The regulation of Osteopontin and soluble Neuropilin-1 in HIV- associated preeclampsia.

Abstract

Background: The prevalence of preeclampsia (PE) and human immunodeficiency virus (HIV) infection in pregnant women remains a concern to the South African healthcare system. The conflicting angiogenic roles of osteopontin (OPN) and soluble neuropilin-1 (sNRP-1) has been highlighted in many diseases. However, there is a dire paucity of data on the influence of OPN and sNRP-1 in PE. Moreover, there is an absence of information of OPN and sNRP-1 in HIV-associated PE. In light of the aforementioned criteria, it was important to study the influence of OPN and sNRP-1 in the synergy of HIV-infection and PE. Therefore, this study evaluated the concentration of angiogenic proteins, OPN and sNRP-1, in the synergy of HIV infection and PE. Additionally, in light of the coronavirus disease 2019 (COVID-19) pandemic, we reviewed maternal endothelial dysfunction in HIV-associated PE comorbid with COVID-19. In this review article, we also explored the potential of antiretroviral therapy (ART) in the therapeutic intervention of COVID-19. Study design: A Bio-plex multiplex immunoassay was used to quantify serum OPN and sNRP-1 concentrations in preeclamptic vs normotensive pregnancy type stratified by HIV status (n=19 per subgroup). Results: Significant differences across all groups, i.e., HIV-negative normotensive (n = 19), HIV-negative preeclamptic (n = 19), HIV-positive normotensive (n = 19) and HIV-positive preeclamptic (n = 19), were reported in maternal age (p = 0.0211), gestational age (p = 0.0004), parity (p = 0.0042), systolic blood pressure (p < 0.0001) and diastolic blood pressure (p < 0.0001). The concentration of OPN was significantly downregulated by pregnancy type (preeclamptic vs normotensive; p = 0.0033) and showed a non-significant elevation when stratified by HIV status (HIV-positive vs HIV-negative; p = 0.5099). In addition, there was a significant upregulation in sNRP-1 concentration by pregnancy type (preeclamptic vs normotensive; p = 0.0054) and by HIV status (HIV-positive vs HIV-negative; (p = 0.0005). In comparison to the normotensive HIV-negative group, there was a significant difference in sNRP-1 concentrations between the sub-groups normotensive HIV-positive (p = 0.0049), preeclamptic HIV-negative (p = 0.0244), and preeclamptic HIV-positive (p < 0.001), respectively. Conclusion: This innovative study validates a significant systemic downregulation of OPN in PE compared to normotensive pregnancies in contrast to an upregulation of sNRP-1, conforming to the anti-angiogenic milieu of PE. Moreover, based on HIV-status, both the systemic OPN and sNRP-1 levels were upregulated in HIV-positive pregnancies. This may be attributed to the HIV trans-activator of transcription protein mimicry of VEGF and/or the immune reconstitution following ART as well as

to integrin expression that mediates endothelial cell tube formation during angiogenesis. Additionally, adverse effects associated with HIV infection and ART promote endothelial dysfunction predisposing PE development; however, higher prevalence and mortality rates among PE cases are still associated with ART use. Pregnancies complicated by the COVID-19 exploitation of angiotensin-converting enzyme 2 have a strong correlation with PE-like symptoms such as endothelial injury, implicating COVID-19 in PE onset. Inconsistent data on the potential effectiveness of ART in COVID-19 and their safety in pregnancy warrants further investigations.