miRNA profiling of primate cervicovaginal lavage and extracellular vesicles reveals miR‐186‐5p as a potential antiretroviral factor in macrophages

Abstract

Cervicovaginal secretions, or their components collected, are referred to as cervicovaginal lavage (CVL). CVL constituents have utility as biomarkers and play protective roles in wound healing and against HIV-1 infection. However, several components of cervicovaginal fluids are less well understood, such as extracellular RNAs and their carriers, for example, extracellular vesicles (EVs). EVs comprise a wide array of double-leaflet membrane extracellular particles and range in diameter from 30 nm to over one micron. The aim of this study was to determine whether differentially regulated CVL microRNAs (miRNAs) might influence retrovirus replication. To this end, we characterized EVs and miRNAs of primate CVL during the menstrual cycle and simian immunodeficiency virus (SIV) infection of macaques. EVs were enriched by stepped ultracentrifugation, and miRNA profiles were assessed with a medium-throughput stem-loop/hydrolysis probe qPCR platform. Whereas hormone cycling was abnormal in infected subjects, EV concentration correlated with progesterone concentration in uninfected subjects. miRNAs were present predominantly in the EVdepleted CVL supernatant. Only a small number of CVL miRNAs changed during the menstrual cycle or SIV infection, for example, miR-186-5p, which was depleted in retroviral infection. This miRNA inhibited HIV replication in infected macrophages in vitro. In silico target prediction and pathway enrichment analyses shed light on the probable functions of miR-186-5p in hindering HIV infections via immunoregulation, T-cell regulation, disruption of viral pathways, etc. These results provide further evidence for the potential of EVs and small RNAs as biomarkers or effectors of disease processes in the reproductive tract. The cervicovaginal canal is a potential source of biological markers for forensics investigations [1-4], reproductive tract cancers [5-7], and infections [8-10].

Longitudinal characterization of circulating extracellular vesicles and small RNA during simian immunodeficiency virus infection and antiretroviral therapy

“…Where do our miRNA findings fit into the existing literature? We previously reported that total plasma miRNA profiles change during acute SIV infection 18 and that EV-borne miRNA miR-186-5p is downregulated in cervicovaginal lavage (CVL) and regulates HIV replication in macrophages 55 . Here, we identified several miRNAs that were dysregulated during latent and rebound infections, but only very few compared with the acute infection phase, consistent with a study comparing productive and latent infection in CD4+ T cell models 16 .…”

Expression of plasma IFN signaling-related miRNAs during acute SARS-CoV-2 infection and its association with RBD-IgG antibody response

“…reported that overexpressed miR-186 could inhibit the JAK/STAT signaling pathway in vitro [ 18 ]. In addition, the increased miR-186-5p expression could inhibit HIV infection by immunoregulation and T cell regulation [ 19 ]. The results from the most recent study also reported that miR-15b-5p were significantly downregulated in hamster lung samples infected by SARS-CoV-2 [ 20 ].…”

Expression Profiles of Plasma IFN Signaling-Related miRNAs (ISR-miRNAs) at the Acute and Recovery Phase of COVID-19

“…Following in silico target prediction and pathway enrichment analyses, Zhao et al suggested that miR-186-5p was depleted in retroviral infection. However, the increased miR-186-5p expression could inhibit HIV infection by immunoregulation and T cell regulation [19]. Moreover, Wu et al reported that overexpressed miR-186 could inhibit the JAK/STAT signaling pathway in vitro [20].…”