Placental progesterone and its receptor in HIV-infected pre-eclamptic women.

Given the high prevalence of HIV infection and pre-eclampsia (PE) in South Africa, this study evaluated and compared the placental immunostaining of progesterone (P) and progesterone receptors (PR) in the synergy of HIV-infected PE compared to normotensive pregnant women using immunohistochemistry interfaced with morphometric image analysis. Progesterone immunostaining was expressed widely across exchange and conducting villi within mesenchymal, endothelial, and trophoblast cells. In contrast, PR was expressed within syncytiotrophoblasts and was absent within endothelial cells. In exchange villi, P and PR immuno-expression was significantly lower in PE compared to the normotensive group (p = < 0.0001 and p = < 0.0001, respectively) and within the early-onset pre-eclampsia (EOPE) compared to the late-onset pre-eclampsia (LOPE) group (p = < 0.0001 and p = < 0.0001, respectively). Progesterone immuno-expression was significantly lower in the HIV+ compared to the HIV- group (p = < 0.0001), whilst PR was non-significant. In conducting villi, P and PR immuno-expression was significantly lower in the EOPE compared to the LOPE group (p = < 0.0001 and p = < 0.0001, respectively) and in the HIV+ compared to the HIV- group (p = < 0.0001 and p = 0.0009, respectively). Progesterone immuno-expression was slightly higher in the PE compared to normotensive group, and PR immuno-expression was non-significant. There was a significant difference between P and PR within exchange versus conducting villi regardless of pregnancy type, with villi type accounting for 34.47% and 15.28% of total variance for P and PR, respectively. Placental P and PR immuno-expression is downregulated in the duality of PE and HIV+ infection. The use of combined antiretroviral therapy (cART) may result in defective P synthesis, which causes insufficient binding to its receptors. Consequently, PI3K/AKT, JAK-STAT, and MAPK signalling pathways are affected, impairing trophoblast invasion and leading to pre-eclampsia development. Notably, the decrease in P and PR immuno-expression in EOPE validates their effect on placentation.

Placental neutrophil reverse trans-migration and maternal serum neutrophil extracellular trap expression in HIV infection co-morbid pre-eclampsia in women of African ancestry.

Neutrophil extracellular traps (NETs) and placental neutrophil reverse transmigration (r-TM) are implicated in the pathogenesis of pre-eclampsia (PE). However, the role of the comorbidity of PE and human immunodeficiency virus (HIV) infection in placental neutrophil r-TM and serum NETs remains unknown. Human placental tissue (n = 160) and serum (n = 80) samples were obtained post-ethical approval and divided by pregnancy type and HIV status and across the study population. Immunohistochemistry and morphometry were performed to localize and quantify junctional adhesion molecule-C (JAM-C) expression as an inverse marker of neutrophil r-TM within placental villi. An enzyme-linked immunosorbent assay (ELISA) was performed to quantify the concentration of citrullinated histone H3 (cit-H3) as a marker of NETs. GraphPad Prism (version 8.0.2) was used to compare the results, and a p value of p < 0.05 was considered statistically significant. The localization of JAM-C was observed on the syncytiotrophoblasts (STBs) and endothelial cells of placental villi. The immunoexpression of JAM-C was elevated in PE vs. normotensive (N) placentae. In the exchange villi, JAM-C immunoexpression was higher in the N+ve vs. N-ve group. However, in PE comorbid HIV infection, JAM-C expression was lower in the PE+ve vs. PE-ve group. Citrullinated histone-H3 concentration was lower in the N+ve vs. N-ve group but elevated in early-onset PE (EOPE)+ve vs. late-onset PE (LOPE)+ve group. These results indicate that PE and HIV-infected placentae individually express elevated JAM-C, manifesting in less neutrophil r-TM. However, in exchange villi of PE comorbid with HIV infection reduced JAM-C enhances neutrophil r-TM, thus supporting the synergistic effect of PE comorbid with HIV.

Genetic Appraisal of RAAS-Associated SNPs: REN (rs16853055), AGT (rs3789678) and ACE (rs4305) in Preeclamptic Women Living with HIV Infection.

PURPOSE OF REVIEW: The primary goal of this review article was to determine whether the three RAAS-associated SNPs, Renin-rs16853055, AGT-rs3789678 and ACE-rs4305 are genetically linked to the development of hypertension in preeclampsia. The secondary goal was to establish if there was a link between these SNPs and HIV infection. RECENT FINDINGS: There is a paucity of findings related to the aforementioned SNPs and preeclampsia. There are no recent findings on the rs16853055 renin polymorphism. The rs3789678 angiotensinogen polymorphism correlated significantly with gestational hypertension. The rs4305 ACE polymorphism showed no significant association with the development of pregnancy-induced hypertension. There are conflicting findings when determining the relationship between ethnicity and the predisposition of preeclampsia and hypertension in relation to the discussed RAAS-associated SNPs. To date, the association between RAAS-associated SNPs and preeclamptic women co-morbid with HIV in South Africa has revealed that certain alleles of the AGT gene are more prominent in HIV-infected PE compared to normotensive pregnant HIV-infected women.

Association of angiogenic factors (placental growth factor and soluble FMS-like tyrosine kinase-1) in preeclamptic women of African ancestry comorbid with HIV infection.

BACKGROUND: Preeclampsia is a significant cause of maternal and fetal morbidity and mortality, particularly in low- and middle-income countries like South Africa. AIM: The aim of our study was to investigate the association between placental growth factor (PlGF) and soluble FMS-like tyrosine kinase-1 (sFlt-1) in South African preeclamptic women of African ancestry, comorbid with HIV infection. METHODS: The study population consisted of women attending a regional hospital in Durban, South Africa, stratified by pregnancy type (normotensive pregnant and preeclampsia) and HIV status. Preeclampsia was defined as new-onset hypertension and proteinuria. DNA was obtained from whole blood. The SNPs of interest were rs722503 in sFlt-1 and rs4903273 in PlGF. RESULTS: Our findings suggest that single nucleotide polymorphisms of rs722503 analysis show no significant associations between the genotypic frequencies of rs722503 variants and preeclampsia risk in either HIV-negative or HIV-positive groups of women of African ancestry. Similarly, the rs493273 polymorphism showed no significant association with preeclampsia risk in either HIV-negative or HIV-positive pregnant women. Additionally, comparisons of dominant, recessive, and over-dominant allele models did not reveal significant associations. These findings suggest that these genetic variants may not significantly contribute to preeclampsia development in this African ancestry population. However, significant differences were observed in the rs4903273 genotype frequencies between normotensive and preeclamptic women, regardless of HIV status, over dominant alleles AA + GG vs AG showed a significant difference [OR = 2.706; 95% Cl (1.199-5.979); adjusted p = 0.0234*], also in normotensive compared to EOPE (OR = 2.804; 95% Cl (1.151-6.89) p = 0.0326* and LOPE (OR = 2.601; 95% Cl (1.0310-6.539) p = 0.0492*), suggesting that they may be the potential role of this variant in preeclampsia susceptibility. CONCLUSION: The findings suggest that the rs722503 and rs493273 polymorphisms do not significantly contribute to preeclampsia susceptibility in HIV-negative or HIV-positive pregnant women. However, the rs4903273 genotype frequencies showed notable differences between normotensive and preeclamptic women, indicating a potential association with preeclampsia development in the African ancestry population irrespective of HIV status.

Is the Complement System Dysregulated in Preeclampsia Comorbid with HIV Infection?

South Africa is the epicentre of the global HIV pandemic, with 13.9% of its population infected. Preeclampsia (PE), a hypertensive disorder of pregnancy, is often comorbid with HIV infection, leading to multi-organ dysfunction and convulsions. The exact pathophysiology of preeclampsia is triggered by an altered maternal immune response or defective development of maternal tolerance to the semi-allogenic foetus via the complement system. The complement system plays a vital role in the innate immune system, generating inflammation, mediating the clearance of microbes and injured tissue materials, and a mediator of adaptive immunity. Moreover, the complement system has a dual effect, of protecting the host against HIV infection and enhancing HIV infectivity. An upregulation of regulatory proteins has been implicated as an adaptive phenomenon in response to elevated complement-mediated cell lysis in HIV infection, further aggravated by preeclamptic complement activation. In light of the high prevalence of HIV infection and preeclampsia in South Africa, this review discusses the association of complement proteins and their role in the synergy of HIV infection and preeclampsia in South Africa. It aims to identify women at elevated risk, leading to early diagnosis and better management with targeted drug therapy, thereby improving the understanding of immunological dysregulation.

Immunoexpression of neuropilin-1 in the chorionic villi of HIV-infected preeclamptic South African women of African ancestry.

Neuropilin-1 (NRP-1) is an essential regulator of maternal immune tolerance, placentation, and angiogenesis. Its dysregulation in preeclampsia (PE) and human immunodeficiency virus (HIV) infection implicates NRP-1 in disease susceptibility and progression. Therefore, this study investigates placental NRP-1 immunoexpression in HIV-complicated preeclamptic pregnancies in South African women of African ancestry receiving antiretroviral therapy. Immunohistochemistry of recombinant anti-neuropilin-1 antibody was performed on placental tissue from 30 normotensive and 60 early onset (EOPE) and late-onset (LOPE) preeclamptic women stratified by HIV status. Qualitative analysis of NRP-1 immunostaining within the chorionic villi revealed a predominant localization in trophoblasts and syncytial knots as well as endothelial, fibroblast-like, and Hofbauer cells. Following morphometric evaluation, we report that PE and HIV infection and/or antiretroviral usage independently downregulate placental NRP-1 immunoexpression; however, as a comorbidity, this decline is further augmented within the conducting and exchange villi. Furthermore, reduced immunoexpression of NRP-1 in EOPE compared with LOPE villi may be due to maternal-fetal maladaptation. It is plausible that the decreased NRP-1 immunoexpression in PE placentae facilitates syncytiotrophoblast apoptosis and subsequent deportation of NRP-1 into the maternal circulation, contributing to the anti-angiogenic milieu of PE. We hypothesize that the intense NRP-1 immunoreactivity observed in Hofbauer cells at the maternal-fetal interface may contribute to the natural prevention mechanism of HIV vertical transmission.

The Clinical Value of Rodent Models in Understanding Preeclampsia Development and Progression.

PURPOSE OF REVIEW: Preeclampsia (PE) is a leading global cause of maternal and fetal morbidity and mortality. The heterogeneity of this disorder contributes to its elusive etiology. Due to the ethical constraints surrounding human studies, animal models provide a suitable alternative for investigation into PE pathogenesis and novel therapeutic strategies. The purpose of this review is to compare and contrast the various rodent models used to study PE, in order to demonstrate their value in investigating and identifying different characteristics of this disorder. RECENT FINDINGS: Several approaches have been employed to create an appropriate animal model of PE, including surgical, genetic manipulation, and pharmacological methods in an attempt to mimic the maternal syndrome. Despite the absence of a model to completely model PE, these models have provided valuable information concerning various aspects of PE pathogenesis and novel therapeutic strategies and have led to the discovery of potential predictive markers of PE. Rodent and murine models have contributed significantly to the study of the pathology associated with specific aspects of the disorder. As a single fully encompassing animal model of PE remains absent, the use of a combination of models has potential value in understanding its etiology as well as in new treatment and management strategies.

Placental Morphology and Morphometry: Is It a Prerequisite for Future Pathological Investigations?

Successful pregnancy is dependent on implantation, nutrient and gas exchange, as well as fetal protection from the immunologic attack. Placental pathologies and preterm delivery closely correlate with the size and shape of the placenta. Additionally, normal vaginal microbiota is disturbed during viral insults such as SARS-CoV-2 and HIV, with consequent placental anomalies. This chapter focuses on placental development, morphology, and pathology while also investigating placental bed structure and function. Placental anomalies with regard to HIV-1 and SARS-CoV-2 infection and placental morphometric image analysis and its relevance for verification of placental pathology are explored. Since image analysis remains optional for routine diagnostic purposes, authentication of placental appraisal warrants the use of measurable predefined definitions. Immunohistochemical analyses of placental morphology and angiogenic, epithelial, and apoptotic mechanisms facilitate research into etiopathogenetic pathways involved in placental anomalies with a focus on discovering novel diagnostic foci. Thus, image analyses as an adjunct to complement pathological investigations are recommended.

The Contribution of Complement Protein C1q in COVID-19 and HIV Infection Comorbid with Preeclampsia: A Review.

Dysregulation in component 1q (C1q) levels is associated with weak placental development in preeclampsia (PE). Human immunodeficiency virus infection (HIV-1) triggers the C1q complex, resulting in opsonization of healthy host cells, contributing to their removal, and augmented progression of HIV disease. In coronavirus disease 2019 (COVID-19)-infected patients, the deposition of C1q activates the complement. Considering the paucity of data, this review highlights a significant gap in the potential of C1q in the immunocompromised state of preeclamptic HIV-infected women and COVID-19 infection. In PE, C1q is downregulated; while in antiretroviral treatment-treated HIV/COVID-19 infected patients, C1q is upregulated. It is plausible that C1q is augmented in the triad and may exacerbate severity of disease. This thereby provides a foundation for future intended research which involves the investigation of single nucleotide polymorphism expression of the C1q gene, specifically in these diseases.

Causal and putative pathogenic mutations identified in 39% of children with primary steroid-resistant nephrotic syndrome in South Africa.

There is a paucity of data identifying genetic mutations that account for the high rate of steroid-resistant nephrotic syndrome (SRNS) in a South African paediatric population. The aim was to identify causal mutations in genes implicated in SRNS within a South African paediatric population. We enrolled 118 children with primary nephrotic syndrome (NS), 70 SRNS and 48 steroid-sensitive NS. All children with SRNS underwent kidney biopsy. We first genotyped the NPHS2 gene for the p.V260E variant in all NS cases (n = 118) and controls (n = 219). To further identify additional variants, we performed whole-exome sequencing and interrogated ten genes (NPHS1, NPHS2, WT1, LAMB2, ACTN4, TRPC6, INF2, CD2AP, PLCE1, MYO1E) implicated in SRNS with histopathological features of focal segmental glomerulosclerosis (FSGS) in 56 SRNS cases and 29 controls; we also performed exome sequencing on two patients carrying the NPHS2 p.V260E mutation as positive controls. The overall detection rate of causal and putative pathogenic mutations in children with SRNS was 27/70 (39%): 15 (21%) carried the NPHS2 p.V260E causal mutation in the homozygous state, and 12 (17%) SRNS cases carried a putative pathogenic mutation in the heterozygous state in genes (INF2 (n = 8), CD2AP (n = 3) and TRPC6 (n = 1)) known to have autosomal dominant inheritance mode. NPHS2 p.V260E homozygosity was specifically associated with biopsy-proven FSGS, accounting for 24% of children of Black ethnicity (15 of 63) with steroid-resistant FSGS. No causal or putative pathogenic mutations were identified in NPHS1, WT1, LAMB2, PLCE1, MYO1E and ACTN4. We report four novel variants in INF2, PLCE1, ACTN4 and TRPC6.   Conclusion: We report putative missense variants predicted to be pathogenic in INF2, CD2AP and TRPC6 among steroid-resistant-FSGS children. However, the NPHS2 p.V260E mutation is a prevalent cause of steroid-resistant FSGS among Black South African children occurring in 24% of children with SRNS. Screening all Black African children presenting with NS for NPHS2 p.V260E will provide a precision diagnosis of steroid-resistant FSGS and inform clinical management. What is Known: • Limited data is available on the genetic disparity of SNRS in a South African paediatric setting. • The high rate of steroid resistance in Black South African children with FSGS compared to other racial groups is partially explained by the founder variant NPHS2 p.V260E. What is New: • We report putative missense variants predicted to be pathogenic in INF2, CD2AP and TRPC6 among steroid-resistant FSGS children. • NPHS2 p.V260E mutation remains a prevalent cause of steroid-resistant FSGS among Black South African children, demonstrating precision diagnostic utility.

Vascular Endothelial Growth Factor Receptor 2: Molecular Mechanism and Therapeutic Potential in Preeclampsia Comorbidity with Human Immunodeficiency Virus and Severe Acute Respiratory Syndrome Coronavirus 2 Infections.

This review explored the role of vascular endothelial growth factor receptor-2 (VEGFR-2) in the synergy of preeclampsia (PE), human immunodeficiency virus (HIV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Downregulation of VEGFR-2 in PE promotes endothelial dysfunction and prevents endothelial cell (EC) migration, proliferation, and differentiation. The HIV-1 accessory protein, tat (trans-activator of transcription), prevents VEGFR-2 signaling via the vascular endothelial growth factor A (VEGF-A) ligand. Combined antiretroviral therapy (cART) may cause immune reconstitution, impaired decidualization, and endothelial injury, thus may be a risk factor for PE development. The VEGF/VEGFR-2 interaction may be associated with SARS-CoV-2-related pulmonary oedema. Endothelial dysfunction and heightened inflammation are both associated with PE, HIV, and SARS-CoV-2 infection; therefore, it is plausible that both characteristics may be exacerbated in the synergy of these events. In addition, this review explored microRNAs (miR) regulating VEGFR-2. An overexpression of miR-126 is evident in PE, HIV, and SARS-CoV-2 infection; thus, modulating the expression of miR-126 may be a therapeutic strategy. However, the involvement of microRNAs in PE, HIV, and SARS-CoV-2 infection needs further investigating. Since these conditions have been evaluated independently, this review attempts to predict their clinical manifestations in their synergy, as well as independently; thereby providing a platform for early diagnosis and therapeutic potential in PE, HIV, and SARS-CoV-2 infection.

Circulating levels of transforming growth factor beta-1, 2 and 3 in HIV associated preeclamptic pregnancies.

The active role of transforming growth factor-beta in implantation, embryonic development and decidualization has driven our interest to evaluate circulating TGF-ß(1-3) in the synergy of HIV associated pregnancy. Serum TGF-ß(1-3) was quantified in normotensive (n = 38) and preeclamptic (n = 38) pregnant women, who were stratified by HIV status, HIV negative (n = 19) and HIV positive (n = 19), using a Bioplex immunoassay.Based on HIV status, we report no significant difference in TGF-ß-1 (p = .95) and TGF-ß2 (p = .80) however, TGF-ß3 was significantly downregulated in HIV positive (p = .03) vs the HIV negative groups. A significant positive correlation (p < .05) was noted between TGF-ß3 and gestational age (p = .03) (r = 0.51), birth weight (p = .04) (r = 0.53) and CD4 count (p = .02) (r = 0.53). Bivariate correlation between isoforms based on HIV status showed several significant positive associations. In the synergy of HIV infected PE, we demonstrate an association between TGF-ß(1-3) with PE emanating from the hypoxic microenvironment that affects receptor-SMAD activity. Decreased TGF-ß3 levels in HIV infected PE, may originate from ARV usage and/or the mutational/physiological dysregulation of SMAD expression. Impact StatementWhat is already known on this subject? TGF-ß overexpression can convert its protective functions into pathogenic variants. It has a significant role in the oxidatively stressed and inflammatory condition of tissue fibrosis and hence may also be dysregulated in the microenvironment of PE. In HIV infection, TGF-ß promotes viral replication and spreading through the induction of cellular proteins which induce TGF-ß production. Also, mononuclear phagocytes infected with HIV also produce increased TGF-ß mRNA and proteins.What do the results of the study add? Our results show no association of TGF-ß isoforms (1-3) based on pregnancy type (PE vs normotensive pregnant) at term. The lack of association may be linked to TGF-ßs dual promoter/suppresser nature or to gestational age.What are the implications of these findings for clinical practice and/or further research? Large-scale comprehensive clinical trials are warranted to elucidate the association and mechanistic role of TGF-ß receptor-SMAD signalling, the effect of its inhibitors on cell invasion and angiogenesis as well as to deliver valuable data for the detection of novel therapeutic agents in pregnancies complicated by HIV infection.

Association of TNF (rs1800629) promoter polymorphism and schistosomiasis with sub-microscopic asymptomatic Plasmodium falciparum infections in a schistosomiasis-endemic area in Zimbabwe.

OBJECTIVES: Infection with Plasmodium falciparum parasites may result in a wide spectrum of symptoms ranging from asymptomatic to mild or severe. A number of factors are associated with this heterogeneous response to P. falciparum infection. In the present study, associations of sub-microscopic asymptomatic P. falciparum with Schistosoma species and TNF (rs1800629) polymorphism were investigated. METHODS: 361 clinically healthy primary school children were microscopically screened for S. haematobium, S. mansoni and P. falciparum. Sub-microscopic asymptomatic P. falciparum infections were determined by PCR. Genotypic profiles were identified using ARMS-PCR. Logistic regression was used to assess the association of sub-microscopic asymptomatic P. falciparum with Schistosoma species and TNF (rs1800629) polymorphism. RESULTS: 17.2% of the children were infected with S. mansoni, and 27.4% were infected with S. haematobium. Microscopic examination of thick smears detected only one child infected with P. falciparum. Based on PCR results, 46.1% were infected with sub-microscopic asymptomatic P. falciparum. Children carrying heterozygous AG (OR: 16.964, 95% CI: 0.496-586.547) and homozygous GG (OR: 2.280, 95% CI: 0.111-46.796) genotypes of rs1800629 were associated with an increased likelihood of sub-microscopic asymptomatic P. falciparum infections compared with those carrying homozygous AA genotype. Children without S. haematobium infections (OR: 1.051, 95% CI: 0.146-8.985) and S. mansoni (OR: 2.658, 95% CI: 0.498-14.184) also had an increased likelihood (risk) of being infected with sub-microscopic asymptomatic P. falciparum compared with the Schistosoma-infected groups. However, all the associations observed were not statistical significant. CONCLUSION: No associations were observed between rs1800629 and schistosomiasis with sub-microscopic asymptomatic P. falciparum infections. This study also reports a high prevalence of sub-microscopic asymptomatic P. falciparum infection concomitant with low malaria transmission.

OBJECTIFS: L'infection par les parasites P. falciparum peut entraîner un large éventail de présentations allant d'asymptomatiques à bénignes ou sévères. Un certain nombre de facteurs sont associés à cette réaction hétérogène à l'infection à P. falciparum. Dans la présente étude, les associations entre la présentation asymptomatique sous-microscopique de P. falciparum avec les espèces de Schistosoma et le polymorphisme du TNF (rs1800629) ont été investiguées. MÉTHODES: 364 écoliers du primaire en bonne santé clinique ont subi microscopique pour S. haematobium, S. mansoni et P. falciparum. Les infections asymptomatiques sous-microscopiques à P. falciparum ont été déterminées par PCR. Les profils génotypiques ont été identifiés en utilisant ARMS-PCR. La régression logistique a été utilisée pour évaluer l'association entre la présentation asymptomatique sous-microscopique de P. falciparum avec les espèces de Schistosoma et le polymorphisme du TNF (rs1800629). RÉSULTATS: Parmi les enfants, 17,2% étaient infectés par S. mansoni et 27,4% étaient infectés par S. haematobium. L'examen microscopique de frottis épais n'a détecté qu'un seul enfant infecté par P. falciparum. D'après les résultats de la PCR, 46,1% étaient infectés par P. falciparum asymptomatique sous-microscopique. Les enfants porteurs des génotypes hétérozygotes AG (OR: 16,964 ; IC95%: 0,496-586,547) et homozygotes GG (OR: 2,280 ; IC95%: 0,111-46,796) de rs1800629 étaient associés à une probabilité accrue d'infections asymptomatiques sous-microscopiques à P. falciparum par rapport à ceux porteurs du génotype homozygote AA. Les enfants sans infection à S. haematobium (OR: 1,051 ; IC95%: 0,146-8,985) et S. mansoni (OR: 2,658 ; IC95%: 0,498 à 14,184) présentaient également une probabilité (risque) accrue d'être infectés par P. falciparum asymptomatique sous-microscopique par rapport à ceux infectés par Schistosoma. Cependant, toutes les associations observées n'étaient pas statistiquement significatives. CONCLUSION: Aucune association n'a été observée entre le rs1800629 et la schistosomiase avec des infections asymptomatiques sous-microscopiques à P. falciparum. Cette étude rapporte une prévalence élevée d' infection asymptomatique sous-microscopique à P. falciparum concomitante à une faible transmission du paludisme.

The Involvement of MicroRNAs in SARS-CoV-2 Infection Comorbid with HIV-Associated Preeclampsia.

PURPOSE OF REVIEW: This review investigated the potential role of microRNAs (miRNAs) in the synergy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, preeclampsia (PE), and human immunodeficiency virus (HIV) infection. Maternal health is a great concern when treating pregnant women fighting this triad of diseases, which is highly prevalent in South Africa. MicroRNAs are involved in fine-tuning of physiological processes. Disruptions to the balance of this minute protein can lead to various physiological changes that are sometimes pathological. RECENT FINDINGS: MicroRNAs have recently been implicated in PE and have been linked to the anti-angiogenic imbalance evident in PE. Recent in silico studies have identified potential host miRNAs with anti-viral properties against SARS-CoV-2 infection. Studies have demonstrated dysregulated expression of several miRNAs in HIV-1 infection along with the ability of HIV-1 to downregulate anti-viral host microRNAs. This review has highlighted the significant gap in literature on the potential of miRNAs in women with HIV-associated PE in synergy with the novel SARS-CoV-2 infection. In addition, this review has provided evidence of the critical role that the epigenetic regulatory mechanism of miRNA plays in viral infections and PE, thereby providing a foundation for further research investigating the potential of therapeutic miRNA development with fewer side-effects for pregnant women.

Current Updates on Pre-eclampsia: Maternal and Foetal Cardiovascular Diseases Predilection, Science or Myth? : Future cardiovascular disease risks in mother and child following pre-eclampsia.

PURPOSE OF REVIEW: Cardiovascular diseases (CVD), including pre-eclampsia (PE), remain the major cause of death and morbidity in women. This review elucidates the current knowledge, state of research and scientific information available on the post-event implications and complications of PE regarding maternal and foetal cardiovascular health. Does PE expose, predispose or aggravate a predilection to maternal and foetal CVD later in life? RECENT FINDINGS: Women with a history of PE are reported to have stiffer arteries and are more likely to develop cardiovascular problems with time, especially aortic stenosis and mitral regurgitation, which were not hitherto linked with hypertensive pregnancy. Foetal cells persistence in the mother long after pregnancy, now clearly established in the lungs of mice postpartum, is suggested to portend an overexpression of STOX1, which may potentiate later life CVD. Moreover, the conventional theories of in utero stress and developmental reprogramming may not adequately explain the risk of later life CVD predilection in offspring born to mothers with pre-eclampsia as recent data has shown that siblings of offspring born from pre-eclamptic pregnancies are also at higher risk of hypertension later in life, irrespective of whether subsequent pregnancies were pre-eclamptic or normotensive. The mechanism involved in adverse cardiovascular outcome in offspring of pre-eclamptic pregnancies is most likely an intricate interaction of foetal programming, environmental and genetic factors. In light of available evidence, the question of whether PE is just a pointer or predisposing factor to maternal development of CVDs in later life begs for answers to facilitate definitive clinical solutions and preventive approaches.

The COVID-19 Pandemic: an Appraisal of its Impact on Human Immunodeficiency Virus Infection and Pre-Eclampsia.

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.

A Narrative Review of the Renin-Angiotensin-Aldosterone System in the Placenta and Placental Bed of HIV Infected Women of African Ancestry with Preeclampsia.

PURPOSE OF REVIEW: Both HIV infection and preeclampsia (PE), a pregnancy-specific disorder of hypertension and multi-system organ involvement, have high prevalence rates especially in low-to-middle-income countries. The immunoexpression of specific renin-angiotensin-aldosterone system (RAAS) receptors in the placenta and placental bed interface may forecast the risk of PE. RECENT FINDINGS: Preeclampsia is a leading risk factor for mortality worldwide and remains a challenge in HIV-infected individuals especially those on antiretroviral therapy (ART). Irregular RAAS stimulation may be linked to the pathophysiology of hypertension in HIV infection and in PE. The AT1 receptor is expressed across all trimesters of pregnancy, within placental tissue, eliciting vasoconstriction. This increased expression is associated with the severity of PE, implying that the increased expression may be involved in the pathogenesis of this pregnancy disorder. The AT2 receptor expression in normotensive pregnancies was shown to be lower as compared to non-pregnant individuals. Furthermore, in the PE placental bed, the AT2 receptor is the predominant receptor subtype and is found in extravillous trophoblast cells where they facilitate vasodilation. However, AT4R in placentae of PE pregnancies are found to be significantly reduced compared to normotensives pregnancies. The data on the role played by the RAAS pathway in pregnancy is conflicting. Investigation into a tissue-based RAAS with emphasis on immune-expression within the placenta and placental bed may help resolve this conundrum.

The function of adipsin and C9 protein in the complement system in HIV-associated preeclampsia.

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.

HIV Associated Preeclampsia: A Multifactorial Appraisal.

Introduction: This review explores angiogenesis, vascular dysfunction, the complement system, RAAS, apoptosis and NETosis as potential pathways that are dysregulated during preeclampsia, HIV infection and ART usage. Results: HIV-1 accessory and matrix proteins are protagonists for the elevation of oxidative stress, apoptosis, angiogenesis, and elevation of adhesion markers. Despite the immunodeficiency during HIV-1 infection, HIV-1 exploits our cellular defence arsenal by escaping cell-mediated lysis, yet HIV-1 infectivity is enhanced via C5a release of TNF-α and IL-6. This review demonstrates that PE is an oxidatively stressed microenvironment associated with increased apoptosis and NETosis, but with a decline in angiogenesis. Immune reconstitution in the duality of HIV-1 and PE by protease inhibitors, HAART and nucleoside reverse transcriptase, affect similar cellular pathways that eventuate in loss of endothelial cell integrity and, hence, its dysfunction. Conclusions: HIV-1 infection, preeclampsia and ARTs differentially affect endothelial cell function. In the synergy of both conditions, endothelial dysfunction predominates. This knowledge will help us to understand the effect of HIV infection and ART on immune reconstitution in preeclampsia.

Clinical morbidity associated with Schistosoma haematobium infection in pre-school age children from an endemic district in Zimbabwe.

OBJECTIVE: To investigate Schistosoma haematobium morbidity in infected pre-school age children and establish their disease burden. METHODOLOGY: Pre-school age children (1-5 years) who were lifelong residents of the study area and had no other infections were included in the study. Participants underwent a physical examination with clinicians blinded to their infection status. Diagnosis of S. haematobium was by urine filtration. RESULTS: The prevalence of S. haematobium was 35.1% (146/416). The clinical features observed in patients with Schistosoma haematobium were as follows: wheezes (morbidity attributable factor (AF = 93.9%), haematuria (AF = 92.6%), ascites (AF = 91.5%), atopy (AF = 76.9%), inguinal lymphadenopathy (AF = 68.4%), stunting (AF = 38.2), malnutrition (MUAC)(AF = 20%) and weight for height scales (AF = 5%). Schistosoma. haematobium infected children were at greater odds ratio of presenting with inguinal lymphadenopathy (AOR)=99.2(95% CI 24.2 to 854.5), wheezes in the chest (AOR = 35.4 95% CI 15.3 to 94.2), Distended abdomen with ascites (AOR = 23.9 95% CI 11.4 to 54), haematuria (AOR = 12.6 95% CI 11.6 to 14.1), atopy history (AOR = 5.6 95% CI 1.85 to 20.2), malnutrition (AOR = 2.3 95% CI 1.4 to 3.2) and stunting (AOR = 1.9 95% CI 1.1 to2.7). CONCLUSION: The study is novel as it demonstrates for the first time clinical morbidity markers associated with S. haematobium infection in pre-school age children. Furthermore the study adds scientific evidence to the call for inclusion of pre-school age children in schistosomiasis control programmes. These morbidity markers highlight the need for early diagnosis and screening for S. haematobium in pre-school age children.

OBJECTIF: Etudier la morbidité de Schistosoma haematobium chez les enfants d'âge préscolaire infectés et établir sa charge de morbidité. MÉTHODOLOGIE: Les enfants d'âge préscolaire (1 à 5 ans) qui avaient toujours résidents de la zone d'étude et qui n'avaient pas d'autres infections ont été inclus dans l'étude. Les participants ont subi un examen physique avec des cliniciens en aveugle sur leur état d'infection. Le diagnostic de S. haematobium a été effectué par filtration d'urine. RÉSULTATS: La prévalence de S. haematobium était de 35,1% (146/416). Les caractéristiques cliniques observées chez les patients infectés par S. haematobium étaient: respiration sifflante (facteur attribuable à la morbidité (FA = 93,9%), hématurie (FA = 92,6%), ascite (FA = 91,5%), atopie (FA = 76,9%), lymphadénopathie inguinale (FA = 68,4%), retard de croissance ( AF = 38,2), malnutrition (MUAC) (AF = 20%) et poids pour les échelles de taille (AF = 5%). Les enfants infectés par S. haematobium présentaient un rapport de cotes plus élevé de présenter une lymphadénopathie inguinale (AOR) = 99,2 ; (IC95%: 24,2 à 854,5), respiration sifflante dans la poitrine (AOR = 35,4 ; IC95%: 15,3 à 94,2), abdomen distendu avec ascite (AOR = 23,9 ; IC95%: 11,4 à 54), hématurie (AOR = 12,6 ; IC95%: 11,6 à 14,1), antécédents d'atopie (AOR = 5,6 ; IC95%: 1,85 à 20,2), malnutrition (AOR = 2,3 ; IC95%: 1,4 à 3,2) et retard de croissance (AOR = 1,9 ; IC95%: 1,1 à 2,7). CONCLUSION: L'étude est nouvelle car elle démontre pour la première fois des marqueurs cliniques de morbidité associés à une infection à S. haematobium chez des enfants d'âge préscolaire. En outre, l'étude ajoute des données scientifiques à l'appel à l'inclusion des enfants d'âge préscolaire dans les programmes de lutte contre la schistosomiase. Ces marqueurs de morbidité mettent en évidence la nécessité d'un diagnostic précoce et d'un dépistage de S. haematobium chez les enfants d'âge préscolaire.