Document text
Principal Investigator: Bernadett Papp
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $354,944
Funding agency: National Institute of Dental and Craniofacial Research
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is large DNA virus, which is the etiological agent of several
AIDS-related malignancies such as Kaposi’s sarcoma, primary effusion lymphoma, and aggressive forms of
multicentric Castleman’s disease. Lytic replication of KSHV is critical for both KSHV-induced tumorigenesis and
dissemination of the virus. Recent studies have shown that following replication in the oral epithelial cells, KSHV
can be transmitted into endothelial and B cells where the virus establishes latency resulting persistent infection
of the host. Infected oral epithelial cells also serve as the source of new viral particles shedding into the saliva,
which mediates the viral transmission in the population. Despite the medical and biological importance of oral
KSHV infection, it is still largely unknown what viral and host factors play a role in the regulation of lytic KSHV
infection of oral epithelial cells. KSHV is unique among human viruses that it encodes four viral interferon
regulatory factors that are homologous to cellular IRFs. These viral proteins have been shown to regulate many
different immune-related pathways and can enhance cell growth and cell survival. While many of these vIRF
functions are linked to the cytoplasmic functions of vIRFs, the nuclear role of vIRFs in gene regulation, especially
in oral epithelial cells, that may promote lytic KSHV infection is still poorly understood. To reveal the role of vIRFs
in viral and cellular gene regulation, we have identified the host target genes of each vIRF in primary human
gingival epithelial cells and revealed a highly specialized function for each vIRF. In addition, we performed a
protein complex purification of vIRF1 from KSHV-infected cells and discovered that vIRF1 can interact with
several host epigenetic factors involved in DNA binding, histone acetylation or histone methylation. Based on
our preliminary data, the goal of this proposal is (Aim 1) to identify the direct target genes of vIRFs and test their
role in lytic KSHV infection, and (Aim 2) to investigate the gene regulatory mechanisms mediated by vIRF1 and
its associated host epigenetic factors, which can be critical for facilitating lytic replication of KSHV. Since many
of the vIRF1-regulated host genes encode factors that are known to be de-regulated in other viral infections as
well, we envision that the investigation of epigenetic mechanisms and host gene targets of vIRF1 during KSHV
infection can provide novel targets for future development of new antiviral therapies.
Terms: <AIDS associated cancer><AIDS related cancer><AIDS-Related Malignancy><AIDS-Related Malignant Neoplasm><AIDS-associated malignancies><Acetylation><Anti-viral Therapy><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Biological><Buccal Cavity><Buccal Cavity Head and Neck><Buccal Mucosa><Causality><Cavitas Oris><Cell Body><Cell Communication><Cell Interaction><Cell Nucleus><Cell Survival><Cell Viability><Cell-to-Cell Interaction><Cells><Cellular Expansion><Cellular Growth><ChIP Sequencing><ChIP-seq><ChIPseq><Complex><Cytoplasm><DNA Binding><DNA Binding Domain><DNA Binding Interaction><DNA Viruses><DNA bound><DNA-Binding Protein Motifs><Data><Development><Down-Regulation><ENX-1><EZH1><EZH2><EZH2 gene><Endothelium><Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Epithelium><Etiology><Future><Gene Action Regulation><Gene Down-Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Targeting><Genes><Gingiva><Gingival><Goals><HHV-8><HHV8><HIV-Associated Cancer><HIV-associated malignancy><HIV-related malignancy><HIV/AIDS-associated malignancy><HIV/AIDS-related cancer><Herpes infection><Herpesviridae><Herpesviridae Infections><Herpesviridae disease><Herpesvirus Infections><Herpesviruses><Histone Acetylase><Histone Acetylation><Histone H3><Host Defense><Host Factor><Host Factor Protein><Human><Human Herpesvirus 8><Immune><Immune Evasion><Immune Response Regulation Pathway><Immunes><Infection><Integration Host Factors><Investigation><KHSV vIRF><KMT6><KMT6A><KSHV><Kaposi Sarcoma><Kaposi Sarcoma-Associated Herpes Virus><Kaposi Sarcoma-Associated Herpesvirus><Kaposi sarcoma associated virus><Kaposi sarcoma herpes virus><Kaposi's Sarcoma><Kaposi's sarcoma (KS)-associated herpesvirus><Knowledge><L-Lysine><Link><Lysine><Lytic><Lytic Cycle><Lytic Infection><Lytic Phase><Mediating><Medical><Methylation><Modern Man><Molecular Interaction><Mouth><Mouth Mucosa><Multicentric Angiofollicular Lymphoid Hyperplasia><Multicentric Castleman's Disease><Multiple Hemorrhagic Sarcoma><Nuclear><Nucleus><Oncogenesis><Oncogenic Viruses><Oral Kaposi's sarcoma><Oral Mucosa><Oral cavity><Oral mucous membrane structure><Palate Kaposi's Sarcoma><Pathway interactions><Polycomb><Population><Proteins><RNA Seq><RNA sequencing><RNAseq><Regulation><Repression><Role><Saliva><Source><Testing><Transcription Repression><Transcriptional Repression><Transmission><Tumor Viruses><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Gene Products><Viral Gene Proteins><Viral Genes><Viral Genome><Viral Physiology><Viral Proteins><Viral reservoir><Virus><Virus Diseases><Virus Replication><Virus reservoir><Virus-HHV8><biologic><causation><cell growth><chromatin immunoprecipitation-sequencing><chronic infection><developmental><disease causation><epigenetically><gene induction><gene induction/repression><gene repression><genome scale><genome-wide><genomewide><herpes virus><histone H3 methyltransferase><histone acetyltransferase><histone methylase><histone methylation><histone methyltransferase><immune evasive><induction of genes><infection mouth><kaposi's sarcoma herpesvirus><kaposi's sarcoma-associated human herpesvirus><lytic replication><lytic viral replication><lytic virus replication><mouth Kaposi's sarcoma><multicastleman's diseases><mutant><novel><oncogenic tumor virus><oral cavity epithelium><oral epithelia><oral epithelium><oral infection><oral infectious><oral kaposi sarcoma><oral ks><oral mucosae><oral mucosal><particle><pathogen><pathway><persistent infection><primary effusion lymphoma><promoter><promotor><protein complex><recruit><shRNA><short hairpin RNA><small hairpin RNA><small molecular inhibitor><small molecule inhibitor><social role><transcriptional reprogramming><transcriptome sequencing><transcriptomic sequencing><transmission process><tumor><tumorigenesis><vIRF><vIRF-3><vIRF1><vIRF3><viral IRF><viral infection><viral infectious disease treatment><viral interferon regulatory factor><viral interferon regulatory factor-1><viral interferon regulatory factor-3><viral multiplication><viral replication><viral transmission><virus genome><virus infection><virus multiplication><virus protein><virus transmission><virus-induced disease>