Immunogenicity of an HIV virus-like particle vaccine

HIV病毒样颗粒疫苗的免疫原性

• 批准号: 6590286
• 负责人: FENG GAO
• 金额: $ 23.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6590286
• 关键词: AIDS vaccines; HIV envelope protein gp120; Semliki Forest virus; biotechnology; cellular immunity; cytotoxic T lymphocyte; guinea pigs; helper T lymphocyte; human immunodeficiency virus 1; humoral immunity; immunomodulators; laboratory mouse; neutralizing antibody; recombinant proteins; recombinant virus; vaccine development; vaccinia virus; vector vaccine

Although AIDS has only been identified for 20 years, nearly 60 million people have been infected with human immunodeficiency viruses globally and currently 36 million of them are living with HIV infection. The most effective way to control the devastating disease is to develop a safe, practical, and effective vaccine that can either prevent new infection or slow down disease progression. Recent studies showed that both humoral and cellular immune responses are needed for such a vaccine. DNA prime and recombinant vaccinia virus boost exhibit a promising approach. We have developed a new DNA based dual semliki forest virus (SFV) expression system. The SFV vector expresses both codon-usage optimized gag and env genes in the form of virus-like particles (VLP) from the cells. Coupled with high expression nature of SFV vector and optimized HIV-1 genes, we expect high expression level of viral proteins in natural viral conformation will elicit both neutralizing antibody and CTL responses in animals. Now we are proposing to evaluate the newly developed unique DNA vaccine candidate in guinea pigs and mice for HIV specific humoral and cellular immune responses. The animals will be immunized with DNA alone for production of VLP in vivo and then boosted with either autologous rgpl20 or recombinant vaccinia viruses expressing autologous gag or env genes. We will collect serum samples from guinea pigs to determine if higher titers of neutralizing antibody will be elicited by the SFV vector that express both gag and env genes, and if humoral immune response can be further augmented by either rgpl20 or recombinant vaccinia virus that expresses env gene. We will also isolate the splenocytes from immunized mice to determine if VLPs generated by our newly developed dual expression SFV vector can induce strong CTL response alone or with recombinant vaccinia virus boost, if both CD4 and CD8 responses will be induced by VLPs, and if VLPs can induce better and broader CTL responses than either the gag or env gene alone. Results from this study will determine if VLPs generated by dual expression SFV vector in vivo can bc developed into an effective AIDS vaccine and used as a guideline to design better immunization strategies in mice and guinea pigs or higher level animals, like monkeys.

虽然艾滋病被发现只有20年的时间，但全球已有近6000万人感染了人类免疫缺陷病毒，目前其中3600万人感染了艾滋病毒。控制这种毁灭性疾病的最有效方法是开发一种安全，实用和有效的疫苗，可以预防新的感染或减缓疾病进展。最近的研究表明，这种疫苗需要体液和细胞免疫应答。DNA初免和重组牛痘病毒加强是一种很有前途的方法。我们建立了一个新的基于DNA的双Semliki森林病毒（SFV）表达系统。SFV载体在大肠杆菌中表达密码子使用优化的gag和env基因。 病毒样颗粒（VLP）的形式。结合SFV载体的高表达性质和优化的HIV-1基因，我们预期天然病毒构象的病毒蛋白的高表达水平将在动物中引发中和抗体和CTL应答。现在我们建议在豚鼠和小鼠中评估新开发的独特DNA候选疫苗的HIV特异性体液和细胞免疫反应。将用DNA单独免疫动物以在体内产生VLP，然后用自体rgpl 20或表达自体gag或env基因的重组牛痘病毒加强免疫。我们将收集豚鼠的血清样品，以确定表达gag和env基因的SFV载体是否会引发更高滴度的中和抗体，以及体液免疫应答是否可以 通过表达env基因的RGP 120或重组牛痘病毒进一步增强。我们还将从免疫的小鼠中分离脾细胞以确定由我们新开发的双表达SFV载体产生的VLP是否可以单独或与重组牛痘病毒加强一起诱导强的CTL应答，VLP是否将诱导CD 4和CD 8应答，以及VLP是否可以诱导比单独的gag或env基因更好和更广泛的CTL应答。本研究的结果将确定由双表达SFV载体在体内产生的VLP是否可以发展成有效的AIDS疫苗，并用作指导在小鼠和豚鼠或更高水平的动物（如猴）中设计更好的免疫策略。