Determinants of HIV-1 innate immune sensing and its role in shaping the lymphoid environment.

HIV-1 先天免疫感应的决定因素及其在塑造淋巴环境中的作用。

• 批准号: 10712594
• 负责人: SUMIT K CHANDA
• 金额: $ 92.25万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-12 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712594
• 关键词: Address; Adjuvant; Antiviral Response; Binding; Binding Proteins; Biochemical; CD4 Positive T Lymphocytes; Capsid; Cell Nucleus; Cells; Coculture Techniques; Coupled; DNA; DNA biosynthesis; Data; Dendritic Cells; Deposition; Dimerization; Disease; Environment; Equilibrium; Event; Flow Cytometry; Gene Expression; Genetic Engineering; HIV-1; Human; Immune; Immune system; Immunohistochemistry; In Vitro; Infection; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Type I; Knowledge; Length; Lymphoid; Lymphoid Tissue; Measures; Mechanics; Mediating; Modeling; Molecular; Mucous Membrane; Mutagenesis; Natural Immunity; Outcome; Pathogenesis; Pathology; Pathway interactions; Pattern; Periodicity; Proteins; Reagent; Reporting; Rest; Retroviridae; Rhesus; Role; Route; SIV; Shapes; Signal Transduction; Site; Structure; Surface; System; T-Lymphocyte; Testing; Vaccine Adjuvant; Vaccine Therapy; Variant; Viral; Viral Genes; Viral Pathogenesis; Virus; cytokine; data integration; design; dimer; experimental study; gastrointestinal; immune activation; in vivo; innate immune sensing; insight; molecular rearrangement; mucosal site; nonhuman primate; pathogen; pharmacologic; polyglutamine; prevent; recruit; response; sensor; superresolution microscopy; targeted treatment; transcriptomics; transmission process; vaccine development; vaccine strategy; viral DNA; viral transmission

PROJECT SUMMARY HIV-1 has a low transmission rate and most new infections via the mucosal route are initiated by a single variant out of a viral quasispecies. Recent studies in non-human primates found that mucosal transmission foci contain infected dendritic cells, and it remains to be determined why their innate responses sometimes fail to prevent viral spread. Selective advantages that allow a virus to cross a recipient's mucosal barrier include the ability to evade restriction factors and suppress innate antiviral responses. Various HIV-1 proteins participate in these evasion tactics, including the viral capsid. After entry, the capsid binds cellular factors necessary for its transit to the nucleus and synthesis of viral DNA, while repelling restriction factors and specialized innate sensors. Over the years, we have studied several innate sensors and, most recently, our studies have focused on HIV-1- dependent activation of cyclic GAMP synthase (cGAS), a cytosolic DNA sensor. We discovered that polyglutamine binding protein 1 (PQBP1) is an adaptor required for cGAS sensing of HIV-1 DNA. PQBP1 binds to the HIV-1 capsid, thereby authenticating it as a danger signal, then recruits cGAS to the capsid as it begins to disassemble and reveal the nascent viral DNA. We assume that PQBP1 transfers cGAS to the emerging DNA by a "bait and switch" mechanism, resulting in cGAS activation and downstream gene expression. We identified both naturally occurring and genetically engineered capsid variants that activate cGAS to different levels, suggesting that capsid structure is a key determinant of this innate pathway. A critical gap in our knowledge that will be addressed by this project is how PQBP1-capsid interactions and molecular rearrangements control the strength of the cGAS signal (Aims 1 and 2). The cGAS pathway is predominanUy responsible for innate immune responses triggered by HIV-1 infection of dendritic cells, resulting in expression of antiviral factors and type I interferons as well as proinflammatory cytokines. Paradoxically, while induction of antiviral genes inhibits replication, proinflammatory cytokines can activate resting CD4+ T cells and may promote infection. We hypothesize that the strength of the cGAS signal activated by HIV-1 can tip the balance from antiviral to proinflammatory responses, thereby contributing to successful transmission. The same mechanism may also be activated in other lymphoid tissues, downstream of the initial transmission event, and may determine the course of reservoir seeding. Another critical gap in our knowledge that will be addressed by this project is how the level of cGAS activation drives the balance between antiviral and proinflammatory responses and the role of the HIV- 1 capsid in determining its magnitude, both in vitro and in vivo (Aim 3). Our findings will provide insight into the molecular events that determine the outcome of viral exposure, and these same mechanisms could also contribute to HIV-1 pathogenesis. Additionally, our findings will provide important guidance for the design of appropriate adjuvant and vaccine strategies for HIV-1 and other pathologies that involve the cGAS pathway.

项目总结