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Oral transmission of KSHV using rhesus macaque rhadinovirus model

使用恒河猴鼻病毒模型经口传播 KSHV

基本信息

批准号：
10686217
负责人：
SCOTT W WONG
金额：
$ 79.11万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686217
关键词：
AIDS related cancer Acquired Immunodeficiency Syndrome Affect Africa South of the Sahara Anatomy B-Cell Lymphomas B-Lymphocytes Bacterial Artificial Chromosomes Binding Cell Culture Techniques Cells Cellular biology Child Chimera organism Data Development Disease Fibromatoses Generations Genome Genomics Glycoproteins Goals HIV Infections Herpesviridae Herpesviridae Infections Homologous Gene Human Human Herpesvirus 8 Immune response Immunologic Deficiency Syndromes Immunology procedure In Vitro Individual Infection Inflammation Intravenous Investigation Kaposi Sarcoma Kinetics Lesion Life Ligature Lymphoproliferative Disorders Macaca mulatta Mesenchymal Modeling Molecular Molecular Biology Molecular Genetics Multicentric Angiofollicular Lymphoid Hyperplasia Oral Oral cavity Oral mucous membrane structure Pathogenicity Pathologic Pathology Patients Periodontitis Physiological Plasma Cells Population Predisposition Primates Procedures Recombinants Research Personnel Retroperitoneal Space Rhadinovirus Risk Rodent Role Route SIV Saliva Site Species Specificity System Tissues Vaccines Variant Viral Viral Load result Virus Virus Diseases acute infection animal resource cell type cofactor density detection assay experimental study gamma-2 herpesvirus in vivo latent infection mRNA Expression nonhuman primate novel oral tissue prevent protein expression receptor receptor expression receptor function response trafficking transmission process viral transmission

项目摘要

SUMMARY The long-term goals and objectives of this proposal is to investigate host and virological factors associated with oral transmission of Kaposi’s sarcoma-associated herpesvirus (KSHV) utilizing the closely related rhesus macaque rhadinovirus (RRV) infection of rhesus macaques (RM) model that parallels KSHV infection and pathogenicity in humans. Like KSHV, RRV is a gamma-2 herpesvirus that is closely related to KSHV at the genomic level, possessing essentially collinear genome organization. Pathologically, RRV closely resembles KSHV, as we have shown that intravenous (iv) inoculation of RRV can induce KSHV-like disease manifestations in RM co-infected with simian immunodeficiency virus (SIV). Similarly, RM are infected with RRV early in life, within the first 2 years, implying RRV infection mimics KSHV infection in children living in sub-Saharan Africa, where KSHV is acquired early in life. Here, we will determine whether RRV can cross the oral mucosa to establish infection, and identify the in vivo conditions necessary. These first of kind studies for RRV will be performed in parallel with in vitro studies to interrogate viral glycoprotein receptor(s) density and cell types expressing the receptor(s) in different regions of the oral cavity, as a means to define the mechanism for transmission. Lastly, as we have created an infectious and pathogenic bacterial artificial chromosome (BAC) clone of wild type RRV (WT-RRVBAC) that provides a molecular genetic system to interrogate viral factors that are necessary for infection, we will undertake a molecular approach to interrogate viral encoded factors that facilitate KSHV infection across the oral mucosa. Specifically, we hypothesize that RRV envelope glycoproteins gB, gH, gL, gM and potentially gR8.1 are necessary for binding to receptors on susceptible cells and that KSHV glycoproteins gB, gH, gL, gM and gK8.1 can functionally substitute for RRV glycoprotein homologues. Hence, establishing this chimeric virus system will enable researchers and vaccinologists, the ability to target the viral glycoproteins for vaccine approaches in a nonhuman primate (NHP) model.

总结