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: 10541061
• 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/10541061
• 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; 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 density; 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.

概括 该提案的长期目标和目标是调查与相关的宿主和病毒学因素 使用密切相关的恒河校的Kaposi肉瘤相关疱疹病毒（KSHV）的口服传播 猕猴（RRV）感染猕猴（RM）模型，与KSHV感染相关 人类的致病性。像KSHV一样，RRV是一种γ-2疱疹病毒，与KSHV密切相关 基因组水平，潜在的共线基因组组织。从病理上，RRV非常相似 正如我们已经表明的，KSHV的静脉内（IV）接种RRV可以诱导KSHV样疾病表现 在与Simian免疫缺陷病毒（SIV）共同感染的RM中。同样，RM在生命的早期就被RRV感染， 在头两年内，暗示RRV感染模仿居住在撒哈拉以南非洲的儿童的KSHV感染， KSHV在生命的早期获得。在这里，我们将确定RRV是否可以越过口腔粘膜建立 感染并确定所需的体内条件。这些对RRV的首先研究将在 与体外研究并行询问病毒糖蛋白受体的密度和表达细胞类型 口腔不同区域的接收器，以定义传播机制的一种手段。最后， 由于我们创建了一种感染性和致病性细菌人造染色体（BAC）野生型RRV的克隆 （WT-RRVBAC）提供了一个分子遗传系统来询问病毒因子的因素 感染，我们将采用一种分子方法来审问病毒编码因子，以促进KSHV 跨口腔粘膜感染。具体而言，我们假设RRV包膜糖蛋白GB，GH，GL，GM 潜在的GR8.1对于与易感细胞上的受体结合和KSHV糖蛋白结合是必需的 GB，GH，GL，GM和GK8.1可以在功能上代替RRV糖蛋白同源物。因此，建立了这个 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的能力 疫苗在非人类灵长类动物（NHP）模型中接近。