Development of HSV Vectors as AIDS Vaccines

HSV 载体作为艾滋病疫苗的开发

• 批准号: 7599617
• 负责人: DAVID M. KNIPE
• 金额: $ 34.79万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7599617
• 关键词: AIDS Vaccines; Africa South of the Sahara; Animals; Antibody Formation; Antigens; Asia; Biological; CD8B1 gene; DNA; Development; Early Promoters; Epidemic; Glycoproteins; HIV; HIV Envelope Protein gp120; HSV vector; Herpes Simplex Virus Vaccines; Herpesvirus 1; Immediate-Early Genes; Immune; Immune response; Immunization; Infection; Intravenous; Introns; Ligands; Macaca; Macaca mulatta; Modification; Mucosal Immunity; Mus; Mutate; Phase III Clinical Trials; Play; Preparation; Property; Proteins; Recombinant Vaccines; Recombinants; Research; Role; SARS coronavirus; SIV; Safety; Simplexvirus; Site; Source; System; T-Lymphocyte; Testing; Toll-like receptors; Vaccines; Viral Load result; Virion; Work; env Gene Products; gag Gene Products; glycosylation; immunogenicity; improved; latent infection; mucosal site; neurovirulence; neutralizing antibody; novel; novel vaccines; protective effect; response; transgene expression; vector

The HIV epidemic continues unabated, in particular in sub-Saharan Africa and parts of Asia. Despite the numerous AIDS vaccines under consideration, only one has been tested in phase III trials, the gp120 envelope protein vaccine, and it showed no protective effect. This project proposes to test and develop novel replication-defective herpes simplex virus vaccine vectors, which have been shown in previous work to induce both T cell and antibody responses, including neutralizing antibodies, against SIV proteins in immunized rhesus macaques. Furthermore, the immunized macaques showed reduced viral loads after intravenous pathogenic SIV challenge. These HSV recombinant vectors are among only a few immunization approaches that have elicited any protection in rhesus macaques against pathogenic SIVmac239 challenge infection either by mucosal SIV challenge or intravenous SIV challenge. Therefore, the continued development of these vectors is highly justified at this point. Nevertheless, the level of transgene expression and immunogenicity of the vector and expressed antigens needs to be optimized. The proposed research in this application tests various modifications that should enhance this vector system and further the development of this novel vaccine vector system. In this proposal our specific aims are 1. To construct improved HSV-1 recombinant vaccine vectors in the HSV-1 d106 strain by testing the hypothesis that increasing expression of HIV gag protein by d106 vectors will increase CD8+ T cell immune responses in mice, by testing the hypothesis that mutating the V1/V2 loops of HIV env or mutating the glycosylation sites on env protein will enhance the antibody responses to env, by testing the hypothesis that co-expression of a Toll-like receptor ligand, the SARS virus spike protein, by the d106 vector will increase immune. 2. To test the hypothesis that mucosal immunity can be induced by immunization at various mucosal sites. 3. Test the hypothesis that glycoproteins on the HSV virion play a role in immune evasion so that HSV vaccine vectors are efficacious in HSV-immune mice. 4. Define the biological properties of the HSV c/106 recombinant vectors by testing persistence of vector DNA, neurovirulence, latent infection, and safety in immunodeficient animals.

艾滋病毒疫情继续有增无减，特别是在撒哈拉以南非洲和亚洲部分地区。尽管有许多艾滋病疫苗正在考虑中，但只有一种疫苗在III期试验中进行了测试，即gp 120包膜蛋白疫苗，并且没有显示出保护作用。该项目提出测试和开发新的复制缺陷型单纯疱疹病毒疫苗载体，这些载体在先前的工作中已被证明可以诱导免疫恒河猴中针对SIV蛋白的T细胞和抗体应答，包括中和抗体。此外，经免疫的猕猴在静脉内致病性SIV攻击后显示病毒载量降低。这些HSV重组载体是仅有的几种通过粘膜SIV攻击或静脉内SIV攻击在恒河猴中引起针对致病性SIVmac 239攻击感染的任何保护的免疫方法之一。因此，在这一点上，继续开发这些载体是非常合理的。然而，转基因表达水平以及载体和表达抗原的免疫原性需要优化。本申请中的拟议研究测试了应增强该载体系统并进一步开发该新型疫苗载体系统的各种修饰。在这一建议中，我们的具体目标是1。目的构建HSV-1d 106株中改进的HSV-1重组疫苗载体，验证d106株增加HIV gag蛋白表达的假设， 载体将增加小鼠中的CD 8 + T细胞免疫应答，这是通过检验突变HIV env的V1/V2环或突变env蛋白上的糖基化位点将增强对env的抗体应答的假设，通过检验d106载体共表达Toll样受体配体（SARS病毒刺突蛋白）将增加免疫的假设。2.检验粘膜免疫可通过在不同粘膜部位免疫诱导的假设。3.测试HSV病毒粒子上的糖蛋白在免疫逃避中起作用的假设，使得HSV疫苗载体在HSV免疫小鼠中有效。4.通过检测载体DNA的持久性、神经毒力、潜伏感染和免疫缺陷动物中的安全性，确定HSV c/106重组载体的生物学特性。