Oral transmission of KSHV using rhesus macaque rhadinovirus model

使用恒河猴鼻病毒模型经口传播 KSHV

• 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
• 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

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 本提案的长期目标和目的是研究与感染相关的宿主和病毒学因素。 卡波西肉瘤相关疱疹病毒（KSHV）利用近亲恒河猴的经口传播 恒河猴（RM）模型的猕猴鼻状病毒（RRV）感染，与KSHV感染平行， 人类的致病性。与KSHV一样，RRV是一种γ-2疱疹病毒，在免疫学上与KSHV密切相关。 基因组水平，具有基本共线的基因组组织。病理学上，RRV与 KSHV，因为我们已经表明，静脉（iv）接种RRV可诱导KSHV样疾病表现 在RM与猴免疫缺陷病毒（SIV）共感染。同样，RM在生命早期感染RRV， 在前2年内，这意味着在撒哈拉以南非洲的儿童中RRV感染与KSHV感染相似， KSHV在生命早期获得。在这里，我们将确定RRV是否可以通过口腔粘膜建立 感染，并确定必要的体内条件。这些RRV的首次同类研究将在 与体外研究平行，以询问病毒糖蛋白受体密度和表达病毒糖蛋白受体的细胞类型。 受体在口腔的不同区域，作为一种手段，以确定机制的传输。最后， 因为我们已经创建了野生型RRV的感染性和致病性细菌人工染色体（BAC）克隆， （WT-RRVBAC）提供了一个分子遗传系统来询问病毒所需的病毒因子， 感染，我们将采取分子方法来询问病毒编码的因子，促进KSHV 口腔粘膜感染。具体而言，我们假设RRV包膜糖蛋白gB、gH、gL、gM 和潜在的gR8.1是与易感细胞上的受体结合所必需的， gB、gH、gL、gM和gK8.1可以在功能上替代RRV糖蛋白同源物。因此，建立这 嵌合病毒系统将使研究人员和疫苗学家能够靶向病毒糖蛋白， 非人灵长类动物（NHP）模型中的疫苗方法。