# Therapeutic targets in gammaherpesvirus infection

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $10,003

## Abstract

PROJECT SUMMARY
The human gammaherpesviruses (gHVs) Kaposi's sarcoma associated herpesvirus and Epstein-Barr virus are
DNA tumor viruses that establish a lifelong infection. These viruses are strongly associated with pathogenic
outcomes in immune suppression, including the AIDS defining malignancies Kaposi's sarcoma and non-
Hodgkin lymphoma. A major challenge of the gHVs is that these viruses present a lifelong risk for viral
reemergence and pathogenesis, especially in the context of acquired or medically-induced
immunosuppression. Lifelong infection is further confounded by the limited therapeutic interventions against
gHV diseases. To date, the best defense against gHV-induced disease is an intact immune system. Despite
this correlation, there remain major knowledge gaps in our understanding of: 1) protective aspects of
successful vaccination to gHV infection, and 2) consequence of vaccination on the composition and frequency
of infected cells, either before or after established infection. In this R01 application, we seek to investigate how
vaccination alters gHV infection, using murine gammaherpesvirus 68 (gHV68), a mouse model of gHV
infection, that facilitates study of infection and associated responses from primary infection through lifelong
latency and re-emergence of lytic infection. We recently undertook studies to characterize how latency is
regulated by viral and host factors at the single-cell level, identifying that the latent pool is heterogeneous
based on expression of the latency associated nuclear antigen (LANA), and that the proportion of LANA+
latently-infected cells is subject to regulation. These studies further identified that CD8 T cells, and the cytokine
interferon-gamma, limit LANA+ latently-infected B cells, and that vaccination with a live-attenuated vaccine is
capable of profoundly restricting LANA+ latent B cell infection in an interferon-gamma-independent manner.
We now seek to investigate the role of myeloid cells in infection and vaccination on gHV infection both in vitro
and in vivo. We will make use of vaccination protocols with defined differences in efficacy to identify the critical
features using single cell analysis and high dimensional methods to distinguish the features of vaccine efficacy.
We hypothesize that vaccination with a live-attenuated vaccine induces: 1) local and systemic myeloid
reprogramming, which 2) redirects gHV myeloid infection into an immune-susceptible myeloid target.
We will test this in three aims. First, we will analyze the impact of vaccination on local and systemic myeloid
cells. Second, define how vaccination affects primary gHV infection of myeloid cells. Third, dissect how viral
tropism is influenced by vaccine-induced effector mechanisms. By analyzing specific viral and host processes
in the context of vaccines with varying efficacy, this proposal seeks to investigate myeloid reprogramming as a
necessary, and therapeutically viable, target for vaccination against gHV latency.

## Key facts

- **NIH application ID:** 10938863
- **Project number:** 3R01AI157201-03S1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** ERIC T CLAMBEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $10,003
- **Award type:** 3
- **Project period:** 2023-10-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938863

## Citation

> US National Institutes of Health, RePORTER application 10938863, Therapeutic targets in gammaherpesvirus infection (3R01AI157201-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10938863. Licensed CC0.

---

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