MicroRNAs Regulated by Pregnancy Target Antiviral and Cancer Immunity Overlapping with the HIV Interactome

Authors

• Paula F. T. Cezar-de-Mello, Harvard Medical School
• Jonathan M. Dreyfuss, Harvard Medical School
• Pai-Lien Chen, FHI 360
• Hidemi Yamamoto, Harvard Medical School
• Xiaoming Gao, FHI 360
• Hui Pan, Harvard Medical School
• Charles Morrison, FHI 360
• Gustavo F. Doncel, Macon & Joan Brock Virginia Health SciencesFollow
• Robert L. Barbieri, Harvard Medical School
• Raina N. Fichorova, Harvard Medical School

ORCID

0009-0009-9641-1325 (Doncel)

Document Type

Article

Publication Date

2026

DOI

10.3390/v18070753

Publication Title

Viruses

Volume

18

Issue

7

Pages

753 (30 pp.)

Abstract

Innate immunity predictors of HIV-1 risk and pathogenesis vary with reproductive hormones, pregnancy, and lactation, yet the underlying mechanisms remain unclear. We hypothesized that pregnancy-associated physiological adaptations alter systemic microRNA (miRNA) expression, thereby regulating immunity, pathogenesis and susceptibility to infection. We analyzed 174 serum samples from 88 participants in a longitudinal cohort from Uganda and Zimbabwe across pre-pregnancy (PP), pregnancy (P), and postpartum breastfeeding (BF). Cell-free peripheral blood miRNAs (n = 2083) were profiled using HTG EdgeSeq. Pregnancy-specific miRNAs were identified by intersecting differentially expressed (DE) miRNAs from P vs. PP and P vs. BF comparisons. miRNA targets and pathways were analyzed using miRWalk, Cytoscape/ClueGO, and cytoHubba. Pregnancy was associated with DE miRNAs (29 upregulated and 131 downregulated) targeting 2733 validated genes. Enriched pathways (FDR < 0.05) included adaptive immune response, Hippo Signaling, Cellular Senescence, HSV-1 infection, and two cancer-related pathways. Pregnancy-enriched targets within each pathway overlapped with the HIV-host interactome by 37-88%. Network analysis identified 47 hub genes interacting with 18 HIV-1 proteins, with Tat and gp120 being most connected viral and HLA-A being the most connected host protein. These findings indicate that pregnancy-driven systemic miRNAs target the HIV-host interactome and specifically identify pregnancy-enriched central hub genes involved in cell cycle control, viral immune evasion and replication to be further investigated for their predictive value in HIV acquisition and pathogenesis in longitudinal cohorts and experimental settings.

Rights

© 2026 by the authors.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Data Availability

Article states: "All data are provided in the Supplemental Tables."

Original Publication Citation

Cezar-de-Mello, P. F. T., Dreyfuss, J. M., Chen, P. L., Yamamoto, H., Gao, X., Pan, H., Morrison, C., Doncel, G. F., Barbieri, R. L., & Fichorova, R. N. (2026). MicroRNAs regulated by pregnancy target antiviral and cancer immunity overlapping with the HIV interactome. Viruses, 18(7), Article 753. https://doi.org/10.3390/v18070753

Repository Citation

Cezar-de-Mello, P. F. T., Dreyfuss, J. M., Chen, P. L., Yamamoto, H., Gao, X., Pan, H., Morrison, C., Doncel, G. F., Barbieri, R. L., & Fichorova, R. N. (2026). MicroRNAs regulated by pregnancy target antiviral and cancer immunity overlapping with the HIV interactome. Viruses, 18(7), Article 753. https://doi.org/10.3390/v18070753