Development of HSV Vectors as AIDS Vaccines

艾滋病毒流行病继续有增无减，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gp120包膜蛋白疫苗在III期试验中进行了测试，并且没有显示出保护作用。本项目拟测试和开发新的复制缺陷性单纯疱疹病毒疫苗载体，该载体已在先前的工作中被证明可在免疫的恒河猴中诱导T细胞和抗体反应，包括中和抗体，以对抗SIV蛋白。此外，免疫后的猕猴在静脉注射致病性SIV后病毒载量降低。这些HSV重组载体是仅有的几种免疫方法之一，这些免疫方法在恒河猴中引起了任何保护，使其免受粘膜SIV攻击或静脉SIV攻击的致病性SIVmac239攻击感染。因此，在这一点上，这些向量的继续发展是非常合理的。然而，载体和表达抗原的转基因表达水平和免疫原性有待优化。本应用程序中提出的研究将测试各种修改，以增强该载体系统并进一步开发这种新型疫苗载体系统。在这项建议中，我们的具体目标是1。目的：通过验证d106增加HIV gag蛋白表达的假设，在HSV-1 d106株中构建改良的HSV-1重组疫苗载体

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.