp120 is explored. I found that this exposure resulted in the enhancement of HIV-1 binding to plates coated with anti-CD4bs antibodies b12 and b6 or the CD4 receptor mimetic CD4-IgG2. This lectin also synergized with b12 and HIVpositive plasma containing antibodies to the CD4bs to neutralize the virus. Furthermore, the glycan at position 386, which shields the CD4bs, was shown to be involved in both GRFT enhancement of HIV-1 binding to b12 and b6 and in the synergistic interaction between the lectin and these antibodies. The importance of this study is that it investigated in details the effect of GRFT binding on HIV-1 envelope and also suggests this lectin can be used in combination with anti-HIV-1 antibodies to synergistically enhance the anti-viral activity. In Chapter Four I investigated GRFT, CV-N and SVN inhibition of the virus binding to the DC-SIGN receptor and their inhibition of the DCSIGN transfer of HIV-1 to target cells. These lectins only moderately inhibited the virus binding to the receptor while they potently inhibited its transfer to target cells. However, the inhibition of transfer was stronger when the virus bound the lectins after binding the DC-SIGN receptor compared to when it bound the lectins prior to binding the receptor. These three lectins can, therefore, inhibit the sexual transmission of HIV-1 since the DCSIGN- mediated transfer of the virus to susceptible cells is pivotal to this mode of transmission. Chapter Five is an investigation of the ability of HIV-1 subtype C to escape GRFT, CV-N and SVN, which involved growing the virus under escalating concentrations of these compounds. This was to know how this virus behaves under conditions of continuous exposure to the lectins. I found that HIV-1 subtype C became increasingly resistant to the lectins and viral envelope sequence analysis showed that this was associated with the deletion of mannose-rich glycans on gp120. Furthermore, of the 11 potential mannose-rich glycosylation sites on gp120 seven (230, 234, 241, 289, 339, 392 and 448) were involved in GRFT, CV-N and SVN resistance. Thus, the conclusion was that although these three lectins are potent inhibitors of HIV-1 infection, the virus is also able to escape their neutralization by deleting mannose-rich glycans on its envelope. However, the fact that escape to these lectins involved multiple deglycosylation and was only partial suggests that HIV-1 subtype C escape from GRFT, CV-N and SVN in a microbicide formulation may not be an easy process. We discuss the implications of these findings in Chapter Six and suggest future studies that could complement data presented in this thesis. Overall our data show that GRFT, CV-N and SVN can prevent the sexual transmission of both free and DC-SIGN associated HIV-1 particles and supports further development of these lectins as microbicides against HIV-1.

Background Risky sexual behaviour, especially among 15-24 year olds, is a public health concern in South Africa since this age group is the most at risk of contracting HIV. The concern is to what extent youth are indulging in risky sexual behaviour. In 2002, the Department of Health conducted a nationally representative survey on issues surrounding HIV/AIDS. A mass media intervention was launched in the same year, i.e. the Khomanani Campaign, and a year later, in 2003, a survey was conducted to assess the impact of the Khomanani Campaign. Objectives The main question being asked is, “What are the factors associated with risky sexual behaviour amongst the young people of South Africa”. The indicators of risky sexual behaviour being explored are age of sexual debut, condom use at last sexual encounter, condom use in the past year and use of condoms consistently over the entire sexual lifetime. The three objectives of the research report are to describe the cohort of the youth in the sample under investigation, to describe the indicators of risky sexual behaviour among youth that are deemed at risk, and to investigate the factors associated with these indicators of risky sexual behaviour. Data The research uses the Khomanani Survey Findings of the Khomanani survey which was conducted in 2003, a year after the Khomanani Campaign. Only youth aged 15-24 years old who indicated that they were sexually active were included in the sample. Method The research is a cross sectional, secondary analysis of existing data, i.e. the Khomanani Survey Findings. Descriptive statistics were carried out and Chi-squares or Fisher’s exact tests were used for the initial bivariate analysis testing for associations between the indicators of risky sexual behaviour and the factors deemed to affect such behaviour. Factors such as media, self-esteem, self-efficacy, beliefs and accessibility of condoms which were deemed to be associated with risky sexual behaviours were explored in this report. Multiple logistic regression models were carried out with variables which were significant at p<0.20 in the bivariate analysis being included in the models. Factors that were significant in the multiple regression models were regarded as the most important variables to be associated with risky sexual behaviour. Results The final sample comprised 481 sexually active respondents with slightly more girls than boys (55% vs. 44% with 1% not indicating the gender); 48% of respondents were aged 15-19 years compared with 52% of respondents in the 20-24 age group. The majority of the youth had a partial secondary education. Only 5% of the youth were reported as married. The proportion of youth that had used a condom at last sexual encounter was 57%. The proportion of youth reporting that they used condoms consistently in the past year was 39% and some 28% of youth had used condoms consistently during the entire sex life. Of the 481 youth in the sample, 31% reported their first sexual encounter as before 16 years (“early sexual debut”). In the final regression model for condom use at last sex, females were 48% (aOR=0.52; 95% CI=0.34, 0.78) less likely to have used a condom at last sexual encounter compared with males. Being a youth from metropolitan areas was associated with condom use at the last sexual encounter (aOR=2.60; 95% CI=1.47, 4.57). Youth who have heard the term ‘safe sex’ were twice (aOR=1.98; 95% CI=1.10, 3.56) as likely to have used a condom at the last sexual encounter as to those who hadn’t heard the term “safe sex”. Being comfortable talking about using condoms with partners was also associated with use of condoms at last sex (aOR=3.86; 95% CI=1.74, 8.53). Concerns over the quality of government issued condoms were postulated to have an impact on condom use. Therefore respondents were asked whether they thought that government condoms differed from those purchased from shops. Respondents who indicated that condoms were the same were 2.71 times (aOR=2.71; 95% CI=2.28, 5.73) as likely to have used condoms consistently in the past year as those who indicated that government condoms were better than the ones from shops. Respondents who indicated that government condoms are of poor quality were 2.18 times (aOR=2.18; 95% CI=1.04, 4.58) as likely to have used condoms consistently in the past year as those who indicated that government condoms were better than the ones from the shops. Consistency in using condoms since being sexually active was associated with being from a metropolitan area (aOR=1.99; 95% CI=1.12, 3.51) and also respondents who had the opinion that condoms are the same (aOR=3.04; 95% CI=1.33, 7.07) whether they are government issued or from the shops.. The age of the respondent and also the belief that one should have sex with a partner to show their love were the only factors associated with early sexual debut. Respondents who were older (20-24 years) were 61 %( OR=0.39; 95% CI=0.23, 0.65) less likely to have had early sexual debut below the age of 16 compared to their counterparts aged 15-19 years. Respondents who did not believe that a person should have sex with their partner to show their love were 41 %( OR=0.59;95% CI=0.37,0.94) less likely to have had early sexual debut to those who believed that a person should have sex with their partner to show their love controlling for gender, area of stay, age group and employment. Conclusions The findings from the survey point out that more than half of the youth are using condoms at most recent activities, with differences between men and women. Some youth are consistently using condoms and not only using at last sex. Hence programs targeting youth should continue taking into account issues that may be contributing to youth not using condoms and not using them consistently. Messages on safe sex, messages encouraging youth to communicate with partners on sexuality issues, as well as the government making condoms accessible in all areas, should continue to be reinforced. Future research should also focus on development and evaluation of interventions to delay sexual debut with issues of beliefs, and community beliefs being discussed.

Thesis (DPhil (Biomedical Science))--Cape Peninsula University of Technology, 2019. / Knowledge of population vulnerabilities to infectious diseases is key in managing many public health problems and for mapping appropriate strategies for prevention or intervention. A number of genes associated with resistance to HIV infection, such as the double deletion of 32 base pairs in the CCR5 gene , have been described and potentially account for lower HIV infections in some populations. The magnitude of the HIV pandemic in Sub-Saharan Africa warrants an investigation of the peculiar genetic factors that may have exacerbated its spread. An understanding of the genetic factors that are involved may aid in the development of specific strategies for prevention such as vaccine development, genetic counselling as well as gene therapy. The aim of this project was therefore to study the relationship between blood groups and HIV-infection in Botswana. HIV infection in Africa has not been linked to particular blood groups. The project was undertaken in two phases from December 2012 to December 2017. In the first phase, 346 subjects of known HIV status (negative or positive) were phenotyped for 23 erythrocyte antigens via standard scientific procedures. A Chi-square analysis was used to determine those antigens associated with increased or reduced risk of HIV infection. In the second phase, 120 samples were phenotyped for the protective blood group (RhC) and the risk-associated groups (Lub and P1). The samples were also characterized according to their laboratory results for viral load, lymphocyte sub-populations, complete blood count and blood chemistry, including total cholesterol. Some of the samples were also assessed for erythrocyte-associated viral RNA. Generally, the prevalence of the blood groups in the general population in Botswana did not differ with the known prevalence for Africans broadly. Three novel findings were established. First, the blood group Rh(C) was associated with a 40% risk reduction for HIV infection. Immunologically, carriage of the C antigen was associated with a more robust cell-mediated immunity as evidenced by enhanced cytotoxic T cell counts. Moreover, this antigen occurred with a frequency lower than 30% in all countries where HIV prevalence was high. There was therefore an inverse relationship between Rh(C) frequency and HIV prevalence. An examination of reports from previous studies revealed that the pattern was consistent in Africa, Europe, Asia, South America and Caribbean countries. It appears that the population frequency of this antigen explains, at least in part, a genetic factor that puts some African populations at higher risk for HIV infection. These results are novel in that Rh antigens have not been previously associated with immunity in any reports. Novel findings regarding the P1 blood group was its association with a double risk for HIV infection. While the plasma viral load did not differ between P1-positive and P1-negative subjects, P1-positive erythrocyte lysate yielded more viral RNA than P1-negative cells, implying more intracellular HIV RNA. Intra-erythrocytic viral RNA was detected even in patients with an undetectable plasma viral load. Glycosphingolipids, of which P1 is an example, have been documented to promote viral fusion to cells independent of CD4 receptors or other ligands. In at least one report, the presence of sphingolipids in lipid rafts was considered to be sufficient for viral fusion. The presence of viral RNA even in erythrocyte lysates corroborates this phenomenon and potentially explains the double risk of HIV infection observed. The occurrence of HIV RNA in erythrocyte lysate is a novel finding that suggests a new viral reservoir. Apparently, P1 has a high frequency among Africans and low in other races.

The world has suffered immensely and disproportionately from the ravages of HIV and AIDS. Oral PrEP is a single pill taken once daily that can reduce the risk of sexually transmitted HIV infection by up to 92% (CDC, 2014a). This study describes African American females’ awareness, beliefs, and perception of PrEP and identifies factors that may motivate women to either accept or reject PrEP. This cross-sectional study occurred over a 3-month period from November 2017 to January 2018, following from a previous pilot study. The sample comprised African American women aged 18 and over receiving STD or HIV screening services at a FQHC in Brooklyn, New York. Women were interviewed using the five characteristics of the Diffusion of Innovation theory and also completed a risk assessment for HIV using CDC recommended guidelines for screening heterosexual women for PrEP. Awareness of PrEP remained extremely low among the 72 African American women interviewed in the study. Using the CDC guidelines, all women reported one or more risk factors for PrEP indication. Awareness about PrEP, negative reactions from partners and shared experiences from female PrEP users were cited as factors that may predict and motivate African American women to use PrEP. Additionally, skills in pill-taking, cost and insurance, and maintaining privacy while using PrEP were strong enabling factors to support PrEP use. Factors such as initiating couple’s PrEP use as an intervention, medical doctors overtly directing PrEP for women, and the role of older women in promoting PrEP use were persuasive factors in reinforcing the utilization of PrEP among African American women in the study. Creative programming within high burden communities is critically important to penetrate with messages of new innovations and best practices. The results of the current research speak volumes to the continued work needed to educate communities with prevention messages.