BACTERIAL TOXINS AND ANTI HIV1 IMMUNITY

细菌毒素和抗 HIV1 免疫力

• 批准号: 2542925
• 负责人: MARNIX L BOSCH
• 金额: $ 6.65万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2542925
• 关键词: AIDS vaccines; HIV envelope protein gp120; antiviral antibody; cholera toxin; crosslink; cytotoxic T lymphocyte; enterotoxins; human immunodeficiency virus 1; immunoregulation; laboratory mouse; leukocyte activation /transformation; microorganism culture; microorganism immunology; neutralizing antibody; vaccine development

DESCRIPTION (adapted from applicant's abstract): Infection with HIV-1 worldwide occurs mostly through mucosal exposure. Therefore first line defense against HIV- 1 must include mechanisms that act at the mucosal surface. In addition it is desirable that cytotoxic T Lymphocytes against the virus are induced in order to combat cells that become infected by virus that escaped from this first line of defense. An ideal HIV-1 vaccine would therefore induce both mucosal antibodies and CTL. Cholera Toxin (CT) and E. cold heat-labile enterotoxin (LT) have the capacity to do both. It is unlikely that immune responses to a single HIV-1 gene product will provide full protection from infection. It has been demonstrated that vaccine strategies for SIV that incorporate responses to multiple SIV gene products provide better and broader protection from subsequent challenges. A vaccine formulation that could be flexibly adapted to induce immune responses to multiple gene products is therefore preferable over one that is inherently limited. Such Flexibility would also provide the opportunity to incorporate multiple antigenic variants which seems necessary in the face of the extreme variability of HIV-1. 1. Chemical cross linking of CT or LT to antigenic peptides of HIV-1 in theory would provide the following possibilities: - oral, rectal, or nasal administration of the immunogen - induction of cytotoxic T Lymphocytes to the peptides - induction of mucosal and systemic antibodies to the peptides and to the HIV-1 proteins - combination of multiple peptides from different HIV genes and from different variants in one immunogen. We have established a successful procedure to crosslink peptides to CT. We will use this procedure to pursue the following aims using mice as experimental animals: AIM 1 Determine whether HIV-1 peptides crosslinked to the CT holotoxin confer enhanced immunogenicity when compared to CT mixed with either free peptides or HIV-1 gp120 proteins both systemically and at the mucosal surfaces when administered intrarectally AIM 2 Determine whether different routes of administration (including intragastrically, intranasally and intrarecatally) of HIV- 1 peptides crosslinked to or mixed with LT mutants induce anti HIV- 1 antibodies and cytotoxic T Imphocytes AIM 3 Determine whether the system of crosslinking HIV - 1 peptides to CT or LT mutants allows for simultaneous immunization with multiple epitopes by using multiple antigenic peptides from both allelic variants of the same gene and of different HIV-1 genes.

描述（改编自申请人摘要）：HIV-1感染 在世界范围内，大多数情况下是通过粘膜接触发生的。 因此，第一行 对HIV- 1的防御必须包括作用于粘膜的机制， 面 此外，希望细胞毒性T淋巴细胞 对抗病毒的细胞被诱导， 感染了从第一道防线逃脱的病毒。 一个 因此，理想的HIV-1疫苗将诱导粘膜抗体， CTL.霍乱毒素（CT）和E.冷不耐热肠毒素（LT） 有能力做到这两点。 免疫反应不太可能是 单一HIV-1基因产物将提供完全保护免受感染。 已经证明，SIV的疫苗策略， 结合对多种SIV基因产物的应答提供了更好且 更广泛的保护，免受随后的挑战。的疫苗制剂 它可以灵活地适应于诱导免疫反应， 因此，基因产物比固有的基因产物更好。 有限公司 这种灵活性还将提供机会， 结合了多种抗原变体，这似乎是 面对HIV-1的极端变异性。 1. CT或LT与HIV-1抗原肽的化学交联 在理论上提供了以下可能性： - 免疫原的口服、直肠或鼻腔给药 - 细胞毒性T淋巴细胞对肽的诱导 - 诱导针对所述肽的粘膜和全身抗体， HIV-1蛋白 - 来自不同HIV基因和来自 同一种免疫原的不同变体 我们已经建立了一个成功的程序交联肽CT。 我们将使用这个程序来追求以下目标，使用小鼠作为 实验动物：AIM 1确定HIV-1肽是否交联 与CT全毒素相比， 与游离肽或HIV-1 gp 120蛋白混合， 直肠内给药时全身和粘膜表面 目的2确定不同的给药途径（包括 胃内、鼻内和直肠内）的HIV- 1肽 与LT突变体交联或混合诱导抗HIV- 1抗体 和细胞毒性T免疫细胞AIM 3确定系统是否 将HIV - 1肽与CT或LT突变体交联允许 通过使用多个表位同时免疫 来自同一基因的等位基因变体和 不同的HIV-1基因