Viral mechanism for engaging lytic cycle promoting host transcription factors

The University of Florida's Division of Sponsored Research received a $402,150 Project Grant award dated July 23, 2025, from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855). The research award, with a completion date of June 30, 2027, supports investigator-initiated biomedical research focused on understanding the viral mechanisms by which Kaposi's Sarcoma-Associated Herpesvirus (KSHV) engages host transcription factors to promote its lytic cycle. This research addresses a critical public health gap in understanding how KSHV, an etiological agent of AIDS-related malignancies including B cell lymphomas and Kaposi's sarcoma, manipulates host cellular functions to enable viral reactivation and transmission.

The research deliverables include scientific investigations into how specific KSHV viral proteins interact with host forkhead-associated (FHA) domain proteins—a unique protein-protein interaction domain critical for cellular transcription, DNA repair, and cell cycle checkpoint regulation. Through mechanistic dissection of novel viral-FHA protein pairs, the research aims to elucidate how KSHV hijacks these host factors to promote lytic reactivation. The ultimate objective is to translate these mechanistic findings into potential antiviral therapeutic targets that could abrogate viral transmission and reduce the burden of KSHV-associated malignancies in immunocompromised populations.

Abstract

Kaposi's sarcoma-associated herpesvirus (kshv) is a human tumor virus that is the etiological agent of several aids-related malignancies such as b cell lymphomas and kaposi's sarcoma. Kshv establishes viral latency in most cell types following primary infection but can undergo lytic reactivation. The key viral factor, which drives the lytic cycle of kshv, is the replication and transcription activator called RTA. We and others have identified the genome-wide targets of RTA and we have also demonstrated the need for the rapid induction of specific host genes concomitantly with the viral genes for efficient lytic reactivation. Uncovering the protein interaction domains of host factors that viral proteins bind to and are crucial for lytic reactivation is important, because they can serve as potential targets for antiviral therapies to abrogate viral transmissions. Our study focuses on one such domain of host factors called the forkhead-associated (FHA) domain. This is a unique protein-protein interaction domain, which recognizes and binds to specific conserved short linear motifs in proteins. FHA proteins have diverse functions in the regulation of transcription, DNA repair, replication stress response and cell cycle checkpoints. Viral proteins often mimic host protein interaction motifs thereby hijacking host factors and alter cellular functions. Through our unbiased in silico protein sequence screening of kshv proteins, we identified several viral proteins possessing putative FHA interaction motifs. We hypothesize that these kshv viral factors can bind to FHA proteins to alter their cellular functions to promote lytic cycle. To test this concept, here we aim to dissect the mechanism of one of these novel viral-FHA protein pairs and determine its role in the regulation of kshv lytic cycle. We will also evaluate how this finding can be used for an antiviral therapy against kshv.