Sub-Saharan Africa bears 70% of the global HIV burden with KwaZulu-Natal (KZN) identified as the epicenter of this pandemic. HIV related nephropathy (HIVRN) exceeds any other causes of kidney diseases responsible for end stage renal disease, and has been increasingly recognized as a significant cause of morbidity and mortality. There is nonetheless a general lack of surveillance and reporting for HIVRN exists in this geographical region. Consequentially, the aim of this study was to outline the histopathogical spectrum of HIVRN within KZN. Moreover, from a pathology standpoint, it is important to address whether HIVRN was a direct consequence of viral infection of the renal parenchyma or is it a secondary consequence of systemic infection. Additionally, an evaluation of the efficacy of Highly Active Anti-Retroviral Therapy (HAART) in combination with angiotensin converting enzyme inhibitors (ACE-I) was performed via a genetic appraisal of localized replication of HIV-1 in the kidney, ultrastructural review and immunocytochemical expression of a podocyte maturity and proliferation marker pre and post-HAART. Blood and renal biopsies were obtained from 30 children with HIV related nephropathy pre- HAART, followed-up clinically for a period of 1 year. This cohort formed the post-HAART group. Clinical and demographic data were collated and histopathology, RT-PCR, sequencing, immunocytochemistry and transmission electron microscopy was performed. The commonest histopathological form of HIVRN in children (n = 30) in KZN was classical focal segmental glomerular sclerosis (FSGS) presented in 13(43.33%); mesangial hypercellularity 10(30%); mesangial, HIV associated nephropathy 3(11%) and minimal change disease 2(6.67%). Post-HAART (n = 9) the predominant pathology was mesangial hypercellularity 5(55.56%); FSGS 3(33.33%) and sclerosing glomerulopathy 1(11.11%). This study also provides data on the efficacy of HAART combined with ACE-I. The immunostaining pattern of synaptopodin, Ki67 and p24 within the glomerulus expressed as a mean field area percentage was significantly downregulated in the pre-HAART compared to the post-HAART group respectively (1.14 vs. 4.47%, p = 0.0068; 1.01 vs.4.68, p < 0.001; 4.5% vs 1.4%, p = 0.0035). The ultrastructural assessment of all biopsies conformed to their pathological appraisal however, features consistent with viral insult were observed. Latent HIV reservoirs were observed within the podocyte cytoplasm but was absent in mesangial or endothelial cells. Real-Time polymerase chain reaction assays provided evidence of HIV-1 within the kidney. Sequence analysis of the C2-C5 region of HIV-1 env revealed viral diversity between renal tissue to blood. In contrast to a collapsing type of FSGS that occurs in adults, the spectrum of paediatric nephropathy in treatment-naive children within KwaZulu-Natal was FSGS with mesangial hypercellularity. Additionally, our study demonstrates podocyte phenotype dysregulation pre- HAART and reconstitution post therapy. Evidence of ultrastructural viral reservoirs within epithelial cells is supported by a genetic appraisal confirming the ubiquitous presence of HIV DNA in renal tissue. Moreover, sequence analysis showed viral evolution and compartmentalization between renal viral reservoirs to blood. Finally, the interplay of viral genes and host response, influenced by genetic background, may contribute to the variable manifestations of HIV-1 infection in the kidney in our paediatric population. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2012.

Introduction. Previous studies have established that infants born to mothers with advanced HIV disease and co-infections are smaller, premature and have rapidly progressive HIV disease and an early death. King Edward VIIIth Hospital, in Durban, admits many sick mothers and manages a large proportion of low birth weight and ill newborns. On discharge and follow-up, the mortality and morbidity of these infants are known to be high and are related to the prematurity. How much is related to being HIV exposed is still uncertain. Aim. To determine the perinatal transmission rate of HIV-1 and mortality at 12 months in HIV exposed infants that were admitted to and discharged from the Neonatal Unit, in Durban, South Africa. Methods. In this observational study, data from the outpatient charts of HIV exposed infants that required specialised neonatal care and subsequent follow up, between the period November 2007 and December 2009, were collected. Perinatal transmission rates and mortality of these infants were compared with maternal and infant risk factors. Results. Data on 463 HIV exposed, predominantly low birth weight infants are presented. The median maternal CD4 count was 309cells/mm3 with 16.8% of mothers commenced on HAART. Maternal co-infection with TB was found in 19.2% of the cohort. Early HIV transmission occurred in 11.5% of infants and was influenced by the type of ARV exposure (None, 20%; single dose NVP, 14.3%; dual therapy, 10.6%; maternal HAART, 8.5%). The dual therapy regimen for 7 days was more protective than that for 28 days (p=0.045). HIV infection was associated with higher risk of neonatal sepsis (RR 1.6; 95% CI, 1.1-2.3; p=0.015). The mortality for the cohort at 12 months was 10%. Maternal HAART was associated with a lower mortality: 2.95% vs.10.2% (RR 3.0; 95% CI, 0.4-20.5). There was a higher mortality rate in those that were low birth weight (RR 4.2; 95% CI, 1.02-18.8; p=0.037); those that were HIV infected (RR 4.8; 95% CI, 1.9-11.6; p=0.002) and those that were breastfeeding compared to formula feeding (RR 2.7; 95% CI, 1.1-6.8; p=0.038). Discussion. Rates of HIV transmission within the PMTCT programme were similar to that reported by the Department of Health. Early maternal ARVs for PMTCT prophylaxis, prevents HIV transmission. The coverage of maternal HAART was sub-optimal. Breastfeeding was associated with a higher HIV transmission rate and was most likely associated with non-exclusive breastfeeding during neonatal admission. Recommendations. Maternal HAART or ARV prophylaxis should be commenced early in the pregnancy for the best benefits. Meticulous attention should be paid to the feeding practices of high risk HIV exposed infants admitted for specialised neonatal care. / Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2012.

HIV-1 specific CD4+ T cell activity in clade C infected subjects has not been studied. CD4+ T cells play a vital role in controlling infectious diseases and there is a need to augment our knowledge of HIV immunology to aid vaccine design. We therefore embarked on a study to characterize HIV-1 specific CD4+ T cell activity in both adults and infants; assess the relationship between CD4+ and CD8+ immune responses; and the relationship between CD4+ T cell activity and markers of disease progression (viral loads and CD4 counts). Our study revealed that the magnitude of CD8+ T cell responses correlated significantly with CD4+ T cell responses, but that the percentage of CD8+ T cells directed against HIV-1 was always greater than that of CD4+ T cells. Gag was the frequently targeted HIV-1 protein by CD4+ T cells and had the highest density of epitopes targeted by CD4+ T cells. Patients with either a dominant CD4 or CD8 T cell response against Gag had significantly lower viral loads than patients in whom non-Gag proteins were the main target (p< 0.0001 for CD4 activity and p= 0.007 for CD8 responses). Single IFN- producing CD4+ T cells were present in significantly higher numbers than cells producing both IFN- and IL-2 simultaneously (p=0.009). Gag also dominated the CD4+ T cell response in acutely infected infants with IFN- production detected more frequently than IL-2 or TNF- . Longitudinal analysis of infants receiving early ARV treatment and then ceasing after 12 months revealed that early treatment conferred no protection against increasing viremia and disease progression. CD4+ T cell responses were detected sporadically in untreated infants indicating a dysfunctional immune response in the face of constant exposure to high levels of viremia. Taken together, the data reveal that a vaccine inducing Gag specific CD4+ T cell responses has the potential to confer some degree of protection, but other immunological parameters need to be investigated especially in infants. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2011.

Globally HIV and AIDS are considered to be a major health and developmental challenge facing humanity. The HIV infection of children is not only an area of great concern for families but for the future of humankind. Caring and nurturing of children generally is considered as a challenging responsibility. Caregivers of HIV infected children are faced with the added responsibility of ensuring that these children have access to life saving health care at all times. Caregivers who are responsible for the health and well being of HIV infected children face constant challenges in their care giving role and this has implications for the quality of care of the child. The needs of HIV infected children are complex and vital to their basic needs is the administration of antiretroviral therapy (ART). This study aimed to explore, describe and interpret the experiences of caregivers, caring for HIV infected children and accessing services from a public hospital in Durban. Using the ecosystems theory, this qualitative study explored the experiences of thirty caregivers caring for HIV infected children. The data was collected using semi structured interviews with the caregivers. Four main themes emerged from the data analysis; namely: The caregivers’ intrapersonal experiences, their perspectives on HIV and ART, their access to health and social services and their coping strategies. This study concludes that caregivers of HIV infected children within the public hospital setting, experience numerous psycho-social and economic challenges on a daily basis. Subsequently, these challenges impacted on the quality of care to the HIV infected child. It was evident that respondents dealt with challenges differently, as the older respondents were more equipped emotionally and psychologically than the younger respondents. Generally, all respondents were negatively affected by poor psychological and socio-economic circumstances that prevented them from ensuring the wellbeing of the child. The challenges that they faced on the micro level (economic and psycho-social experiences), the mezzo (stigma, community and family support) and exo levels (health and welfare services) together with the macro level (DOH strategic plans and childcare legislations) determined how they provided for the care of the HIV infected child. Despite these challenges respondents’ resilience and commitment to providing for the health and wellbeing of the HIV infected child was consistent and remained a priority. Multi-level intervention programmes are required to help caregivers cope with their challenges. As such social work practitioners need to take cognizance of the psycho-social, emotional and material support required by caregivers of HIV infected children. / Thesis (M.A.)-University of KwaZulu-Natal, Durban, 2013.