Browsing by Author "Naude, Pieter"

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    Open Access
    An investigation of a neuro-inflammatory profile of HIV-associated neurocognitive disorders
    (2021) Williams, Monray Edward; Naude, Pieter; Joska, John; Stein, Dan
    Background HIV-associated neurocognitive disorder (HAND) is the consequence of the effects of HIV-1 within the central nervous system (CNS). HIV-associated neurocognitive impairment differs in severity with milder forms presenting in 50% of people living with HIV (PLWH), regardless of treatment status. Chronic immune dysregulation has been associated with HAND; in particular, it has been noted that inflammation persists despite the successful treatment with antiretroviral therapy (ART). However, the nature to which (neuro)inflammation influences cognitive performance and brain integrity remain unclear. Further, it is not clear how sequence variation in neurotoxic viral proteins, including Tat, affects inflammation in PLWH. This study aimed to 1) perform a systematic review of the existing literature to identify changes in peripheral immune markers that are associated with HAND in ART-experienced PLWH, 2) determine the association of blood peripheral immune markers with domain-based neurocognitive performance and structural brain changes in South African PLWH, and 3) lastly, to evaluate the possible influence of Tat sequence variation on a dysregulated immune profile in HIV-1C infection (i.e. Tat-C). Methods A systematic review of the published literature was performed to identify the most common markers associated with HAND in the ART-era. A panel of markers was measured in a treatment naïve South African cohort by enzyme-linked immunosorbent assays (ELISA). Cognitive performance was established using a battery of tests sensitive to HIV-associated neurocognitive impairment, with domain based scores utilized in analysis. Thickness and surface area of all cortical regions were derived using automated parcellation of T1-weighted images acquired at 3T. Markers were correlated with neurocognitive performance and cortical thickness and surface area. Further, a prospective review of the literature was performed to determine the association between Tat sequence variation and underlying mechanisms (and inflammation) of HAND. The HIV-1 was genotyped and the influence of Tat sequence variation on immune marker levels was evaluated in a subset of South African participants. Results A systematic review of the existing literature suggested that peripheral immune markers of monocyte activation (sCD14 and sCD163) and inflammation (IL-18 and IP10) were associated with HAND in the majority of studies. Evaluation of blood immune markers in a treatment naïve South African cohort showed that thymidine phosphorylase (TYMP) and neutrophil gelatinase-associated lipocalin (NGAL) levels were significantly higher, while matrix metalloproteinase (MMP)9 levels were significantly lower in PLWH. The results further showed that in PLWH, worse psychomotor processing speed was associated with higher TYMP and NGAL levels and worse motor function was associated with higher NGAL levels. Further, in imaging analysis, it was reported that higher NGAL levels were associated with the reduced thickness of the bilateral orbitofrontal cortex. The association of NGAL withworse motor function was mediated by the cortical thickness of the bilateral orbitofrontal cortex. The associations between higher NGAL and TYMP levels with cortical thickness were largely found in the regions of the frontal cortex. A review of the literature suggests that key protein signatures (C31S and R57S) present in the Tat protein from HIV-1 subtype C (Tat-C) infection may contribute to the lowered inflammation. Supporting this hypothesis, the results from this thesis showed that HIV-1C participants with the R57S mutation had lower peripheral TYMP levels. Conclusions Current literature supports the premise that chronic inflammation may be an important contributor to the development of the milder forms of HAND. For patients on ART, other strategies are required to address the ongoing peripheral inflammation, in addition to simply suppressing the viral load. In a South African context, TYMP and NGAL may be promising markers for their involvement in HAND. Patients were largely treatment-naïve; therefore, these markers may represent HIV related effects without the potential confounding effects of ART. Therefore, these findings may represent long-standing effects which might persist in treatment experienced participants. In HIV-1C infection, the level of certain inflammatory markers may be influenced by the R57S Tat protein signature. To our best knowledge, this is the first thesis to report the association of these markers with HAND. These immune markers need to be investigated for their potential role in the underlying mechanisms of HAND.
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    Open Access
    The association of maternal HIV status during pregnancy on longitudinal neuro-immune regulation, and neurodevelopment in HIV-exposed uninfected children
    (2020) Sevenoaks, Tatum; Naude, Pieter; Donald, Kirsty; Stein, Dan
    Introduction: It has long been established that the Human Immunodeficiency Virus (HIV) and its effects, such as its impact on the immune system and then the numerous consequences on other biological systems including the central nervous system (CNS), have had a significant effect worldwide. This is particularly relevant in South Africa, where the prevalence of adults living with HIV remains high. However, with the improved access to antiretroviral therapy (ART), more children are now being born uninfected with HIV while still being exposed to the virus in utero. Exposure to HIV in utero may still negatively affect the developing brain of these children. However, the biological mechanisms involved in the neurodevelopmental outcomes in HIV-exposed uninfected (HEU) children are still largely unknown. Evidence from clinical studies showed that HEU children have an altered immune regulation compared to their unexposed counterparts, and this is hypothesised to play a role in neurodevelopmental outcomes in HEU children. The aim of this study was to evaluate the longitudinal relationship between the inflammatory environment of pregnant mothers living with HIV on ART and their children and the association of the inflammatory environment with neurodevelopmental outcomes in HEU children. Methods: This study was performed in a sub-sample of the Drakenstein Child Health Study (DCHS), a South African birth cohort of 1137 mother-infant pairs. This sub-study included mothers at ≈26 weeks gestation (n=267), their infants at 6-10 weeks (n=222) and children at 24-28 months (n=267). Maternal HIV status was determined at ≈26 weeks gestation. This sub-study included n=190 HIV negative mother-infant pairs and n=77 HIV positive mother-infant pairs. Serum inflammatory markers (Granulocyte-macrophage colony-stimulating factor (GM CSF), Interferon-γ (IFN-γ), Interleukin IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, tumour necrosis factor-α (TNF-α), neutrophil gelatinase-associated lipocalin (NGAL/Lcn2) and metalloproteinase-9 (MMP-9)) were analyzed in all study participants with a multiplex bead array and ELISA. The Bayley Scales of Infant and Toddler Development (Bayley-III) were used to assess the neurodevelopmental domains: cognitive, motor, language, social-emotional behaviour and adaptive behaviour at 24-28 months of age. Results: Mothers living with HIV on ART had significantly lower levels of the inflammatory markers GM-CSF and MMP9 compared to mothers without HIV. Serum levels of inflammatory markers IFN-γ and IL-1β were significantly lower in HEU infants at 6-10 weeks compared to HIV-unexposed uninfected (HUU) infants. At 24-28 months of age, HEU children also proved to have significantly lower serum levels of the inflammatory markers IFN-γ, IL-1β, IL-2 and IL-4 compared with HUU children. Increased levels of the inflammatory markers; GM-CSF, IFN-γ, IL-10, IL-12p70, IL-1β, IL-2, IL-4, IL-6 and Lcn2 in HEU infants at 6-10 weeks of age was associated with impaired motor neurodevelopment at 24-28 months of age. Conclusion: This is the first study to evaluate the longitudinal associations of immune markers with neurodevelopment in HEU children. The results show that maternal HIV infection was associated with lower levels of inflammatory markers in mothers and their children. Our results further indicate that an altered immune system in HEU infants, specifically at the earliest stages of life, was associated with impaired motor function at 2 years of age. These findings may provide further insights into the involvement of immune regulation, linking maternal HIV status and neurodevelopment in South African HEU children.
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    Open Access
    The role of the astrocytic marker S100B in HIV-associated neurocognitive disorders
    (2019) Groenewald, Engelina; Joska, John; Combrinck, Marc; Naude, Pieter
    There are as yet no ideal biomarkers of HIV-associated neurocognitive disorders. As astrocytosis is a feature of HIV encephalitis, the marker S100β may hold promise as a biomarker of HAND. We explored associations between S100β and neurocognition in individuals with HIV in Cape Town, South Africa, before and after antiretroviral therapy (ART) was initiated. The S100β levels in the cerebrospinal fluid (CSF) of forty-six participants with HIV, but not yet on antiretroviral therapy, was quantified using an enzyme-linked immunoassay (ELISA). A battery of cognitive tests was performed and the global deficit score (GDS) was calculated. In twenty of these patients, the S100β analysis and the cognitive tests were repeated approximately six months after the initiation of ART. There was no significant association between cerebrospinal fluid S100β and GDS at baseline (r= -0.070; p= 0.66) or after six months of ART (r= 0.16; p= 0.52). Cerebrospinal fluid S100β levels at baseline did not predict a change in neurocognition on ART (B(SE) = 0.001, (0.001), β=0.025, p=0.85). S100β in the cerebrospinal fluid may not adequately reflect neurocognitive impairment in individuals with HIV. Our results further demonstrate that CSF S100β levels are not affected by ART, indicating persistent neuroinflammation.