Neuropilin-1 in the pathogenesis of preeclampsia, HIV-1, and SARS-CoV-2 infection: A review.

This review explores the role of transmembrane neuropilin-1 (NRP-1) in pregnancy, preeclampsia (PE), human immunodeficiency virus type 1 (HIV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Since these conditions are assessed independently, this review attempts to predict their comorbid clinical manifestations. Dysregulation of NRP-1 contributes to the pathogenesis of PE by (a) impairing vascular endothelial growth factor (VEGF) signaling for adequate spiral artery remodeling and placentation, (b) inducing syncytiotrophoblast (ST) cell apoptosis and increasing ST-derived microparticle circulation and (c) by decreasing regulatory T cell activity predisposing maternal immune intolerance. Although NRP-1 is upregulated in SARS-CoV-2 placentae, its exploitation for SARS-CoV-2 internalization and increased infectivity may alter angiogenesis through the competitive inhibition of VEGF. The anti-inflammatory nature of NRP-1 may aid its upregulation in HIV-1 infection; however, the HIV-accessory protein, tat, reduces NRP-1 expression. Upregulated NRP-1 in macrophages and dendritic cells also demonstrated HIV-1 resistance/reduced infectivity. Notably, HIV-1-infected pregnant women receiving antiretroviral therapy (ART) to prevent vertical transmission may experience immune reconstitution, impaired decidualization, and elevated markers of endothelial injury. Since endothelial dysfunction and altered immune responses are central to PE, HIV-1 infection, ART usage and SARS-CoV-2 infection, it is plausible that an exacerbation of both features may prevail in the synergy of these events. Additionally, this review identifies microRNAs (miRNAs) mediating NRP-1 expression. MiR-320 and miR-141 are overexpressed in PE, while miR-206 and miR-124-3p showed increased expression in PE and HIV-1 infection. Additionally, miR-214 is overexpressed in PE, HIV-1 and SARS-CoV-2 infection, implicating treatment strategies to reduce these miRNAs to upregulate and normalize NRP-1 expression. However, inconsistencies in the data of the role and regulation of miRNAs in PE, HIV-1 and SARS-CoV-2 infections require clarification. This review provides a platform for early diagnosis and potential therapeutic intervention of PE, HIV-1, and SARS-CoV-2 infections independently and as comorbidities.

Maternal endothelial dysfunction in HIV-associated preeclampsia comorbid with COVID-19: a review.

This review assesses markers of endothelial dysfunction (ED) associated with the maternal syndrome of preeclampsia (PE). We evaluate the role of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected preeclamptic women. Furthermore, we briefly discuss the potential of lopinavir/ritonavir (LPV/r), dolutegravir (DTG) and remdesivir (RDV) in drug repurposing and their safety in pregnancy complicated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In HIV infection, the trans-activator of transcription protein, which has homology with vascular endothelial growth factor, impairs angiogenesis, leading to endothelial injury and possible PE development despite neutralization of their opposing immune states. Markers of ED show strong evidence supporting the adverse role of ART in PE development and mortality compared to treatment-naïve pregnancies. Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 infection, exploits angiotensin-converting enzyme 2 (ACE 2) to induce ED and hypertension, thereby mimicking angiotensin II-mediated PE in severe cases of infection. Upregulated ACE 2 in pregnancy is a possible risk factor for SARS-CoV-2 infection and subsequent PE development. The potential effectiveness of LPV/r against COVID-19 is inconclusive; however, defective decidualization, along with elevated markers of ED, was observed. Therefore, the safety of these drugs in HIV-positive pregnancies complicated by COVID-19 requires attention. Despite the observed endothelial protective properties of DTG, there is a lack of evidence of its effects on pregnancy and COVID-19 therapeutics. Understanding RDV-ART interactions and the inclusion of pregnant women in antiviral drug repurposing trials is essential. This review provides a platform for further research on PE in the HIV-COVID-19 syndemic.