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.

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.

The Role of Neutrophils and Their Extracellular Traps in the Synergy of Pre-eclampsia and HIV Infection.

PURPOSE OF THE REVIEW: In our innate immune system, neutrophils are the first cells to sense signals of infection and to proceed to kill the invading pathogen. This is mediated by their production of neutrophil extracellular traps (NETS) to entrap pathogenic micro-organisms, preventing their amplification and dissemination. Pre-eclampsia (PE) is the leading cause of global maternal mortality, yet to date, there is no cure nor a gold-standard diagnostic strategy. The purpose of this review is to discover the role of neutrophils in PE as early identification markers. Additionally, this review aims to explore the role of neutrophils in HIV-infected pregnancies with PE as a source of synergy. RECENT FINDINGS: Recent findings demonstrate an elevation of neutrophils and neutrophil extracellular traps (NETs) in PE placentae. This is due to their activation by excessive release of syncytiotrophoblast microparticles (STBM). There is also an elevation of NETs in HIV-infected placentae-where histone H3 entraps HIV by binding to its glycoprotein envelope. Additionally, histones H1 and H2A inhibit HIV infection. It is interesting to note that women with both PE and HIV infection have supressed NETs. This review focuses on the role of neutrophils in the synergy of PE and HIV infection. It is plausible that the deregulation of NETs in the synergy of pre-eclamptic HIV-infected women is strategic for the entrapment of the HIV-1 virus. Finally, it is plausible that neutrophils and NETS may act as early biomarkers of PE development. Graphical abstract.

Neutrophil extracellular traps: The synergy source in the placentae of HIV infected women with pre-eclampsia.

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.

Evaluation of placental chorionic villi histone 2A expression in HIV-infected women with pre-eclampsia.

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.