NET-EN treatment leads to delayed HSV-2 infection, enhanced mucin and T cell functions in the female genital tract when compared to DMPA in a preclinical mouse model

M Firoz Mian; Sidney Pa; Nuzhat Rahman; Amy Gillgrass; Charu Kaushic

doi:10.3389/fimmu.2024.1427842

NET-EN treatment leads to delayed HSV-2 infection, enhanced mucin and T cell functions in the female genital tract when compared to DMPA in a preclinical mouse model

Front Immunol. 2024 Nov 6:15:1427842. doi: 10.3389/fimmu.2024.1427842. eCollection 2024.

Authors

M Firoz Mian^{1

2}, Sidney Pa^{1

2}, Nuzhat Rahman^{1

2}, Amy Gillgrass^{1

2}, Charu Kaushic^{1

2}

Affiliations

¹ McMaster Immunology Research Centre, Department of Medicine, McMaster University, Hamilton, ON, Canada.
² Department of Medicine, McMaster University, Hamilton, ON, Canada.

Abstract

Depot-medroxyprogesterone acetate (DMPA) and Norethisterone Enanthate (NET-EN) are progestin-only injectable contraceptives widely used by women in sub-Sharan Africa, where incidence of HIV-1 and HSV-2 infection remains high. Studies indicate that DMPA usage can increase the risk of HSV-2 infection, but limited data indicate no increased risk with use of NET-EN. We therefore investigated the effects of NET-EN and DMPA on susceptibility to vaginal HSV-2 infection in ovariectomized (OVX) mice and effects on immune responses, particularly in the vaginal tract (VT). OVX mice, when treated with NET-EN and infected intravaginally, had delayed genital pathology, decreased viral shedding, and extended survival compared to DMPA- or untreated OVX mice. CD4+ T cells isolated from VT showed no significant change in frequency with either contraceptive. However, DMPA significantly decreased the total number of VT CD4+ and CD8+ T cells and the number of IFN-γ producing CD4 and CD8 T cells and increased the percentage of CD4 and CD8 T cells producing TNF-α compared to untreated mice. In contrast, NET-EN significantly enhanced percentages of CD8+ T cells compared to DMPA treated mice, and frequencies of IFN-γ+ CD4 and CD8 T cells in the VT compared to untreated mice. Comparative analysis of splenic lymphocytes indicated that DMPA treatment resulted in reduction of CD4+ T cell frequency, but enhanced TNF-α+ CD4 T cells compared to untreated mice. NET-EN enhanced the frequency of CD8 T cells, as well as IFN-γ+ and TNF-α+ CD4, and IFN-γ+ CD8 T cells in the spleen compared to untreated mice. Importantly, we found DMPA treatment that significantly reduced mucin production, whereas NET-EN enhanced expression of cell-associated mucin in VT. High levels of mucin in NET-EN mice were associated with lower levels of HSV-2 virus detected in the vaginal tract. This study provides the first evidence that NET-EN treatment can delay HSV-2 infection compared to DMPA.

Keywords: DMPA; IFN-γ; NET-EN; TNF-α; herpes simplex virus type 2; mucin; vaginal tract.

Publication types

Comparative Study

MeSH terms

Animals
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
Contraceptive Agents, Female / administration & dosage
Contraceptive Agents, Female / pharmacology
Disease Models, Animal*
Female
Genitalia, Female / drug effects
Genitalia, Female / immunology
Genitalia, Female / virology
Herpes Genitalis* / immunology
Herpesvirus 2, Human* / immunology
Medroxyprogesterone Acetate* / pharmacology
Mice
Norethindrone* / analogs & derivatives
Norethindrone* / pharmacology
Ovariectomy
Vagina / drug effects
Vagina / immunology
Vagina / virology

Substances

Medroxyprogesterone Acetate
Norethindrone
norethindrone enanthate
Contraceptive Agents, Female

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by grants from the Canadian Institutes of Health Research (CIHR Operating Grant FRN#126019 (CK); NR received funding support from the Ontario Graduate Scholarship (OGS).