# Determining how Kaposi’s sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $352,662

## Abstract

Project summary. During lytic infection, the AIDS-associated tumor virus Kaposi’s sarcoma-associated
herpesvirus (KSHV) blocks cells from activating the anti-viral type I interferon (IFN) responses. This block of
the innate immune response facilitates efficient viral replication, which in turn contributes to development of
Kaposi’s sarcoma. Thus, elucidating the mechanisms by which KSHV evades the host innate immune
response may provide insights on how to target this and other KSHV-induced tumors. However, because of
the complex and redundant nature of the type I IFN induction pathway, how KSHV blocks this early antiviral
response is still incompletely understood. In a previous study, we found that the host protease caspase-8 is a
major mediator of type I IFN inhibition by KSHV. KSHV reactivation from latency only triggers minimal type I
IFN induction, but there is a much stronger transcriptional induction and secretion of type I IFNs when
caspase-8 is also inhibited. This stronger IFN induction, in turn, reduces KSHV reactivation. These results
indicate that caspase-8 activity is necessary to inhibit IFN induction, and thus promotes KSHV replication.
This finding was surprising because caspase-8 activation is generally considered antiviral as it induces
apoptotic cell death. However, we do not detect wide-spread cell death during reactivation from latency
despite caspase-8 activation, suggesting that caspase-8 is hijacked and repurposed by KSHV to inhibit type I
IFN responses. At present, the molecular mechanisms that lead to caspase-8 activity and the pathways that
are targeted by caspase-8 to control type I IFN during KSHV infection remain unclear. We have new
preliminary data suggesting that caspase-8 is activated by a pathogen sensing pathway, the Toll-like receptor
(TLR) pathway, as a cellular response to infection. Caspase-8 then proceeds to inhibit a different pathogen
sensing pathway, cGAS-mediated DNA sensing. Therefore, we hypothesize that KSHV is taking advantage
of a TLR-mediated cellular response to infection that activates caspase-8. KSHV is then able to redirect this
activity to inhibit DNA sensing instead of activating apoptosis. We will test this hypothesis and determine how
caspase-8 is activated by TLR signaling in KSHV-infected cells without triggering cell death (Aim 1), and
which host protein(s) are cleaved by caspase-8 to block cGAS-induced type I IFN responses (Aim 2).
Moreover, we will also investigate whether and how caspase activity is connected to other previously
described mechanisms of immune evasion by KSHV (Aim 3). As caspase-8 is a druggable target,
understanding how caspase-8 is used by KSHV to regulate type I IFNs and promote its replication will reveal
whether and how this enzyme could be exploited for KSHV therapy. This is important as there are no target
therapies for this virus, and Kaposi’s sarcoma remains one of the leading types of cancers in sub-Saharan
Africa and the second most common AIDS-associated ...

## Key facts

- **NIH application ID:** 10751037
- **Project number:** 5R01CA268976-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Marta Maria Gaglia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $352,662
- **Award type:** 5
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10751037

## Citation

> US National Institutes of Health, RePORTER application 10751037, Determining how Kaposi’s sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses (5R01CA268976-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10751037. Licensed CC0.

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