Robust innate immune responses at the placenta during early gestation may limit in utero HIV transmission

• Type of Material: Article
• Authors: Erica Johnson, Emory University; Dominika Swieboda, Emory University; Amanda Olivier, Morehouse School of Medicine; Elizabeth Ann L Enninga, Mayo Clinic; Rana Chakraborty, Emory University
• Language: English
• Date: 2021-08-01
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Johnson et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1009860
• Title of Journal or Parent Work: PLOS PATHOGENS
• Volume: 17
• Issue: 8
• Start Page: e1009860
• End Page: e1009860
• Grant/Funding Information: This work was funded by NIH NICHD grant 5R01HD097843-03 (E. L. J. and R. C.).; This work was also supported by the Center for AIDS Research at Emory University (P30AI050409 [E. L. J.]). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: Parasitology; IMMUNODEFICIENCY-VIRUS TYPE-1; Life Sciences & Biomedicine; Virology; AMNIOTIC-FLUID; INTERFERON-STIMULATED GENES; Science & Technology; HOFBAUER CELLS; INFLAMMATORY RESPONSE; PREGNANT-WOMEN; MACROPHAGES; Microbiology; TO-CHILD TRANSMISSION; VIRAL-INFECTION; FETAL TRANSMISSION
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Immunology; Biology, Microbiology

Abstract

In 2019, >90% of new HIV infections in infants globally occurred vertically. Studies suggest intrauterine transmission most often occurs in the third trimester; however, there are no mechanistic studies to support these observations. We therefore obtained early/mid-gestation and term placentae from 20 HIV/Hepatitis B/CMV negative women. Isolated primary placental macrophages (Hofbauer cells [HCs]) were exposed to HIV-1BaL and/or interferon (IFN)-α, IFN-β, IFN-λ1, and RIG-I-like receptor (RLR) agonists. qRT-PCR, FACS, ELISA, Luminex, and Western blot analyses determined expression of activation markers, coreceptors, viral antigen, cytokines, antiviral genes, and host proteins. Early gestation HCs express higher levels of CCR5 and exhibit a more activated phenotype. Despite downregulation of CCR5, term HCs were more susceptible to HIV replication. Early gestation HCs displayed a more activated phenotype than term HCs and HIV exposure lead to the further upregulation of T-cell co-stimulatory and MHC molecules. Limited HIV replication in early/mid gestation HCs was associated with increased secretion of anti-inflammatory cytokines, chemokines, and a more robust antiviral immune response. In contrast, term HCs were more susceptible to HIV replication, associated with dampening of IFN-induced STAT1 and STAT2 protein activation. Treatment of early/mid gestation and term HCs, with type I IFNs or RLR agonists reduced HIV replication, underscoring the importance of IFN and RLR signaling in inducing an antiviral state. Viral recognition and antiviral immunity in early gestation HCs may prevent in utero HIV infection, whereas diminished antiviral responses at term can facilitate transmission. Defining mechanisms and specific timing of vertical transmission are critical for the development of specific vaccines and antiviral therapeutics to prevent new HIV infections in children globally.