Browsing by Author "Ramsuran, Duran."

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HIV-1 transactivator of transcription (TAT) protein causes neurotoxicity via astrocyte activation.
(2015) Ganga, Yashica.; Daniels, William Mark Uren.; Ramsuran, Duran.
HIV is most well-known for its negative effects on the immune system and the resulting development of AIDS, however it also has severe damaging effects on the central nervous system. Many infected individuals exhibit neuropsychological and behavioral dysfunctions which are collectively referred to as HIV-associated dementia (HAD). One of the worrying aspects of HAD is the fact that current anti-retroviral therapy, while being effective in managing the onslaughts of HIV on the immune system, is less efficient in addressing the impact of HIV on the CNS. The HIV-1 regulatory protein, transactivator of transcription (Tat), is responsible for the transactivation of viral transcription, and has been identified as a possible etiological factor of HAD. Neurotoxicity caused by HIV-1 is an indirect effect since the virus is unable to infect neurons directly. We subsequently hypothesized that HIV-1 infects non-neuronal cells in the CNS which leads to their activation, resulting in the release of cytokines that are detrimental to neurons. The aims of this study was therefore to (i) determine whether Tat activates astrocytes, (ii) establish whether astrocytes exposed to Tat result in the release of IL-6 and TNF-α, and to (iii) assess whether these cytokines can induce apoptosis of neuronal cells. Our study has shown that Tat does activate astrocytes and that activated astrocytes do indeed release cytokines IL-6 and TNF-α into their growth medium. Tat treated cells release more than double the amount of IL-6 than the control group of untreated astrocytes. We also observed that exogenous administration of these cytokines (individually or collectively) to neurons has the ability to cause neuronal apoptosis. Interestingly in combination, these cytokines show no cooperative effect. Our data also showed that neurons, when exposed to the culture medium of astrocytes that were subjected to Tat, exhibit hallmarks of apoptosis similar to that induced by IL-6 and TNF-α. Our findings led us to conclude that in individuals with HIV-infection, the virus activates astrocytes possibly via the production and release of Tat. This causes the astrocytes to secrete pro-inflammatory cytokines (e.g. TNF- α and IL-6) that may induce apoptotic cell death of neurons. This mechanism may explain the development of HAD.
The spectrum of HIV related nephropathy in KwaZulu-Natal : a pathogenetic appraisal and impact of HAART.
(2012) Ramsuran, Duran.; Naicker, Thajasvarie.; Bhimma, Rajendra.
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.
TRIM5α and TRIM22 are differentially regulated according to HIV-1 infection phase and compartment.
(American Society for Microbiology., 2014) Singh, Ravesh.; Patel, Vinod B.; Mureithi, Marianne W.; Naranbhai, Vivek.; Ramsuran, Duran.; Tulsi, Sahil.; Hiramen, Keshni.; Werner, Lise.; Mlisana, Koleka Patience.; Altfeld, Marcus.; Luban, Jeremy.; Kasprowicz, Victoria.; Dheda, Keertan.; Abdool Karim, Salim Safurdeen.; Ndung'u, Peter Thumbi.
The antiviral role of TRIM E3 ligases in vivo is not fully understood. To test the hypothesis that TRIM5α and TRIM22 have differential transcriptional regulation and distinct anti-HIV roles according to infection phase and compartment, we measured TRIM5α, TRIM22, and type I interferon (IFN-I)-inducible myxovirus resistance protein A (MxA) levels in peripheral blood mononuclear cells (PBMCs) during primary and chronic HIV-1 infection, with chronic infection samples being matched PBMCs and central nervous system (CNS)-derived cells. Associations with biomarkers of disease progression were explored. The impact of IFN-I, select proinflammatory cytokines, and HIV on TRIM E3 ligase-specific expression was investigated. PBMCs from individuals with primary and chronic HIV-1 infection had significantly higher levels of MxA and TRIM22 than did PBMCs from HIV-1-negative individuals (P < 0.05 for all comparisons). PBMCs from chronic infection had lower levels of TRIM5α than did PBMCs from primary infection or HIV-1-uninfected PBMCs (P = 0.0001 for both). In matched CNS-derived samples and PBMCs, higher levels of MxA (P = 0.001) and TRIM5α (P = 0.0001) in the CNS were noted. There was a negative correlation between TRIM22 levels in PBMCs and plasma viral load (r = -0.40; P = 0.04). In vitro, IFN-I and, rarely, proinflammatory cytokines induced TRIM5α and TRIM22 in a cell type-dependent manner, and the knockdown of either protein in CD4(+) lymphocytes resulted in increased HIV-1 infection. These data suggest that there are infection-phase-specific and anatomically compartmentalized differences in TRIM5α and TRIM22 regulation involving primarily IFN-I and specific cell types and indicate subtle differences in the antiviral roles and transcriptional regulation of TRIM E3 ligases in vivo.