Non-CD4 tropic SIV: Enhancing CD4 T-cell help in antiviral immune responses

非 CD4 tropic SIV：增强 CD4 T 细胞有助于抗病毒免疫反应

• 批准号: 8732145
• 负责人: James A Hoxie
• 金额: $ 84.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732145
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Alleles; Animals; Antibodies; Antigen-Presenting Cells; Antiviral Agents; Area; Aspartic Acid; B-Lymphocytes; Binding; Binding Sites; Blood; CCR5 gene; CD3 Antigens; CD4 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Chronic; Competence; Confocal Microscopy; Defect; Disease Progression; Engineering; Epithelial; Event; Flow Cytometry; Glycoproteins; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class II; Human; Immune; Immune response; Immunohistochemistry; Immunologic Deficiency Syndromes; Immunologics; In Vitro; Infection; Infection Control; Knowledge; Label; Link; Lymph Node Cortex; Macaca; Macaca mulatta; Mediating; Memory B-Lymphocyte; Modeling; Molecular; Molecular Cloning; Mutation; Natural History; Pathogenesis; Pathogenicity; Phenotype; Physiological; Pilot Projects; Plasma; Primate Lentiviruses; Principal Investigator; Property; Research; Role; SIV; Staining method; Stains; Subfamily lentivirinae; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tropism; Vaccine Design; Vaccines; Variant; Viral; Viremia; Virus; Virus Diseases; adaptive immunity; base; cell type; cytokine; design; env Glycoproteins; fitness; immune activation; immune function; improved; in vivo; innovation; insight; macrophage; microbial; mucosal site; neutralizing antibody; novel; novel virus; programs; public health relevance; regenerative; response; simian human immunodeficiency virus

DESCRIPTION (provided by applicant): An invariant feature of HIV and SIV pathogenesis is CD4 tropism, mediated by a highly conserved CD4 binding site on the envelope glycoprotein. By focusing infection onto T-cell subsets that provide help for adaptive immunity (e.g. Th1, Th17, Tfh), it is likely that CD4 tropism has profound effects on antiviral immune responses, which are ultimately inadequate to contain viral replication and disease progression. Binding of gp120 to CD4 also has the potential to disrupt CD4's physiologic interaction with HLA class-II on antigen presenting cells, which underlies T-cell immunologic helper functions. We are exploring a highly innovative hypothesis that lentiviruses engineered to retain infectivity while lacking a CD4 binding site and CD4 tropism would be fundamentally altered in their pathogenesis, enabling more potent helper T-cell functions to be generated that are typically not permitted in the context of CD4-tropic infection. An understanding of the possible expansion in the repertoire of antiviral immune responses in this context could be informative for the HIV vaccine field. We have derived a highly CD4-independent variant of SIVmac239 and shown that it is infectious in vitro and in vivo in rhesus macaques even after its CD4 binding site has been ablated. This virus, termed "iMac-?D," replicates to a high acute peak in plasma and is then controlled to elite levels; infects macrophages and other non-T-cell types; does not deplete CD4+ T-cells; spares cortical T-cell regions in nodes; and generates high and sustained levels of neutralizing antibodies long after plasma viremia is cleared. This first non-CD4 tropic primate lentivirus will be evaluated with 4 specific aims: 1) To define and characterize in vivo its pathogenicity, tropism, and qualitative and/or quantitative differences in host humoral and cellular antiviral immune responses compared to CD4-tropic SIVmac239 infection; 2) To identify components of the host adaptive immune response responsible for iMac-?D's control and to determine if they can protect animals from a pathogenic heterologous SIV challenge; 3) To further examine the effects of CD4 interactions by evaluating pathogenicity and immunological parameters of infection when this virus retains its CD4 binding site; and 4) To extend this approach to an HIV-1 envelope glycoprotein by creating and characterizing in vitro and in vivo a non-CD4 tropic, simian/human immunodeficiency virus (SHIV) that, like iMac- D, can replicate in rhesus PBMCs and macaques while lacking a CD4 binding site. This non-CD4 tropic SHIV will provide a bridge to further studies that will be relevant to anti-HIV-1 immune responses in the setting of CD4+ helper T-cell sparing. These unique viruses and this novel model will enable us to address new and potentially paradigm-shifting themes of HIV and SIV pathogenesis and vaccine design.

描述（由申请人提供）：HIV和SIV发病机理的不变特征是CD4的TROPISM，是由高度保守的CD4结合位点介导的。通过将感染集中在T细胞亚群上，这些亚群为适应性免疫提供帮助（例如TH1，TH17，TFH），CD4 Tropism可能对抗病毒免疫反应具有深远的影响，这些反应最终不足以容纳病毒复制和疾病进展。 GP120与CD4的结合也有可能破坏CD4与HLA类-II的生理相互作用在抗原呈递细胞上，这是T细胞免疫辅助助手功能的基础。我们正在探索一种高度创新的假设，即慢病毒在其发病机理中从根本上改变了齿状病毒，而缺乏CD4结合位点和缺乏CD4结合位点和CD4向tropism的慢病毒将在其发病机理中有所改变，从而使更有效的助手T细胞功能通常在CD4 Tropic Invection的背景下产生。在这种情况下，了解抗病毒免疫反应的曲目可能的扩张可能对HIV疫苗领域具有丰富的信息。我们衍生了SIVMAC239的高度CD4独立于CD4的变体，并表明它在恒河猕猴中具有感染性的体外和体内，即使在其CD4结合位点被烧毁后也是如此。该病毒称为“ imac-？d”，重复到血浆中的高急性峰，然后将其控制为精英水平。感染巨噬细胞和其他非T细胞类型；不会耗尽CD4+ T细胞；节点中的皮质T细胞区域；并在清除血浆病毒血症后很长时间产生高和持续的中和抗体水平。第一个非CD4热带灵长类动病毒将以4个特定目的进行评估：1）与CD4特性SIVMAC239感染相比，在体内定义和表征其在体内的致病性，Tropism和定性和/或定量差异； 2）确定负责iMac-控制的宿主自适应免疫反应的组成部分，并确定它们是否可以保护动物免受致病性异源SIV挑战的影响； 3）当该病毒保留其CD4结合位点时，通过评估感染的致病性和免疫学参数来进一步检查CD4相互作用的影响； 4）将这种方法扩展到HIV-1包膜糖蛋白，通过创建和表征体外和体内非CD4热带，邻肌/人类免疫缺陷病毒（SHIV）（SHIV），例如iMac- D，可以在缺乏CD4粘合位点的恒河类PBMC和麦卡Que中复制。这种非CD4热带SHIV将为进一步的研究提供一座桥梁，该研究将与CD4+辅助辅助T细胞支撑物相关的抗HIV-1免疫反应有关。这些独特的病毒和这种新型模型将使我们能够解决HIV和SIV发病机理和疫苗设计的新的和潜在的范式转移主题。