Viruses

Research

30 pages, 23332 KB

Open AccessArticle

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

by Paula F. T. Cezar-de-Mello, Jonathan M. Dreyfuss, Pai-Lien Chen, Hidemi Yamamoto, Xiaoming Gao, Hui Pan, Charles Morrison, Gustavo F. Doncel, Robert L. Barbieri and Raina N. Fichorova

Viruses 2026, 18(7), 753; https://doi.org/10.3390/v18070753 - 7 Jul 2026

Viewed by 799

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Viruses in the Reproductive Tract)

► Show Figures

Figure 1

22 pages, 6967 KB

Open AccessEditor’s ChoiceArticle

Type I Interferon Regulation of HLA-F Expression in Human Trophoblasts During Viral Infection

by Diana Manchorova, Jiahui Ding, Annie Thy Nguyen, Tanya Dimova, Sergey Slavov, Liubomir Djerov, Ruqun Zheng and Gil Mor

Viruses 2026, 18(6), 603; https://doi.org/10.3390/v18060603 - 26 May 2026

Viewed by 933

Abstract

The role of human leukocyte antigen F (HLA-F) at the maternal–fetal interface (MFI) during viral infection and its regulation by interferon signaling remains poorly understood. Here, we investigated HLA-F expression and regulation in first-trimester trophoblast cells following activation of the type I interferon [...] Read more.

The role of human leukocyte antigen F (HLA-F) at the maternal–fetal interface (MFI) during viral infection and its regulation by interferon signaling remains poorly understood. Here, we investigated HLA-F expression and regulation in first-trimester trophoblast cells following activation of the type I interferon pathway and viral infection. We demonstrate that HLA-F is significantly upregulated at both mRNA and protein levels in response to Poly(I:C) and IFN-β in a dose- and time-dependent manner, suggesting its regulation as an interferon-stimulated gene (ISG). Zika virus (ZIKV) infection similarly induced HLA-F upregulation over time. In contrast, HSV-2 infection downregulated HLA-F mRNA while maintaining steady protein levels, indicative of virus-specific regulatory mechanisms. Moreover, we identified a soluble form of HLA-F secreted following Poly(I:C) stimulation. These findings reveal that HLA-F is dynamically regulated in trophoblasts during viral challenge and type I IFN signaling activation, supporting its broader immunomodulatory role in antiviral defense and immune tolerance at the MFI. Full article

(This article belongs to the Special Issue Viruses in the Reproductive Tract)

► Show Figures

Figure 1

15 pages, 3194 KB

Open AccessArticle

Sphingosine-1-Phosphate Receptor and Kinase Expression in the Reproductive Tract Is Associated with HIV Infection and Preterm Birth in a Cohort of Pregnant Women in Zambia

by Rachel S. Resop, Innocent Mwape, Yuri V. Sebastião, Katelyn J. Rittenhouse, Ntazana Sindano, Humphrey Mwape, Margaret P. Kasaro, Bellington Vwalika, Joan T. Price, Jeffrey S. A. Stringer and Kristina De Paris

Viruses 2026, 18(5), 559; https://doi.org/10.3390/v18050559 - 14 May 2026

Viewed by 823

Abstract

Women living with HIV face an increased burden of spontaneous preterm birth (sPTB); however, the underlying immunological mechanisms of sPTB and its association with HIV infection are poorly understood. Although the limited earlier literature implicates sphingosine-1-phosphate (S1P), a lysosphingolipid signaling molecule, in reproductive [...] Read more.

Women living with HIV face an increased burden of spontaneous preterm birth (sPTB); however, the underlying immunological mechanisms of sPTB and its association with HIV infection are poorly understood. Although the limited earlier literature implicates sphingosine-1-phosphate (S1P), a lysosphingolipid signaling molecule, in reproductive biology, the association of S1P signaling with HIV and sPTB has not been investigated. We examined whether two S1P signaling components, S1P receptors and sphingosine kinases, are expressed in the female reproductive tract and whether levels are associated with HIV status or spontaneous preterm birth. We quantified the mRNA expression of sphingosine-1-phosphate receptors 1 and 3 (S1PR1/S1PR3) and sphingosine kinases 1 and 2 (SPHK1/SPHK2) in 167 banked vaginal swab specimens collected between 14 and 26 weeks of gestation in a longitudinal pregnancy cohort in Lusaka, Zambia. We evaluated the expression of S1PR1, S1PR3, SPHK1, and SPHK2 by real-time quantitative reverse transcription PCR (RT-qPCR) in four groups (n = 41–42 each): women without HIV (WWoH) with term birth (≥37 weeks of gestation; TB), WWoH with spontaneous preterm birth (<37 weeks of gestation, sPTB), women with HIV (WWH) with TB, and WWH with sPTB. We found that S1P receptors and sphingosine kinases are expressed in the female reproductive tract. SPHK1 and SPHK2 mRNA expression were generally comparable among women independent of HIV status or birth outcome, though SPHK2 trended toward higher expression in women with HIV and women with sPTB. In contrast, S1PR1 mRNA trended toward higher expression in WWH vs. WWoH overall, as well as in WWH vs. WWoH among women with sPTB. Similarly, S1PR3 mRNA expression was greater in women with HIV than in women without HIV, and WWH, both with TB and sPTB, had higher S1PR3 mRNA expression than WWoH with TB. Perturbations in S1PR1 and S1PR3 mRNA expression may be associated with inflammation related to HIV infection and spontaneous preterm birth, suggesting that further studies of S1P signaling in pregnancy, especially among women with HIV, are warranted. Full article

(This article belongs to the Special Issue Viruses in the Reproductive Tract)

► Show Figures

Figure 1

18 pages, 6709 KB

Open AccessArticle

Genomic Diversity of Vaginal Lactobacillus crispatus Prophages from South African Women

by Adijat Ozohu Jimoh, Anika Chicken, Brandon Maust, Colin Feng, Seth Rakoff-Nahoum, Jo-Ann S. Passmore, Brian R. Kullin, Simona Kraberger, Fatima Aysha Hussain, Heather B. Jaspan, Arvind Varsani and Anna-Ursula Happel

Viruses 2026, 18(5), 519; https://doi.org/10.3390/v18050519 - 30 Apr 2026

Viewed by 1330

Abstract

Lactobacillus crispatus is widely associated with optimal sexual and reproductive health outcomes. While L. crispatus genomes commonly harbor prophages, little is known about their genomic diversity and potential inducibility by clinically relevant compounds. We induced and characterized four bacteriophages from four L. crispatus [...] Read more.

Lactobacillus crispatus is widely associated with optimal sexual and reproductive health outcomes. While L. crispatus genomes commonly harbor prophages, little is known about their genomic diversity and potential inducibility by clinically relevant compounds. We induced and characterized four bacteriophages from four L. crispatus strains isolated from vaginal secretions of South African adolescents. Sequenced viral DNA from induced phages was assembled, and their respective genomes were annotated and compared to bacteriophage reference genomes. All the phage genomes range in size from 42.9 to 48.3 kbp. Of the four phages, UC101 and UC164 shared <90% pairwise intergenomic similarity to reference phages, suggesting that they represent new species. To explore factors potentially associated with prophage activation, L. crispatus strains were exposed to physiological concentrations of copper ions and tenofovir, selected based on their common use by women in Africa and reported associations with altered vaginal bacterial community composition. The presence of phage-like particles following exposure to copper ions (2.0 × 10⁻⁶ M–3.0 × 10⁻⁶ M) and tenofovir (500 ng/mL) was observed by transmission electron microscopy, suggesting possible prophage activation under these conditions. This study provides new insights into the genomic diversity of inducible L. crispatus phages and presents hypothesis-generating evidence regarding their potential inducibility using copper ions and tenofovir. Full article

(This article belongs to the Special Issue Viruses in the Reproductive Tract)

► Show Figures

Figure 1

18 pages, 288 KB

Open AccessArticle

Mental Health, Mucosal Immunity, and HIV Susceptibility Following Sexual Violence: Evidence from the THRIVE Study

by Katherine M. Anderson, Eleanor Capozzi, Stephanie A. Meyers-Pantele, Maile Y. Karris, Fernando Cabezas Mejia, Ella Meyer, Melodie A. Nasr, Mimi Ghosh and Jamila K. Stockman

Viruses 2026, 18(1), 119; https://doi.org/10.3390/v18010119 - 15 Jan 2026

Cited by 1 | Viewed by 1069

Abstract

Sexual violence against women is a global issue with profound health consequences, including elevated HIV risk due to genital tract inflammation and injury. However, limited research has examined the influence of mental health on HIV-related immunity after violence. We analyzed longitudinal data from [...] Read more.

Sexual violence against women is a global issue with profound health consequences, including elevated HIV risk due to genital tract inflammation and injury. However, limited research has examined the influence of mental health on HIV-related immunity after violence. We analyzed longitudinal data from female survivors of past-month rape (N = 25) to explore associations between mental health (perceived stress, depression, post-traumatic stress disorder [PTSD], and resilience) and HIV-associated immune biomarkers in the female genital tract. In bivariate analyses, mental health improved over the three-month follow-up period. Immune biomarker levels remained largely stable, except for TNF-α and SLPI. At baseline, depression was significantly correlated with TNF-α, IL-6, and IL-1β. In regression analyses, depression was associated with TNF-α (β = −0.133 to −0.152) and IL-6 (β = −0.171 to −0.207). PTSD was significantly associated with IL-1α (β = 0.576 to 1.681). Depression and resilience were negatively associated with percent HIV inhibition in adjusted models. These findings suggest that depression and PTSD are associated with genital tract inflammation following sexual violence, which may compromise mucosal immunity and enhance HIV risk. This highlights the importance of integrated mental health and immunological care for survivors and the need for further research into psychoneuroimmune pathways influencing HIV risk after trauma. Full article

(This article belongs to the Special Issue Viruses in the Reproductive Tract)

Review

Jump to: Research, Other

18 pages, 2872 KB

Open AccessReview

Mucosal Dynamics Contributing to Innate Immune Responses to HIV in the Human Female Genital Tract

by Genna E. Moldovan, Gabriel P. Faber and Marta Rodriguez-Garcia

Viruses 2026, 18(5), 542; https://doi.org/10.3390/v18050542 - 8 May 2026

Viewed by 1342

Abstract

HIV is primarily acquired in women at the female genital mucosa through heterosexual contact. Mucosal immune cells reside adjacent to, within, below, and distant from the epithelium that lines the surface of the female genital tract (FGT) mucosa. Innate immune cells play dual [...] Read more.

HIV is primarily acquired in women at the female genital mucosa through heterosexual contact. Mucosal immune cells reside adjacent to, within, below, and distant from the epithelium that lines the surface of the female genital tract (FGT) mucosa. Innate immune cells play dual roles in HIV acquisition, both poised to rapidly recognize and respond to HIV, but are also capable of promoting HIV infection locally and distantly in the lymph nodes. In this review we emphasize recent human research on the roles of specific innate immune cells in HIV pathogenesis in the FGT, including dendritic cells, macrophages, neutrophils and innate lymphoid cells. We review how FGT mucosal dynamics, including anatomical compartmentalization, menstrual cycle regulation, reproductive history, menopause and chronological aging contribute to tissue conditioning of these cells and changes in HIV susceptibility in women throughout their lives. Full article

(This article belongs to the Special Issue Viruses in the Reproductive Tract)

► Show Figures

Figure 1

24 pages, 10101 KB

Open AccessReview

Unraveling the Rectal Virome: Microbial Crosstalk, Immune Modulation, and Clinical Outcomes in People with and Vulnerable to HIV

by Ruth S. Bako and Colleen F. Kelley

Viruses 2026, 18(5), 511; https://doi.org/10.3390/v18050511 - 29 Apr 2026

Viewed by 1468

Abstract

The rectal mucosa houses a large number of viruses with important roles in shaping the local microbial communities and modulating immune responses, which could influence host susceptibility to infection and other diseases. Unique composition of the gut microbiome, including the predominance of clinically [...] Read more.

The rectal mucosa houses a large number of viruses with important roles in shaping the local microbial communities and modulating immune responses, which could influence host susceptibility to infection and other diseases. Unique composition of the gut microbiome, including the predominance of clinically significant eukaryotic viruses like herpesviruses, cytomegalovirus, and human papillomavirus, has been described in both people with HIV (PWH) and men who have sex with men (MSM) vulnerable to HIV. Despite these insights, the rectal virome and the clinical implications of virome–bacteriome–immune interactions in the rectal mucosa remain poorly understood. In this review, we synthesize existing data on the composition of the rectal virome, its interactions with the bacteriome and the immune system, and implications on clinical outcomes in people living with or vulnerable to HIV. We also highlight the gaps and research needed to further explore and unravel these relationships. Full article

(This article belongs to the Special Issue Viruses in the Reproductive Tract)

► Show Figures

Graphical abstract

Other

Jump to: Research, Review

10 pages, 979 KB

Open AccessBrief Report

Cervical Secretions from Women After Depot Medroxyprogesterone Acetate (Depo-Provera) Administration Promote HIV Infectivity Ex Vivo

by Carley Tasker, Natalie E. Roche, Yungtai Lo and Theresa L. Chang

Viruses 2025, 17(9), 1283; https://doi.org/10.3390/v17091283 - 22 Sep 2025

Viewed by 1957

Abstract

Depot medroxyprogesterone acetate (Depo-Provera) has been associated with an increased risk of HIV acquisition. We have previously shown that Depo-Provera administration increases immune markers for HIV preference on peripheral and cervical CD4⁺ T cells but decreases the levels of most immune mediators [...] Read more.

Depot medroxyprogesterone acetate (Depo-Provera) has been associated with an increased risk of HIV acquisition. We have previously shown that Depo-Provera administration increases immune markers for HIV preference on peripheral and cervical CD4⁺ T cells but decreases the levels of most immune mediators at vaginal and cervical mucosa. In this study, we determined the effect of cervicovaginal secretions from women before (visit 1), one month (visit 2) and three months (visit 3) after Depo-Provera treatment on HIV infectivity ex vivo. The effect of supernatants from vaginal, endocervical, and rectal swabs and from cervical cytobrush on HIV infectivity were assessed by a single-cycle infection assay using CCR5-using HIV-luciferase reporter viruses. We found that endocervical secretions from women after Depo-Provera treatment promoted HIV infectivity. When analyzing the association between endocervical mediator changes in response to Depo-Provera, available in our previous study, and the changes in HIV infectivity pre- and post-treatment, we found that changes in IL-17 and VEGF were positively associated with changes in HIV infectivity at visit 2 compared with visit 1, whereas changes in RANTES and IL-4 were negatively associated with HIV infectivity. The negative association between RANTES and HIV infectivity was also observed at visit 3 compared with visit 1. Additionally, changes in IL-1α at visit 3 were positively associated with changes in HIV infectivity compared with visit 1. These findings suggest that Depo-Provera may increase the HIV risk by shifting the mucosal milieu that promotes HIV infectivity. Full article

(This article belongs to the Special Issue Viruses in the Reproductive Tract)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Viruses in the Reproductive Tract

Share This Special Issue

Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (8 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI