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NIH grant 1R21AI203618-01: INVESTIGATING THE IMPACT OF MENOPAUSE AND MENOPAUSE HORMONE THERAPY ON IMMUNE DETERMINANTS OF HIV-1 SUSCEPTIBILTY IN CERVICAL MUCOSA
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: CHRISTINA OCHSENBAUER. Award: $223500.
Start: 2026-07-22T00:00:00.
PROJECT SUMMARY / ABSTRACT
Aging women represent a growing demographic with increasing HIV-1 infection prevalence and
incidence. Estrogen decline, the hallmark of menopause, leads to immunosenescence and
“inflammaging”, which is associated with increased vulnerability to infections. Estrogen
replacement via menopausal hormone therapy (MHT) partially restores blood immune cell
homeostasis but is understudied for its impact on age-related immune decline in cervicovaginal
mucosa, a primary site of sexually transmitted infections (STIs) including HIV-1. It is of
SIGNIFICANCE to discover how menopause and MHT reshape mucosal immune competence and
impact STI susceptibility to better inform patient and healthcare provider decision making, and
HIV-1 prevention efforts in aging women. We will test the HYPOTHESIS that the cervical mucosal
immune environment is altered by menopause in ways that are relevant to HIV-1 susceptibility,
and that MHT modulates innate and adaptive immunological determinants. Our research strategy
integrates (a) our highly sensitive ex vivo cervical explant tissue (CET) model to study infection
with transmitted/founder HIV-1 strains with (b) high-parameter spectral flow cytometry, and (c)
single cell RNA sequencing (scRNA-Seq) to assess the hormone-regulated immunobiology of
cervical tissue obtained from pre-, peri- and menopausal women -/+ MHT who undergo medically
indicated hysterectomies at UAB clinics. In AIM 1, 34-color flow cytometric analyses, conducted
in FlowJo (traditional gating) and as unbiased clustering using FlowSOM and tSNE/UMAP in R,
will show how aging and hormonal decline reshape the phenotypes of cervical T-cells and
macrophages. We will also discover immune states that are either enhanced or diminished with
MHT. Findings from AIM 2 on ex vivo HIV-1 infection in cervical tissue from women across the
lifespan will be integrated with immune phenotyping data to identify cellular determinants of HIV-1
susceptibility associated with menopause and MHT use. These analyses will reveal whether
estrogen loss enhances, and MHT mitigates cervical tissue vulnerability to HIV-1 infection ex vivo.
AIM 3 will generate the first menopause/MHT focused single-cell transcriptome atlas of cervical
mucosal immunobiology and test for correlates of scRNA-seq data with phenotypic and ex vivo
HIV-1 infection/replication data from Aims 1 and 2. Hypothesis-generating scRNA-seq data will
underpin future mechanistic studies on candidate biomarkers and hormone-regulated pathways.
STUDY IMPACT: Novel insights into how aging-related estrogen loss and MHT impact cervical
immune function and vulnerability to HIV-1 will guide future work towards the ultimate goal of
informing aging women’s clinical health decision-making, and STI/HIV prevention efforts.document fetched 2026-08-02 08:24