Role of HIV Env glycosylation in mucosal transmission

HIV Env 糖基化在粘膜传播中的作用

• 批准号: 8892997
• 负责人: Siddappa N Byrareddy
• 金额: $ 86.69万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-16 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892997
• 关键词: Acute; Address; Affinity; Antibodies; Antigen-Presenting Cells; Antigens; Area; Binding; CD 200; Cell Line; Cell surface; Cells; Chronic; Competence; Data; Dendritic Cells; Disease Progression; Dose; Drug Formulations; Enhancers; Evolution; Fingerprint; Foundations; Future; Galactose Binding Lectin; Glycoproteins; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Health; Helper-Inducer T-Lymphocyte; Immune response; In Vitro; Infection; Interferon-alpha; Kinetics; Knowledge; Lectin; Ligands; Link; Macaca; Macaca mulatta; Modeling; Molecular Cloning; Mucous Membrane; Mutate; Pathogenesis; Play; Polysaccharides; Positioning Attribute; Predisposition; Property; Proteins; Reagent; Receptor Cell; Recombinants; Research Design; Research Personnel; Resources; Role; SIV; Series; Site; Source; Surface; T-Lymphocyte; Testing; Vaccine Design; Vaccines; Vagina; Variant; Vertebral column; Viral; Viral Antigens; Virus; base; cohort; deep sequencing; design; env Gene Products; glycosylation; immune function; in vivo; neutralizing antibody; nonhuman primate; particle; prevent; receptor; simian human immunodeficiency virus; sugar; tool; transmission process; vaginal transmission

DESCRIPTION (provided by applicant): A refined understanding of virus/host relationships that promote transmission and those that contribute to the rate of disease progression following infection is critical for the design of effective vaccines against HIV-1. One parameter that is increasingly recognized as being critical and understudied is the role of viral env glycosylation not only in preferential transmission but also in the ability of the virus to select receptors for entry and for its susceptibility to neutralizing antibodies. In addition, data is now accumulating o show that a variety of cell surface molecules that serve as ligands/receptors for the glycosylated env proteins and those that are influenced by glycosylated versus de-glycosylated viruses, could contribute to the quality of immune response the virus engenders. These issues can only be objectively addressed using appropriate nonhuman primate models such as macaques infected with SHIVs that contain the env from primary HIV-1 isolates, particularly from transmitted/founder viruses to study the roles of env glycosylation in preferential transmission. Therefore, we plan to explore the role of env glycans using sets of HIV molecular clones obtained from transmitted/founder (T/F) viruses from a Zambian cohort-where clade C viruses predominate. We have generated several unique tools/reagents and assembled a highly talented team of Investigators and a series of systematic logically designed studies are outlined which will first focus on the composition and arrangement of glycans in paired clones from T/F circulating HIV strains including N-and O-glycans as outlined in aim 1. Based on glycan profiles, we proposed to select a) a highly glycosylated, b) low level of env glycosylated viruses from transmitter and c) as control, a founder virus to prepare corresponding replication competent Simian Human Immunodeficiency viruses (SHIV) for further advanced studies, which include detailed in vitro characterization of replication kinetics in primary cells and cell lines, glycan content, particle envelope glycoprotein content, dendritic cell (DC) capture, DC-T cell trans-infection, sensitivity to IFN-α, anti-α4ß7 and blocking mAbs against select lectin-like molecules (Galectin-9, SIGLECs, MINCLE, and CD200/200R). Then we will select the viruses to test in vivo for transmission efficiency studies in rhesus macaques based primarily on comparable in vitro replication but differing glycan content (aim 2). Under specific aim 3, we will define whethe it is the signature site(s) of Env glycosylation that facilitates transmission, using isogenic SHIV based on the backbone of the "poor" transmitter and mutating only those select residues corresponding to the founder virus from aim 2b, using a repeated multiple-low-dose Intra-Vaginal (IVAG) challenge model. Results of these studies will provide a strong foundation for future rational HIV vaccine design.

描述（由申请人证明）：对促进传播的病毒/宿主关系的精致理解，促进疾病进展的疾病进展对于对HIV-1的有效疫苗的设计至关重要。病毒Env糖基化不是to糖基的传播，而是abirusol tol Ect受体的ALSSO，用于中和抗体的敏感性，此外，数据还表明了各种细胞表面，这些细胞表面是用于糖脂的env env env env envy的配体/受体蛋白质以及受糖基化DE-GL影响的蛋白质可以客观地受到良好的良好感受性的可爱的可爱的良性，如适当的非人类灵长类动物模型，例如猕猴Ith Shivs，其中包含ENV Frimary HIV-1隔离株，传播/创建者病毒到Envlycosylation在Envlycosylation中的作用因此，我们计划使用从Zambian Cohort的传播/创始人（T/F）病毒获得的一组HIV分子克隆来发挥ENV Glycans。概述了研究人员和系统设计的研究研究，该研究将重点介绍来自T/F循环HIV菌株的配对克隆中的聚糖的组成和排列，包括N和Glycans（包括n和Glycans）作为概述的AIM 1。基于Glycan曲线。 ）一种高度gllycosylation，B低水平的Env糖基化病毒蛋白酶和C）作为对照，这是一种为Corresspond的病毒准备，以准备有能力的Simian人类人体缺陷病毒（SHIV）进行进一步的高级研究，以详细详细介绍了原始LLS和初级LLS和复制动力学的体外体外表征细胞系，聚糖含量，颗粒包膜糖蛋白含量，树突状细胞（DC）捕获，DC-T细胞转染，对IFN-α阻断MAB的敏感性针对精选的凝集素样分子（Galectin-9，Siglecs，MinClos和CD200） /200R）。较差的“ utatating onle onle的那些选择与AIM 2B阴道内（IVAG）挑战模型相对应的选择。这些研究的结果将为未来的理性HIV疫苗设计提供巨大的基础。