HIV-1 gp120 induced CTL chemorepulsion:dysregulation of migration & localization

HIV-1 gp120诱导的CTL化学排斥：迁移失调

• 批准号: 7900116
• 负责人: MARK Coleman POZNANSKY
• 金额: $ 16.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900116
• 关键词: AIDS/HIV problem; Active Sites; Acute; Animals; Antigens; Ascaridil; Binding; Biological Assay; Biomedical Engineering; Bone Marrow; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Cancer Model; Cells; Chemotactic Factors; Chemotaxis; Collaborations; Cytolysis; Cytotoxic T-Lymphocytes; Data; Development; Disease Progression; Down-Regulation; Dyes; Elements; Emigrations; Functional disorder; Generations; HIV; HIV 1 Envelope Protein gp120; HIV Envelope Protein gp120; HIV-1; Helper-Inducer T-Lymphocyte; Highly Active Antiretroviral Therapy; Histocompatibility Antigens Class I; Human; Image; Immune; Immune system; Immunologist; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Individual; Infection; Label; Laboratories; Leukocytes; Ligands; Lymphocyte Function; Lymphoid Tissue; Magnetic Resonance Imaging; Malignant Neoplasms; Mature T-Lymphocyte; Measures; Mediating; Medicine; Modeling; Monkeys; Movement; Mus; Mutation; Nature; Pathologic Processes; Physiological; Play; Prevalence; Process; Proteins; Publishing; Research Project Grants; Rest; Role; Signal Pathway; Signal Transduction; Site; Stromal Cell-Derived Factor 1; Surface; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Therapeutic Intervention; Thymus Gland; Tissues; United States National Institutes of Health; Upper arm; V3 Loop; Vaccine Design; Viral; Viral Proteins; Virus; cell motility; cell type; cellular engineering; chemokine; chemokine receptor; design; env Gene Products; human data; in vivo; innovation; intravital microscopy; lymph nodes; migration; monocyte; neoplastic cell; novel; prevent; response; vaccine candidate

DESCRIPTION (provided by applicant): Immune control of HIV-1 is dependent on the migration of HIV-1 specific CTLs towards and colocalization with infected cells. This process is orchestrated by the action of chemokines serving as chemoattractants at sites of infection. We recently demonstrated that leukocytes could also be repelled from specific agents including chemokines and viral proteins including SDF-1 and the HIV-1 envelope protein, gp120 via a chemokine receptor mediated mechanism termed fugetaxis or chemorepulsion (Nature Medicine.2000.6.543; J Virol. 2004: 2004: 78.5184; Reviewed in J.Mol.Med..2005.83:752). We propose that T cell and in particular CTL chemorepulsion in response to CXCR4 or CCR5 binding gp120 generated from retrovirally infected cells plays a role in a novel mechanism by which HIV-1 evades the immune system. First we developed novel fully quantitative assays for measuring leukocyte migration to SDF-1 or HIV-1gp120 and demonstrated that chemorepulsion was mediated via a signaling pathway which was distinct from that for chemoattraction (Nature Med., J. Virol op cit; J. Leuk. Biol. 2005. in press.). In order to determine whether T cell chemorepulsion to SDF-1 or HIV-1gp120 was demonstrable in vivo, we established novel assays for quantitating leukocyte chemorepulsion and subsequently demonstrated its role in physiological and pathological processes including thymic emigration and immune evasion by cancer (J. Clin. Invest. 2002.109:1101; J. Immunol. 2005.175:5115)( J. Immunol. Accepted Dec.2005). We also showed that antigen specific CTLs and monocytes move away from X4 or R5 binding HIV-1 gp120 in vitro and in vivo and that this response was critically dependent on the presence of the V3 loop of the envelope protein (./ Virol. op cit.}. We have demonstrated in pilot that cells engineered to express gp120 repel and thereby dysregulate CTL migration and function in vitro and their subsequent localization in vivo and that chemorepellent concentrations of gp120 are detectable within the lymph nodes of acutely SHIV-1 infected monkeys. We now plan to explore the mechanism and pathophysiological relevance of these findings to HIV/AIDS. The aims of this proposal are 1: Definition of mechanistic elements of HIV-1gp120 induced CTL chemorepulsion and the effect of chemorepellent concentrations of the retroviral protein on CTL function. 2. Quantitation of the effects of X4gp120 on CTL migration, localization and function in murine models using multiphoton intravital microscopy and MRI for imaging dye or nanomagnetically labeled CTLs in vivo. 3. Quantitation and modeling of gp120 gradients in tissues and correlation with the localization and function of CTLs in acutely SHIV-1 infected monkeys. This focused and innovative exploration of the pathophysiological relevance of HIV-1 gp120 induced CTL chemorepulsion to HIV/AIDS is supported by synergistic and ongoing collaborations between retrovirologists, immunologists and bioengineers and access to recently developed fully quantitative technologies for examining T cell migration and localization in vitro and in vivo. We hope, in this way, to delineate both a novel mechanism by which HIV-1 evades the immune system and a new immunotherapeutic target for HIV-1 infected individuals.

描述（由申请人提供）：HIV-1的免疫控制取决于HIV-1特异性CTL向受感染细胞的迁移和共定位。通过在感染部位用作趋化因子的趋化因子的作用来策划此过程。我们最近证明，白细胞也可以通过特定药物从包括趋化因子和病毒蛋白在内的特定药物中排除，包括SDF-1和HIV-1包膜蛋白，通过趋化因子受体介导的机制称为fugetaxis或chemorepulsion的机制GP120（自然药物。 J.Mol.Med..2005.83：752）。我们提出，响应于逆转录病毒感染细胞产生的CXCR4或CCR5结合GP120的T细胞，尤其是CTL化学螺栓，在HIV-1逃避免疫系统的新机制中起作用。首先，我们开发了用于测量白细胞迁移到SDF-1或HIV-1GP120的新型全定量测定法，并证明化学栓塞是通过信号传导途径介导的，该信号传导途径与趋化疗法不同（Nature Med。，J。Virol op Cit; J. Leuk cit; J.Leuk。Biol。Biol。2005in Press。）。 In order to determine whether T cell chemorepulsion to SDF-1 or HIV-1gp120 was demonstrable in vivo, we established novel assays for quantitating leukocyte chemorepulsion and subsequently demonstrated its role in physiological and pathological processes including thymic emigration and immune evasion by cancer (J. Clin. Invest. 2002.109:1101; J. Immunol. 2005.175:5115)( J.疫苗。我们还表明，抗原特异性CTL和单核细胞在体外和体外和体外从X4或R5结合HIV-1 GP120转移，并且这种反应非常依赖于包膜蛋白的V3环的存在（./virol。pirol。pirol.OP CIT。}。我们已经在PILENERENDERNECREND和FIRMITING tONERNERING tONERNERING和CP1220中恢复了CRENTBY rep120 rep120 rep120 rep。它们随后在体内的定位和化学浓度的GP120在急性SHIV-1感染的猴子的淋巴结中可检测到。逆转录病毒蛋白对CTL功能的化学浓度2。 3。组织中GP120梯度的定量和建模与急性SHIV-1感染猴子中CTL的定位和功能相关。对HIV-1 GP120的病理生理相关性的这种集中和创新的探索诱导了CTL化学渗透对HIV/AIDS的促进性，得到了逆转录病毒学家，免疫学家和生物工程师之间的协同和持续的合作，并持续的合作以及最近开发了用于检查T细胞迁移和本地化的全面定量技术的访问。我们希望通过这种方式描绘出一种新型的机制，HIV-1通过该机制逃避免疫系统，也是针对HIV-1感染个体的新免疫治疗靶标。