HIV is known to affect the epidemiology, transmission, pathogenesis and natural history of HCV infection whilst studies on the effects of HCV on HIV have shown conflicting results and are confounded by the influence of intravenous drug use and anti-retroviral therapy. This study was conducted in KwaZulu-Natal Province in South Africa where HIV is predominantly a sexually transmitted infection. Intravenous drug use is rare in this region and the study population was naive to anti-retroviral therapy. For this study, specimens from selected sentinel sites submitted to a central laboratory for routine HIV testing were screened for anti-HCV IgG antibodies. HIV positive HCV-positive patients were compared to HIV-positive HCV-negative patients in a subgroup of patients within this cohort in order to determine if HCV sero-prevalence was associated with clinical outcomes in a linked anonymous retrospective chart survey. The prevalence of HCV was 6.4% and that of HIV, 40.2%. There was a significantly higher prevalence of HCV among HIV infected patients as compared to HIV negative patients (13.4% vs. 1.73% respectively). HCV-HIV co-infected patients had significantly increased mortality (8.3 vs. 21%). A significant association was found between HCV serostatus and abnormal urea and creatinine levels. Hepatitis B surface antigen seropo-sitivity was not found to be a confounding factor. This study has found that hepatitis C co-infection is more common in HIV positive individuals and is associated with an increased mortality and renal morbidity. / Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2008.

Certain HLA-B-restricted CD8+ T cell responses are associated with control of viremia whereas HLA-Cw* restricted responses, including Gag epitopes are associated with high viremia. To better understand the role of HLA-Cw* restricted epitopes in viral control, HLA-Cw* restricted epitopes were optimally defined. Seventy eight study subjects from a cohort of 451 chronically infected participants had HLA-Cw* restricted CD8+ T cells responses as quantified by intracellular cytokine staining assessing IFN-γ secretion. Fine mapping and HLA restriction of the optimally defined HLA-Cw* restricted epitopes were performed using ELISPOT assay. Functional avidity of responses was assessed by peptide dilution in an ELISPOT assay. Two novel HLA-Cw* restricted epitopes Cw*04- TF10 (in reverse transcriptase) and Cw*08-RM9 (in gp120) were optimally defined. A previously described epitope, Cw*07- KY11 (Nef) was the most frequently targeted epitope in this cohort (30/78) and has high functional avidity compared to other HLA-Cw restricted CD8+ T cell responses. The polyfunctionality of HLA-B*57/5801-restricted Gag-specific HIV-1 CD8+ T cell responses and HLA-Cw*07-KY11 restricted CD8+ T cell responses within the same study subject was determined. Polyfunctionality of CD8+ T cell responses to HLAB* 57/5801 and HLA-Cw*07 restricted epitopes were determined in nine study subjects assessing IFN-γ, TNF-α, IL-2, MIP-1β, and CD107a by multicolour flow cytometry. Additionally gag and nef genes were sequenced from plasma. HLA-B*57/5801-restricted IFN-γ-producing CD8+ T cell responses were of lower magnitude than HLA-Cw*07 responses (p=0.0012) for the nine subjects. The majority of responses were monofunctional (75%), irrespective of HLA restriction. HLA-B*57/5801 and HLACw* 07 restricted CD8+ T cells did not differ significantly in polyfunctionality (p=0.84). Possession of ≥3 functions correlated positively with CD4+ T cell counts (r=0.85; p=0.006). The percentages of monofunctional CD8+ T cells inversely correlated with CD4+ T cell counts (r=-0.79; p=0.05). There was no correlation between polyfunctionality and viral load and sequence variation within targeted epitopes did not impact polyfunctionality. These results suggest that polyfunctionality of HIV-1-specific CD8+ T cells is associated with disease progression independent of restricting HLA alleles, and that loss of these polyfunctional cells correlates with increased in the frequency of monofunctional virus-specific CD8+ T cells. In addition, sequence variation does not appear to significantly impact CD8+ T cell polyfunctionality in chronic HIV infection. / Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2010.

Weight loss is a common occurrence in patients with human immunodeficiency virus (HIV) and contributes to further debilitation in the acquired immune deficiency syndrome (AIDS). Wasting syndrome (WS) is defined as 10% or more unintentional weight loss from usual body weight. The etiology of WS includes alterations in metabolism, which contribute to loss of lean body mass. Cytokine driven oxidative stress may play a critical role in the metabolic pathways that lead to HIV wasting. Studies have shown that that patients infected with HIV may have a depleted antioxidant (AO) defense system, the integrity of which is needed to efficiently scavenge reactive oxygen species (ROS). It has been theorised that low AO intake may contribute to a depressed AO defense system, which drives oxidative stress (OS). In this study we examined 16 subjects who had documented WS but no active infectious process, stratified into 10 to 15% weight loss (n = 7) and over 15% weight loss (n = 9) groups, and reported on oxidative stress measures and AO intake. (Abstract shortened by UMI.)

No abstract available. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2010.

Background: Multiple factors contribute to mother-to-child transmission (MTCT) of HIV-1, including virological, obstetric and biological factors. Other possible contributory determinants for high MTCT rates include immunological factors such as host genetics and viral genetic variations. Despite several therapeutic, prophylactic and obstetric interventions to reduce the proportion of infants infected during labour and delivery, mechanisms for intrapartum HIV-1 transmission remain elusive and current interventions, could, therefore remain sub-optimal. Much controversy has surrounded the correlation of HIV-1 RNA (viral load) in the systemic and genital compartments of women. The influence of short-term antiretroviral (ARV) drugs on genital tract HIV-1 is also unclear. At the time the present study was initiated, a regimen of maternal intrapartum and neonatal postpartum single-dose Nevirapine (sdNVP) was the standard of care for the prevention of mother-to-child transmission (PMTCT). In most low and middle-income countries, including South Africa, sdNVP has been documented as effective intrapartum HIV-1 prevention based on plasma pharmacokinetic levels, decreased viral loads (HIV-1 RNA) and reduced rates of intrapartum transmission, yet operational studies continue to report high intrapartum transmission rates despite the administration of sdNVP. As a result perinatal HIV-1 transmission remains a significant public health concern in several African countries. Aim: The primary aim of this study was to describe the pharmacological dynamics of Nevirapine in association with virological and immunological risk factors for intrapartum HIV-1 transmission in a South African PMTCT programme where sdNVP was the standard of care. Methods: Following regulatory approval from the Biomedical Research Ethics Committee at the University of KwaZulu-Natal (UKZN), one hundred and twenty pregnant HIV-infected women who received the sdNVP regimen for prevention of mother-to-child HIV-1 transmission were enrolled between April-December 2006 at King Edward VIII Hospital (KEH) in Durban. Blood and cervicovaginal lavage (CVL) samples were collected from women at pre-NVP (during pregnancy) and post-NVP dosing (during labour/delivery). In addition to infant blood sampling at birth (post-NVP), postnatal infants were assessed at four and six weeks postnatally. Pharmacological laboratory investigations involved measurement of NVP drug concentration by Tandem Mass spectrophotometry. Virological investigations comprised HIV-1 RNA (viral load) quantitation, HIV-1 drug resistance testing (HIV-1 transmitting women only) and HIV-1 DNA PCR testing (infants only). Immunological investigations were only undertaken in a selected case-control subset of HIV-1 transmitting women and their infants. In this component, laboratory investigations included the determination of CCL3 and CCL3-L1 gene copy numbers, identification of single nucleotide polymorphisms (SNP’s) and haplotype characterisation of the CCL3 gene. All women were also screened for the presence of sexually transmitted infections (STI’s) during pregnancy. Results: One hundred and twenty women were enrolled onto this study. Of these, 110 women delivered 117 live infants (103 singletons and 7 twin pairs). Twelve (10.9%) women transmitted HIV-1 to their infants, while 95 (86.0%) were classified as non-transmitters. As a result of seven twin deliveries, the infant cohort comprised of 117 infants in total. Following two separate DNA PCR tests, HIV-1 infection was identified in 14 (11.9%) of study infants while the remaining 90 (76.9%) were exposed-uninfected. HIV infection status remained unknown for 13 infants due to infant demise (1.7%), lost to follow-up (7.7%) or study withdrawal (1.7%). During active labour (sampling that was best representative of the intrapartum phase) and within 20 hours of dosing, the median NVP concentration of 1070 ng/ml in the maternal systemic compartment was almost 44 times higher than the NVP levels detected in the genital compartment [24.5 ng/ml] (p < 0.001). NVP drug levels were below the 100 ng/ml therapeutic target in seven (13.7%) of 51 plasma and in all 39 CVL samples. While no significant association was found between NVP concentration in the systemic compartment and HIV-1 transmission (p = 0.4), this association was statistically significant in the genital compartment(p = 0.02). The median plasma NVP level detected among infants at birth was 83 times above the IC50 WT (10 ng/ml) and eight times higher than the 100 ng/ml therapeutic target for NVP. More than 71.0% of the infants achieved NVP drug levels above the therapeutic target. In general, higher levels of HIV-1 RNA (viral load) were observed in maternal plasma when compared to CVL. Following intrapartum sdNVP dosing, reduction in HIV-1 RNA levels did occur, however R80.0% of the women experienced no change to their HIV-1 RNA levels in both systemic and genital compartments during active labour. These findings were further supported by the strong correlation observed when comparing pre and post-NVP HIV-1 RNA levels in both maternal systemic [r = 0.81, p < 0.0001] and genital compartments [r = 0.80, p < 0.0001] during active labour. HIV-1 transmitting women had significantly higher viral loads than their non-transmitting counterparts in systemic and genital compartments, before and after intrapartum sdNVP administration. In terms of perinatal transmission this observation was only statistically significant for plasma (p = 0.02) and not CVL (p = 0.7). Maternal viral load was inversely correlated with maternal CD4 cell counts in both systemic and genital compartments. Almost 40.0% of women in this study had at least one type of STI detected during pregnancy. Maternal STI’s were detected in four (66.6%) intrapartum transmitting women and in 38 (38.8%) of non-transmitting women. No significant association was observed between the presence of maternal STI’s and the risk for intrapartum MTCT (p = 0.2,RR: 2.90, 95% CI: 0.60-15.40). The presence of maternal STI’s was associated with higher median viral loads in both systemic and genital compartments of all women, independent of intrapartum HIV-1 transmission. Despite trial-like conditions and optimal sdNVP dosing, the overall MTCT rate in this exclusively formula-fed cohort was 11.9%, of which 50.0% were in utero and 50.0% were intrapartum HIV-1 transmissions. In utero and intrapartum MTCT rates were 5.9% and 5.9% respectively. Discussion/Conclusion: Detectable CVL HIV-1 RNA that correlated well with plasma HIV-1 RNA, in conjunction with sub-optimal NVP drug concentration in maternal CVL during active labour, suggests that intrapartum HIV-1 infected women continue to act as reservoirs for both vertical and horizontal HIV-1 transmission throughout the duration of pregnancy. These findings confirm that the role of sdNVP in PMTCT was primarily one of infant prophylaxis. This was further supported by relatively unchanged maternal HIV-1 RNA (viral load) during active labour, in both systemic and genital compartments. Early identification of women who need highly active antiretroviral therapy (HAART), and initiation of such therapy as early as possible during pregnancy, not only benefits maternal health but remains the best prophylaxis against mother-to-child HIV-1 transmission. Universal access to HAART and improving strategies to optimize coverage of the current dual ARV regimen sdNVP and Zidovudine for PMTCT remain urgent research priorities in several resource-limited settings. Ongoing STI counseling, intensive screening/testing of women and their partners together promotion of condom usage, safer sex practices and aggressive STI treatment are simple interventions with tremendous impact for PMTCT in resource-limited settings. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2009.

Background: HIV-1 envelope (Env) diversity is arguably the most significant challenge for the development of an efficacious vaccine. An ideal vaccine would elicit the production of broadly neutralizing antibodies (nAb), capable of retaining potent activity against a diverse panel of viral isolates. The evolutionary forces that shape the diversity of envelope and ensuing nAb responses are incompletely understood in HIV-1 subtype C infection, the dominant subtype globally. Therefore there is an urgent need to define the patterns of envelope diversity, determine the correlates of immune protection and to discover subtype C immunogens in order to develop a globally relevant vaccine. Methods: We applied the single genome sequencing strategy to study plasma derived viruses from four slow progressors and four progressors over a median of 21 months between study entry and study exit. The participants‘ samples were from the Sinikithemba cohort of antiretroviral therapy-naïve chronically infected individuals and were termed slow progressors or progressors based on CD4 T-cell counts and viral loads over two years. We analyzed env sequence diversity, divergence patterns and envelope characteristics across the entire HIV-1 subtype C gp160. We studied the evolution of autologous nAb (AnAb) and heterologous nAb responses in order to test the hypothesis that slow disease progression is associated with more potent autologous or heterologous nAb responses. Furthermore, genotypic env characteristics were correlated to potency of neutralization in order to understand possible differences in nAb responses with divergent rates of disease progression and to describe genotypic differences associated with differential nAb potencies. In addition, the binding affinities of HIV-specific immunoglobulins (IgGs) and the affinities of the IgGs to various Fcγ receptors (both activating- FcγRI, FcγRIIa, FcγRIIIa; inhibitory- FcγRIIb) were assessed. These binding affinities were used as a surrogate for the recruitment of effector functions of cells of the innate immune system e.g. macrophages or natural killer cells to initiate antibody-dependent cell-mediated cytotoxicity (ADCC) or antibody dependent cell-mediated viral inhibition (ADCVI) and these were correlated to markers of disease progression namely CD4 T-cell counts and viral loads. Results: Intra-patient diversity was higher in slow progressors for regions C2 (p=0.0006), V3 (p=0.01) and C3 (p=0.005) compared to progressors. Consistent with this finding, slow progressors also had significantly increased amino acid length in V1-V4 with fewer potential N-linked glycosylation sites (PNGs) compared to progressors (p=0.009 and p=0.02 respectively). Similarly, in progressors, the gp41 region was significantly longer and had significantly fewer PNGs compared to slow progressors (p=0.02 for both parameters). Positive selection was prominent in regions V1, C3, V4, C4 and gp41 in slow progressors, whereas in progressors, it was prominent in gp41. Signature consensus sequence differences between the groups occurred mainly in gp41. Neutralizing antibodies (nAb) evolved over time in progressors, as evidenced by significantly higher nAb IC50 titers to baseline (study entry) viruses when tested against study exit time-point plasma compared to contemporaneous responses (p=0.003). In contrast, slow progressors‘ nAb titers did not differ significantly between study entry and study exit time points. nAb IC50 titers significantly correlated with amino acid lengths for C3-V5 (p=0.03) and V1-V5 (p=0.04) for slow progressors and V1-V2 for progressors (p=0.04). Slow progressors and progressors displayed preferential heterologous activity against the subtype C panel. There were no significant differences in breadth of responses between the groups for either subtype A or C. Neutralization breadth and titers to subtype B reference strains however, was significantly higher in progressors compared to slow progressors (both p<0.03) with increasing nAb breadth from study entry to study exit in progressors. Progressors had cross-reactive neutralizing antibodies that targeted V2 and V3. Binding affinities of non-neutralizing antibodies to HIV-specific gp120, gp41 and p24 and to activating and inhibitory Fcγ receptors (FcγRs) were similar in both groups. However, in slow progressors, CD4 T-cell counts correlated inversely with antibody binding affinity for the activating FcγRIIa (p=0.005). Conclusions: These data suggest that separate regions of Env are under differential selective forces, and the heterogeneity of env diversity and evolution differ with HIV-1 disease course. Single genome sequence analysis of circulating viruses in slow progressors and progressors indicate that diversity, length polymorphisms, sites under positive selection pressure, and PNGs consistently map to specific regions in Env. Cross-reactive neutralizing antibodies targeting epitopes in V2 and V3 indicate that nAb breadth may be dictated by a limited number of target Env epitopes. Certain key N-linked glycosylation sites were shown to be crucial for antibody neutralization. The potencies of autologous nAbs were directly affected by the amino acid lengths in certain regions of Env gp160 and by the numbers of PNGs. Target vaccine immunogens may have to be given over long periods of time and may have to include multiple subtype immunogens to elicit the production of potent, broad cross neutralizing antibodies with high binding affinity. Overall, the data suggest that neither nAbs nor non-neutralizing antibodies could be directly associated with disease attenuation in this cohort of chronically infected individuals. However, continuous evolution of nAbs was a potential marker of HIV-1 disease progression. Further studies on larger cohorts to identify people with potent nAbs and to identify specific targets of these antibodies are needed. Furthermore studies of non-neutralizing antibodies in HIV-1 infection using functional assays will be required in order to determine their role in HIV-1 pathogenesis. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2011.

That the HIV and AIDS epidemic is fuelled by structural injustices is not a new discovery. Several studies reveal the link between the HIV transmission and the spread of the epidemic and the structural inequalities created by human beings themselves in terms of economic and political structures sustained by the patriarchal socio-cultural and religious beliefs systems. In most African rural contexts, faith communities have the potential to alter the course of the epidemic given their moral authority in community and their direct connection with people. However, they are seldom theologically equipped to address the structural inequalities that fuel the spread of HIV and AIDS. This study critically analyses the specific factors driving the HIV and AIDS epidemic in Burundian context and the challenge that they pose to the Burundian Pentecostal churches‘ theology of mission. The study argues that Burundian Pentecostal churches are not responding the epidemic as they should because their responses are informed by a theological framework of mission that was elaborated in the early years of the 20th century and which was responding to theological and social questions quite different to the questions raised by the current HIV context. To overcome this theological irrelevancy that has led to a failure to respond to the political, socio-economic, and cultural factors that fuel the spread of HIV infection, the study suggests that there is a need to adopt a theological framework rooted in a holistic understanding of the mission of the church in the world as defined by the concept of missio Dei. The practical implication of this theological framework is that it challenges faith communities in general and Burundian Pentecostals in particular to become transforming agents not only interested in right relationships between God and humans but also committed to the transformation of political, economic, socio-cultural and religious structures that sustain unequal relationships between humans and between humanity and the rest of creation. / Thesis (M.Th.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.

<p>Curricula should be strengthened by teaching the curability of STIs and the importance of STI treatment to prevent HIV transmission. This study focused on the control of sexually transmitted infections as a key HIV prevention strategy. Sexually transmitted infections act as a strong cofactor in the sexual transmission of HIV. Effective STI management can limit the spread of HIV.</p>

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.