The association of maternal HIV status during pregnancy on longitudinal neuro-immune regulation, and neurodevelopment in HIV-exposed uninfected children

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

Association of maternal and infant inflammation with neurodevelopment in HIV-exposed uninfected children in a South African birth cohort.

HIV-exposed uninfected (HEU) children may have altered immune regulation and poorer neurodevelopment outcomes compared to their HIV-unexposed (HU) counterparts. However, studies investigating the association of maternal and infant inflammation with neurodevelopment in HEU children are limited and longitudinal data are lacking. This study investigated serum inflammatory markers in women living with HIV vs. HIV-uninfected women during pregnancy and in their children, as well as associations with neurodevelopmental outcomes at two years of age in an African birth cohort study. A sub-group of mother-child dyads from the Drakenstein Child Health Study had serum inflammatory markers measured at ?26?week's gestation (n?=?77 HIV-infected mothers; n?=?190 HIV-uninfected mothers), at 6-10?weeks (n?=?63 HEU infants and n?=?159 HU infants) and at 24-28?months (n?=?77 HEU children and n?=?190 HU children). Serum inflammatory markers [granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-? (IFN-?), interleukin IL-1?, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor-? (TNF-?), neutrophil gelatinase-associated lipocalin (NGAL) and metalloproteinase-9 (MMP-9)] were analyzed with a multiplex bead array and ELISA assays. The Bayley Scales of Infant and Toddler Development, third edition, was used to assess neurodevelopment at 24-28?months. After correcting for multiple comparisons, HIV infection during pregnancy was associated with lower serum levels of inflammatory markers in mothers at 26?weeks gestation (GM-CSF and MMP-9, p?<?0.05) and HEU children at 6-10?weeks (IFN-? and IL-1?, p?<?0.01), and at 24-28?months (IFN-?, IL-1?, IL-2 and IL-4, p?<?0.05) compared to HIV-uninfected mothers and HU children. In HEU infants at 6-10?weeks, inflammatory markers (GM-CSF, IFN-?, IL-10, IL-12p70, IL-1?, IL-2, IL-4, IL-6 and NGAL, all p?<?0.05) were associated with poorer motor function at two years of age. This is the first study to evaluate the associations of follow-up immune markers in HEU children with neurodevelopment. These findings suggest that maternal HIV infection is associated with immune dysregulation in mothers and their children through two years of age. An altered immune system in HEU infants is associated with poorer follow-up motor neurodevelopment. These data highlight the important role of the immune system in early neurodevelopment and provide a foundation for future research

Motivation levels and white matter microstructure in children living with HIV

Abstract Central nervous system involvement in HIV infection leads to neurobehavioural sequelae. Although apathy is a well-recognised symptom in adults living with HIV linked to alterations in brain structure, there is scarce research examining motivation in children living with HIV (CLWH). We used the Children’s Motivation Scale (CMS; normative mean = 50, SD = 10) to assess motivation levels in 76 CLWH aged 6–16 years (63 on antiretroviral therapy [ART]; 13 ART-naïve slow progressors) in South Africa. Overall, CLWH scored low on the CMS (mean = 35.70 [SD = 5.87]). Motivation levels were significantly reduced in children taking ART compared to ART-naïve slow progressors (p = 0.02), but were not correlated with markers of HIV disease (CD4 + cell count or viral load), or neurocognitive function (p > 0.05). CMS scores were correlated with diffusion tensor imaging metrics of white matter microstructure in specific frontostriatal brain regions (p < 0.05). On multiple regression, associations with the anterior limb of the internal capsule, a subcortical white matter region, remained significant after adjusting for potential confounders. These findings suggest that reduced motivation may be an important neurobehavioural symptom in CLWH and may reflect changes in white matter microstructure of frontostriatal brain regions

Shape analysis of subcortical structures in obsessive-compulsive disorder and the relationship with comorbid anxiety, depression, and medication use: A meta-analysis by the OCD Brain Imaging Consortium

Objective: Neuroimaging studies of obsessive-compulsive disorder (OCD) patients have highlighted the important role of deep gray matter structures. Less work has however focused on subcortical shape in OCD patients. Methods: Here we pooled brain MRI scans from 412 OCD patients and 368 controls to perform a meta-analysis utilizing the ENIGMA-Shape protocol. In addition, we investigated modulating effects of medication status, comorbid anxiety or depression, and disease duration on subcortical shape. Results: There was no significant difference in shape thickness or surface area between OCD patients and healthy controls. For the subgroup analyses, OCD patients with comorbid depression or anxiety had lower thickness of the hippocampus and caudate nucleus and higher thickness of the putamen and pallidum compared to controls. OCD patients with comorbid depression had lower shape surface area in the thalamus, caudate nucleus, putamen, hippocampus, and nucleus accumbens and higher shape surface area in the pallidum. OCD patients with comorbid anxiety had lower shape surface area in the putamen and the left caudate nucleus and higher shape surface area in the pallidum and the right caudate nucleus. Further, OCD patients on medication had lower shape thickness of the putamen, thalamus, and hippocampus and higher thickness of the pallidum and caudate nucleus, as well as lower shape surface area in the hippocampus and amygdala and higher surface area in the putamen, pallidum, and caudate nucleus compared to controls. There were no significant differences between OCD patients without co-morbid anxiety and/or depression and healthy controls on shape measures. In addition, there were also no significant differences between OCD patients not using medication and healthy controls. Conclusions: The findings here are partly consistent with prior work on brain volumes in OCD, insofar as they emphasize that alterations in subcortical brain morphology are associated with comorbidity and medication status. Further work is needed to understand the biological processes contributing to subcortical shape