# CMV responses in autoantibody positive subjects advocate antiviral treatments for prevention of T1D

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $728,669

## Abstract

Project Abstract
While environmental entities instigate T1D development, their identity is unknown. Genetics greatly increases
risk, but the discordance between identical twins proves an equally critical role for exogenous factors. To identify
causal entities, sampling must occur before clinical disease develops. Although labor intensive and costly,
prospective longitudinal testing is the only way to illuminate the mysterious events that precede disease. Results
from our recent collaboration with the TrialNet Pathway to Prevention study point to a role for CMV
infection in T1D development. We found a striking expansion of terminally-differentiated short lived effector
CD8 T cells (SLEC) in seroconverted (AA+) at-risk subjects. The frequencies of SLEC are highest in
seroconverted subjects that progress to disease. This SLEC subset is identical to the well-characterized
CD8 response to CMV. Importantly, we found the SLEC expansion is strongly associated with CMV
seropositivity. Our findings demonstrate that an expanded, exhausted antiviral response occurs one
year before autoimmune T1D develops. We also determined that SLEC levels correlate strongly with IA-2
autoantibodies, demonstrating a connection between CMV and autoimmunity. T1D results from autoreactive
CD8 T cell-mediated attack on pancreatic islets. These autoreactive T cells may arise as a byproduct of the anti-
viral response. Our overarching hypothesis is that CMV is an important environmental factor accelerating T1D
development in children with genetic risk. The objective of this application is to longitudinally probe the
preclinical disease process and unravel the mechanisms connecting CMV and T1D. In Aim 1 we propose
to derive kinetic measurements through a longitudinal study. We hypothesize that genetically susceptible
pre-T1D children show increased levels of exhausted CD8 T cells prior to the development of
autoantibodies and/or clinical autoimmunity. In aim 2 we will measure CMV replication and persistence in at
risk subjects that develop autoimmunity. We hypothesize that the accumulation of exhausted CD8 T cells
causes viral persistence. In aim 3 we will test mechanisms whereby the virus activates islet specific CD8 T
cells. We hypothesize that CMV infection induces the expansion of islet antigen-specific CD8 T cells. An
established connection between CMV replication and T1D will point to antiviral therapies as efficacious in
subjects with high genetic risk. Furthermore, levels of CMV replication and SLEC represent interlocking
biomarkers for stratifying subjects for antiviral and/or vaccine trials. Several CMV vaccines are currently being
tested in the clinic. Our results will also facilitate the understanding of other CMV-related human diseases.

## Key facts

- **NIH application ID:** 10468752
- **Project number:** 5R01AI150274-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Nora E Sarvetnick
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $728,669
- **Award type:** 5
- **Project period:** 2019-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468752

## Citation

> US National Institutes of Health, RePORTER application 10468752, CMV responses in autoantibody positive subjects advocate antiviral treatments for prevention of T1D (5R01AI150274-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10468752. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*