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Objective: In preeclampsia, there are excessive complement components expressed due to increased complement activation; therefore, this study investigated the concentration of adipsin and C9 in HIV-associated preeclampsia., Method: The study population (n = 76) was stratified by pregnancy type (normotensive pregnant and preeclampsia) and by HIV status. Serum was assayed for the concentration of adipsin and C9 using a Bioplex immunoassay procedure., Results: Maternal weight did not differ (p = 0.1196) across the study groups. The concentration of adipsin was statistically different between the PE vs normotensive pregnant groups, irrespective of HIV status (p = 0.0439). There was no significant difference in adipsin concentration between HIV-negative vs HIV-positive groups, irrespective of pregnancy type (p = 0.6290). Additionally, there was a significant difference in adipsin concentration between HIV-negative normotensive vs HIV-negative preeclampsia (p < 0.05), as well as a difference between HIV-negative preeclampsia vs HIV-positive preeclampsia (p < 0.05). C9 protein expression was not statistically different between the normotensive and PE groups, regardless of HIV status (p = 0.5365). No statistical significance in C9 expression was found between HIV-positive vs HIV-negative groups, regardless of pregnancy type (p = 0.3166). Similarly, no statistical significance was noted across all study groups (p = 0.0774)., Conclusion: This study demonstrates that there is a strong correlation between the up-regulation of adipsin and PE and that adipsin is a promising biomarker to use as a diagnostic tool for PE., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Pre-eclampsia (PE) accounts for 14.8% of maternal deaths in South Africa. Tenascin C (TN-C) is an anti-inflammatory cytokine expressed in the extracellular matrix and may be dysregulated in the hyperinflammatory PE microenvironment., Material and Methods: This study examined serum TN-C in normotensive pregnant (n = 36) and pre-eclamptic (n = 36) HIV positive and negative women using an immunoassay., Results: TN-C was significantly upregulated in PE vs normotensive pregnant women (p = 0.0075) and HIV-positive vs negative pregnant women (p = 0.0009). TN-C levels across all groups was statistically different (p < 0.0001)., Conclusion: This study demonstrates an elevation of TN-C in HIV-associated PE. The potential benefit of TN-C as a biomarker to detect PE development requires investigation., (Copyright © 2021 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: The impact of the coronavirus disease 2019 (COVID-19) pandemic is profound, with distressing consequences on many individuals, especially those with co-morbidities. Pregnant women are one such group of individuals who are at in increased risk of contracting COVID-19, due to their immunocompromised state. In South Africa, HIV infection and pre-eclampsia are the leading causes of maternal morbidity and mortality, with South Africa being the HIV epicentre of the world. The relationship between COVID-19 superimposed on HIV infection and preeclampsia is complex and uncertain due to their different immune responses, and therefore requires further research., Recent Findings: Notably evidence suggests that pregnant women with chronic comorbidities (HIV and pre-eclampsia) may be at a greater risk of contracting or encountering complications from COVID-19. Maternal stress, during a pandemic, as well as home delivery have become potential options for pregnant woman. Nonetheless there is currently a paucity of information on the combined effect of COVID-19 in HIV-associated preeclampsia. Understanding the pathogenesis of COVID-19 could potentially aid in developing effective treatment strategies for COVID-19 in HIV associated preeclampsia. This review article presents a comprehensive analysis of the current data in relation to COVID-19 and its effect on pregnant women, including symptoms, pathogenesis and the possible risk of vertical transmission. This paper also reviews its' interactions and effects on preeclamptic and HIV positive pregnant women with suspected or confirmed COVID-19.

Objective: To investigate the expression of plasma NF-κB and the inhibitory subunit IκB-α in HIV-associated pre-eclampsia. Method: This retrospective study examined plasma NF-κB and IκB-α expression expressed as Mean Fluorescence Intensity (MFI) in normotensive (n = 32) and pre-eclamptic (n = 34) pregnant women stratified by HIV status. Results: A significant decrease in the level of plasma NF-κB expression between pre-eclamptic and normotensive pregnant women was observed, irrespective of HIV status (MFI = 82.8 vs 134.3; p = 0.03). Similarly, a significant decline in the level of plasma IκB-α expression was noted in the pre-eclamptic compared to normotensive pregnant women, irrespective of HIV status (MFI = 91.2 vs 120.1; p = 0.04). Plasma NF-κB ( p = 0.7) and IκB-α ( p = 0.8) expression was similar between HIV positive and HIV negative pregnant women, irrespective of pregnancy type. Conclusion: This study demonstrates decreased plasma NF-κB and IκB-α expression in preeclampsia compared to normotensive pregnant women irrespective of HIV status.

Objective: To determine the cytokine profile of HIV infected women treated with highly active anti-retroviral therapy (HAART) of variable duration in pregnancy., Methods: HIV infected women were enrolled at a large tertiary hospital in Durban, South Africa in their antenatal period and stratified into those that initiated HAART before pregnancy (pre-pregnancy HAART or PPH group) and those who initiated HAART during pregnancy (in-pregnancy HAART or IPH group). These were compared with HIV negative women (HN group), matched for gestational age at the time of enrolment. Serum was obtained and Th1 and Th2 cytokines expression determined using the Bio-Plex Pro™ Human Cytokine Treg Panels., Results: The overall cytokine profile of the cohort was pro-inflammatory as a result of significant IL-6 and TNF alpha expression. The anti-inflammatory markers (i.e. Th2 cytokines, namely IL4 and IL10) were poorly expressed by the whole cohort, with IL 4 seen almost exclusively in the IPH group, thus counter-balancing the predominantly pro-inflammatory milieu only in this group. PPH group had a pro-inflammatory milieu comparable to the HN control. IL 6 was the predominant cytokine in all groups, and as expected, it increased with advancing gestation in all the groups. This highly pro-inflammatory milieu was unexpected and needs further review CONCLUSION: Long use of HAART suppresses the anti-inflammatory markers previously reported to be conducive for the wellbeing of pregnancy. This effect needs further review as it was similarly observed in our HIV uninfected controls.

Objectives: HLA-G, part of the major histocompatibility complex (MHC), is associated with the risk of developing preeclampsia (PE). In this study, we determined the contribution of specific HLA-G polymorphisms on the risk of developing preeclampsia in HIV-infected and uninfected South Africans of African ancestry., Methods: One hundred and ninety-three women of African ancestry were enrolled (74 HIV-uninfected normotensive, 60 HIV-infected normotensive, 34 HIV-uninfected, and 25 HIV-infected preeclamptics). Sanger sequencing of the untranslated region was performed to genotype six SNPs, i.e., 14 bp Ins/Del of rs66554220, rs1710, rs1063320, rs1610696, rs9380142, and rs1707)., Results: For rs66554220, we have the following results: (a) based on pregnancy type-the Ins/Ins and Del/Ins genotype frequency was higher in preeclampsia (PE) compared to normotensive pregnancies (Ins/Ins vs . Del/Ins, P = 0.02 ∗ : OR (95%CI) = 13.44 (0.7222-249.9); Del/Del vs . Del/Ins, P = 0.03 ∗ : OR (95%CI) = 2.95 (1.10-7.920)); (b) based on HIV status-the Ins/Ins showed both genotypic and allelic association with HIV infection. HIV-infected PE has higher Ins/Ins genotypic and allelic frequencies compared to HIV-uninfected PE (Ins/Ins vs . Del/Ins, P = 0.005 ∗∗ : OR (95%CI) = 21.32 (1.71-4.17); Ins, P = 0.005 ∗∗ ; OR (95%IC) = 21.32 (1.71-4.17)). For rs1707, we have the following results: (a) based on pregnancy type-there were CT genotypic frequencies in PE, more especially LOPE compared to normotensive pregnancies (TT vs . CT, P = 0.0092 ∗∗ : OR (95%CI) = 5.(1.39 - 25.64)), and no allelic association was noted; (b) based on HIV status-CT was higher in HIV-infected LOPE compared to uninfected LOPE (TT vs . TC, P = 0.0006 ∗∗∗ : OR (95%CI) = 40.00 (2.89 - 555.1)). For rs1710 and rs1063320, no significant differences in the genotype and allele frequencies were noted based on pregnancy type and HIV status. For rs9380142, we have the following results: (a) based on pregnancy type-no significant differences were noted between normotensive compared to PE pregnancies; (b) based on HIV status-AA genotypes occurred more in the HIV-infected PE group (AA vs . GG, P = 0.02 ∗ : OR (95%CI) = 13.97 (0.73 - 269.4)), while A allelic frequency occurred more in HIV-infected PE, especially LOPE compared to uninfected groups (A vs . G, P = 0.0003 ∗∗∗ : OR (95%CI) = 10.72 (2.380 - 48.32); P = 0.02 ∗ : OR (95%CI) = 9.00 (1.07 - 75.74)). For rs1610696, we have the following results: (a) based on pregnancy type-genotypic and allelic frequencies of CC were higher in PE compared to normotensive pregnancies (CC vs . GG, P = 0.0003 ∗∗∗ : OR (95%CI) = 31.87 (1.861 - 545.9); C, P = 0.0001 ∗∗∗ : OR (95%IC) = 21.91 (2.84 - 169.0)); (b) based on HIV status-GG frequencies were higher in the HIV-infected PE more especially LOPE groups (GG vs . GC, P = 0.02 ∗ : OR (95%CI) = 16.87 (0.81 - 352.1); GG vs . CC, P = 0.0001 ∗∗∗ : OR (95%CI) = 159.5 (13.10 - 1942))., Conclusion: Selected HLA-G 14 bp polymorphisms (Ins/Ins) and genotypic and allelic differences in rs9380142, rs1610696, and rs1707 are associated with the pathogenesis of preeclampsia in HIV-infected South African women of African ancestry. More genetic studies evaluating the association between preeclampsia and HIV infection are needed to improve diagnosis and antenatal care., Competing Interests: There are no conflicts of interest in this study., (Copyright © 2020 Wendy N. Phoswa et al.)

Objectives: To immuno-localize histone H2A expression as a marker of neutrophil extracellular traps (NETs) in the placenta; and to quantify and compare the percentage H2A immune-expression as a marker of NETs in the placental intervillous space according to: pregnancy type, HIV status and across the study population., Study Design: The participants to the study were a pregnant South African population group of African ancestry (n = 60) stratified as normotensive (N) (n = 30) or pre-eclamptic (PE) (n = 30) and further subdivided as HIV infected (HIV+) (n = 15) or HIV naïve (HIV-) (n = 15). Following informed consent placental tissue samples were obtained at the time of delivery. Immunohistochemistry using the anti-histone 2A (H2A) antibody as a biomarker of NETs, and morphometric image analysis was used to immuno-localize and quantify placental H2A immuno-expression respectively in the placental inter-villous space. Statistical analysis was performed using Graph Pad Prism software (Version 5)., Main Outcome Measures: To determine if HIV neutralizes the elevated NETs in PE., Results: NETs were localized within the inter-villous space surrounding the exchange villi and conducting villi of placental tissue. Based on HIV status, a significant elevation in H2A immuno-expression was observed in the HIV+ compared to the HIV- group (p = 0.0008) and in the pre-eclampsia HIV- compared to the normotensive HIV- group (p = 0.0008). However, a significant decline in H2A immuno-expression was observed in the PEHIV+ group compared to the NHIV+ group (p = 0.0072)., Conclusions: Both PE and HIV elevate placental NETs; however, they synergistically downregulate NETs expression. Further investigations are required to interrogate the signaling pathways involved to establish potential NET-targeted therapeutic actions., (Copyright © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: In this study, the role of Gal1, a regulatory protein involved in receptor binding and gene transcription within trophoblast cells, in the pathophysiology of HIV associated preeclampsia was determined by immunolocalizing its expression in the placenta of a South African cohort., Study Design: this is an analytical study carried out at the Optics and Imaging Center, Neslon R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa. A hundred and twenty HIV negative or positive, Black African primigrad or multigravid women with pre-eclamptic and normotensive pregnancies were involved in the study. Post-delivery, full thickness of centrally located placental tissue obtained was fixed for immunohistochemistry. The expression of Gal1 was immunolocalized using immunohistochemical assay kit and further quantified with using AxioVision Image analysis software package. Student t-test was used to compare the levels of the analytes while One-way ANOVA was used for comparison across the groups., Results: Gal1 immunoreactivity was observed within the Hofbauer cells, cytotrophoblast, syncytial knots and in the endothelial cells lining blood vessels in both exchange and conducting villi of both normotensive and preeclamptic pregnancies regardless of HIV status. There was a down regulation in Gal1 immunoreactivity in both the exchange and conducting villi of preeclamptic compared to normotensive pregnancies. However, there was no significant effect of HIV infection on Gal1 immunostaining in both villi types., Conclusion: The down regulation of Gal1 in preeclampsia may be due to the inhibition of the MAPK pathway. Since Gal1 influences differentiation and migration, the defective trophoblast invasion in preeclampsia may emanate from its decreased immunoexpression. This highlights the role of Gal1 in angiogenesis and placentation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest in this study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Chorionic syncytiotrophoblasts (STB) function as an essential regulator of feto-maternal exchange. Therefore, STB actively differentiate to maintain their continuity for barrier function. However, the placental pathology reported in disorders such as pre-eclampsia (PE) threaten the homeostatic differentiation of STB. Since, HIV-1 requires the expression of co-receptors on STB to undergo vertical transmission, the aim of this study was to determine the effect of PE and HIV infection on the different stages of STB maturation [mature (H2A+) versus differentiating (H2A-)] and to immuno-localize and quantify the expression of histone 2A (H2A) i.e., positive (H2A+) and H2A negative (H2A-) nuclei within placental conducting and exchange villi. We also compared the expression of H2A + and H2A- nuclei between normotensive versus PE groups, HIV status and across the study population., Study Design: Placental tissue was obtained from pregnant normotensive (n = 30) and pre-eclamptic (n = 30) women after informed written consent. The study groups were further categorized by their HIV status. Immunohistochemistry using the anti-histone 2A (H2A) antibody to identify fully differentiated functional (mature) STB was performed using conventional techniques. Morphometric image analysis was utilized to quantify placental histone H2A immuno-expression in placental exchange and conducting villi. Statistical analysis was performed using GraphPad Prism software., Results: H2A + and H2A- nuclei were immuno-localized within STB of the exchange and conducting villi with H2A- nuclei prominent on the periphery. In the exchange villi, the immuno-expression of H2A + and H2A- nuclei were lower in the PE group compared to the normotensive group (p = 0.0003 and p < 0.0001 respectively). A reduced immuno-expression of H2A+ and H2A- nuclei was lower in exchange villi of HIV+ compared to HIV- placentae (p = 0.0002 and p = 0.0276 respectively)., Conclusions: PE and HIV reduces the percentage of H2A + and H2A- immuno-expression indicative of mature STB and actively differentiating STB respectively. We speculate that the different maturation states of STB and their orientation resultant of PE pathogenesis may be protective against the process of HIV-1 vertical transmission., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Epidermal growth factor (EGF) and Hepatocyte growth factor (HGF) both have tyrosine kinase receptors (EGFR and c-Met) which upon binding, activates and regulates many important cellular processes such as cell survival, growth, proliferation, differentiation, invasion, repair and so forth via the RAS/MAPK/ERK1/2, PI3K/AKT and JAK STAT3 pathways. These processes are crucial for the development of a placenta and other functions in order for a normal pregnancy to occur. Hence, this study determined the concentrations of HGF and EGF to find the correlation between HIV and preeclampsia (PE)., Study Design: A total sample size of n = 80 was used, n = 40 preeclamptic women and n = 40 normotensive women these were further stratified into HIV-positive and HIV-negative women. Analysis of the growth factors were done by using the multiplex Bio-Plex immunoassay method., Results: Irrespective of HIV status, based on pregnancy type, EGF in PE women displayed an upregulation compared to normotensive women. However, for HGF no variance was found between pregnancy type. Based on HIV status, regardless of pregnancy type, both HGF and EGF levels were significantly increased in HIV-positive women compared to HIV-negative women. Across all groups for HGF, significant difference was found between HIV-negative normotensive women (lower) vs HIV-positive normotensive women (higher). Nevertheless, for EGF across all groups, a statistically significant decrease was found in HIV-negative normotensive women compared to HIV-positive normotensive women, HIV-positive PE women and HIV-negative PE women., Conclusion: The study demonstrates that there is a strong association between HIV and PE and that HGF and EGF are promising biomarkers to use as a diagnostic tool for PE., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose of the review: This review highlights the role of angiogenesis, lymphangiogenesis, and immune markers in human immunodeficiency virus (HIV)-associated preeclamptic (PE) pregnancies in an attempt to unravel the mysteries underlying the duality of both conditions in South Africa. Recent findings: Studies demonstrate that HIV-infected pregnant women develop PE at a lower frequency than uninfected women. In contrast, women receiving highly active anti-retroviral therapy (HAART) are more inclined to develop PE, stemming from an imbalance of angiogenesis, lymphangiogenesis, and immune response. Summary: In view of the paradoxical effect of HIV infection on PE development, this study examines angiogenesis, lymphangiogenesis, and immune markers in the highly HIV endemic area of KwaZulu-Natal. We believe that HAART re-constitutes the immune response in PE, thereby predisposing women to PE development. This susceptibility is due to an imbalance in the angiogenic/lymphangiogenic/immune response as compared to normotensive pregnant women. Further large-scale studies are urgently required to investigate the effect of the duration of HAART on PE development.

Purpose of Review: This review provides a comprehensive insight into the angiogenic profile of hypertensive and normotensive pregnancies compromised by HIV infection. Furthermore, we evaluate the economic implementation of the sFlt-1/PlGF ratio and review the reports on therapeutic apheresis in limiting sFlt-1 production., Recent Findings: In preeclampsia, an increased expression of sFlt-1 triggers angiogenic imbalance. Women of African ancestry have high levels of angiogenic factors than other racial groups. The sFlt-1/PlGF ratio shows promise in the early assessment of preeclampsia, while sFlt-1 apheresis restores angiogenic imbalance. Studies suggest antiretroviral therapy does not impact the angiogenic shift in preeclampsia development. The angiogenic profile in pregnant women of different races influences preeclampsia development. Despite the opposing immune response in HIV infection and preeclampsia, the HIV tat protein strongly mimics vascular endothelial growth factor (VEGF); hence, it is plausible to assume that HIV infection may ameliorate the angiogenic imbalance in preeclampsia.

Background/aim: Impaired lymphatic function is associated with pathological conditions. The presence of placental lymphatics is still under debate. This study evaluates the placental podoplanin expression in normotensive and preeclamptic women with and without HIV. Materials and methods: Normotensive (n = 60) and preeclamptic (n = 120) pregnant women were stratified into early and late onset preeclampsia and further divided by HIV status. Immunostaining was performed using the podoplanin antibody prior to the morphometric image analysis. Results: Podoplanin was immunolocalized in a reticular-like stroma complex within the exchange and conducting villi. The immunoexpression of podoplanin was significantly upregulated in the exchange villi (P = 0.001) irrespective of the pregnancy type and HIV status. Based on pregnancy type, podoplanin was downregulated in early onset preeclampsia (15.33 ± 4.27%) compared to late onset preeclampsia in the exchange villi (17.85 ± 4.74%; P = 0.04). Podoplanin was upregulated in HIV+ vs. HIV- cases regardless of pregnancy and villi type. Irrespective of pregnancy type, podoplanin immunoexpression within exchange villi was different (P = 0.008) between the HIV+ and HIV- groups. Conclusion: Placental fluid homeostasis is maintained by a podoplanin reticular-like complex within conducting and exchange villi, being upregulated in HIV-positive pregnancies., (CC-BY 4.0)

Objective: To compare expression of markers of HIV and associated receptors (p24, CD4, CCR5 and ICAM-2) in placentae and umbilical cords of HIV-associated and pre-eclamptic pregnancies to elucidate any association between these conditions in mother-to-child transmission., Design: Cross-sectional immunohistochemical analysis of target receptor expression., Setting: Laboratory-based study of primigravidae attending a district hospital in South Africa., Population or Sample: Retrospectively collected placental tissue (stratified into four groups according to HIV status of normotensive and pre-eclamptic participants (n = 20/group)., Method: Immunohistochemistry utilising CD4 (1:1), p24 (1:10), CCR5 (1:80) and ICAM-2 (1:100) antibodies was performed using light microscopy for image acquisition and analysis., Main Outcome Measures: Evaluate the expression of receptors on syncytiotrophoblast involved in in utero transmission of HIV., Results: Syncytiotrophoblast was immunopositive for CD4 and CCR5 antibody with greater expression of CCR5 in HIV-positive versus HIV-negative groups (F 1,159  = 6.979, P = 0.009) and normotensive versus pre-eclamptic groups (F 1,159  = 8.803, P = 0.003). p24 was present in both placentae and umbilical cords of babies that were HIV-negative at 6 weeks. ICAM-2 immunostaining was observed in the syncytiotrophoblast across study groups and was significantly higher in the HIV-negative pre-eclamptic group (χ 2 (3)  = 45.3; P < 0.001)., Conclusion: Concurrent CD4 and CCR5 receptor expression demonstrates possible in utero viral entry routes across the placental barrier. ICAM-2 expression may influence HIV passage across the placenta or restoration of risk of pre-eclampsia in HAART-treated mothers. HIV was found in fetal circulation regardless of antiretroviral treatment. Further confirmatory ultrastructural and molecular work is warranted., Tweetable Abstract: CD4, CCR5 and ICAM-2 on syncytiotrophoblast may facilitate HIV infection of passage across the placenta., (© 2016 Royal College of Obstetricians and Gynaecologists.)

Leptin, primarily produced by adipocytes, is implicated in the development of pre-eclampsia. This study examines placental leptin production and serum leptin levels in HIV infected and uninfected normotensive and pre-eclamptic pregnancies. Placental leptin production was analysed by RT-PCR and serum leptin levels by ELISA in normotensive (n = 90) and pre-eclamptic (n = 90) pregnancies which were further stratified by HIV status. Placental leptin production was higher in pre-eclampsia compared to normotensive pregnancies irrespective of HIV status (p = .04). Serum leptin was non-significantly raised in HIV uninfected (p = .42) but lower in HIV-infected (p = .03) pre-eclampsia. The latter had lower BMI (p = .007) and triceps skin-fold thickness (p < .001) than the HIV uninfected groups with a significant correlation between serum leptin and triceps skin-fold thickness (p < .001), indicative of less adipose tissue in HIV-infected women with consequently lower serum leptin. Thus, serum leptin levels are not indicative of increased placental production when pre-eclampsia is associated with HIV infection.

Objective: The delicate balance which exists between complement activation and its regulation is altered in HIV infection and pregnancy disorders such as pre-eclampsia. Therefore, the purpose of this study was to investigate the expression of complement regulatory (Creg) proteins (CD35 and CD55) in HIV associated normal and pre-eclamptic pregnancies., Study Design: The total study population (n=100) consisted of normotensive pregnant (n=50) and pre-eclamptic (n=50) women. These groups were equally sub-stratified into HIV infected and uninfected groups (n=25 per group). Standard haematological tests were conducted. Flow cytometric analysis of isolated neutrophils were performed using fluorescein isothiocyanate-conjugated anti-CD35 and phycoerythrin-cyanine 5 conjugated anti-CD55., Results: HELLP syndrome characteristics of increased lactate dehydrogenase enzymes levels, low platelet counts, cell morphological abnormalities (red cell fragmentation) and anaemia were observed in 40% of the HIV infected pre-eclamptic group. Red cell fragmentation inclusive of burr cells and schistocytes were also noted. Activated partial thromboplastin time and fibrinogen differed significantly between the HIV uninfected pre-eclamptic compared to the HIV infected pre-eclamptic groups (p<0.01). Irrespective of HIV status, the mean fluorescence intensity of CD35 and CD55 were significantly higher in the pre-eclamptic compared to the normotensive pregnant (p=0.0001; p=0.0001 respectively) groups. In the pre-eclamptic groups, the expression of both CD35 and CD55 did not significantly differ between HIV infected and uninfected women (p=0.486; p=0.767 respectively)., Conclusions: This study demonstrates an up-regulation of complement regulatory proteins, CD35 and CD55 in HIV associated pre-eclamptic compared to normotensive pregnancy. This elevation of the Creg proteins is an adaptive immune response to the high complement-mediated cell lysis that occurs in HIV infection and further aggravated by the complement activated state of pre-eclampsia., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Introduction: Hypertensive disorders of pregnancy are the commonest direct cause of maternal deaths in South Africa, 83% being attributed to pre-eclampsia. Elevated placental sFlt-1 levels are linked with angiogenic disruption and subsequent pre-eclampsia development. The impact of HIV infection on pre-eclampsia is controversial. Its effect on angiogenic imbalance in both normotensive and pre-eclamptic pregnancies remains unknown., Methods: We examined the immunolocalisation of both membrane bound and soluble forms of Flt-1, within placentae of HIV negative and positive normotensive and pre-eclamptic pregnancies at term using immunohistochemistry and immuno-electron microscopy., Results: Strong Flt-1 and sFlt-1 immunoreactivity was observed within endothelial, syncytio and cytotrophoblast cells. Subcellularly, gold particles were localised predominantly within the endoplasmic reticulum and mitochondria and occurring free within the cytoplasm. There was no significant effect of HIV on Flt-1 and sFlt-1 immunoexpression in both exchange and stem villi. A significant effect of type of pregnancy (normotensive vs pre-eclamptic) on Flt-1 and sFlt-1 immunoexpression (p = 0.003) within exchange rather than stem villi, indicated that the pre-eclamptic had elevated Flt-1 and sFlt-1 expressions compared to the normotensive pregnant women. There was no interaction between HIV and pregnancy type (normotensive vs pre-eclampsia) for Flt-1 and sFlt-1 expressions in both exchange and stem villi. A weak correlation of Flt-1 and sFlt-1 intensity between the exchange and stem villi was noted., Discussion: Elevated immunoexpression of Flt-1 and sFlt-1 within trophoblasts suggests an autocrine mode of action on trophoblast invasion and differentiation thereby contributing to abnormal placentation with consequential endothelial dysfunction in pre-eclampsia., Conclusion: Irrespective of the HIV status, placental Flt-1 and sFlt-1 expressions remain elevated in pre-eclampsia compared to normotensive pregnancies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: HIV-associated preeclampsia reflects a combination of opposing influences on the immune status. The adipocyte hormone leptin has been implicated in the pathophysiology of preeclampsia and in enhancing immunity. This study is the first, to our knowledge, to determine whether leptin levels in the placenta differ between HIV-associated normotensive and preeclamptic pregnancies. The study also compares leptin levels between the exchange and conducting areas of the placenta., Study Design: Pregnant women were recruited antenatally and grouped as follows: normotensive HIV uninfected (n=30), normotensive HIV infected (n=60), preeclamptic HIV uninfected (n=30) and preeclamptic HIV infected (n=60). Anthropometric data were collected and placental leptin was analysed by immunohistochemistry and ELISA., Results: Leptin levels were similar in the central and peripheral regions of the placenta. Leptin immunoreactivity was observed amongst the different trophoblast cell populations. Both ELISA and immunohistochemistry of the placental exchange villi indicated that leptin levels were higher in preeclampsia compared to normotensive pregnancies (p<0.001). HIV status had no effect on leptin levels but levels were higher in participants on highly active antiretroviral treatment (HAART) compared to those on prophylaxis for prevention of mother to child transmission (PMTCT) with normotensive (p=0.006) and preeclamptic (p=0.002) pregnancies. The area of immunostaining was greater in the exchange compared to the conducting villi in HIV infected and uninfected preeclampsia., Conclusions: This novel study establishes an elevation of leptin in preeclamptic placentae, irrespective of HIV status. Leptin elevation was not focal in that it occurred in both central and peripheral regions of the preeclamptic placenta. This suggests a role of leptin in the pathophysiology of preeclampsia., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: Preeclampsia is characterized by endothelial dysfunction combined with increased concentrations of sFlt1, which antagonizes the biological effects of VEGF and PlGF, and of sEng, which antagonizes TGFβ1. This angiogenic imbalance may have a role in its etiology. This study evaluated the expression of VEGF, PlGF, sFlt1 and sEng amongst third trimester pregnancies in women with HIV-associated pre-eclampsia., Method: Serum and placental tissue were obtained from 76 pregnancies in women who were normotensive and HIV negative (N-) or positive (N+), and in women who were pre-eclamptic and HIV negative (P-) or positive (P+). The serum and placental samples were quantitatively evaluated using ELISAs and RT-PCR respectively., Results: Placental sFlt1 expression differed significantly between the N- and P- groups (p=0.001). Similarly, sEng expression differed between the N- and P- groups (p=0.001). No significant effect was shown between HIV status and pregnancy. Serum sFlt1 (p=0.02) and sEng (p=0.001) were up-regulated in the P- compared to the N- groups. Similarly, no significant effect was shown between HIV status and pregnancy. Both VEGF and PlGF did not differ significantly between groups. Notably, sEng expression was elevated in both placenta and serum, whilst placental sFlt1 differed from serum. A weak but significant correlation between serum and placental concentration for sFlt1, sEng and PlGF (r=0.26, p=0.031; r=0.42, p<0.001 and r=-0.3, p=0.014) was observed., Conclusions: This novel study demonstrates an up-regulation of serum sFlt1 and sEng in preeclamptic compared to normotensive groups irrespective of the HIV status of the pregnancy. This implicates a contributory role of sFlt1 and sEng in preeclampsia development. The serum reduction of sFlt1 and sEng within the HIV positive compared to HIV negative cohorts may imply a neutralization of the immune hyperreactivity of preeclampsia., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Angiogenic imbalance contributes to the development of preeclampsia. We evaluated the protein expression of the proangiogenic placental growth factor (PlGF) and transforming growth factor beta 1 (TGF-β1) compared with the anti-angiogenic soluble fms-like tyrosine kinase receptor (sFlt1) and soluble endoglin (sEng) in HIV-infected normotensive and pre-eclamptic pregnancies. Blood was obtained from 110 pregnant women, enrolled in four groups, namely, HIV-negative normotensives (27); HIV-positive normotensives (31); HIV-negative pre-eclamptics (27) and HIV-positive pre-eclamptics (25), and was used to measure PlGF, TGF-β₁, sFlt1 and sEng levels. Increased sFlt1 and sEng levels were associated with the pre-eclamptics (HIV negative and positive) compared with their counterparts. Decreased PlGF levels were observed between the HIV-negative pre-eclamptics versus HIV-negative normotensives, but levels differed significantly (p = 0.02) among the normotensives (HIV negative and positive). TGF-β₁ remained unchanged across all groups. Higher sEng/TGF-β₁ ratios were associated with the pre-eclamptics (HIV negative and positive) compared with their counterparts. This study demonstrated increased sFlt1 and sEng levels in pre-eclamptic compared with normotensive pregnancies, irrespective of the HIV status.