A New DNA Vaccine Against HIV Disease in Macaques

一种针对猕猴 HIV 疾病的新型 DNA 疫苗

• 批准号: 7433286
• 负责人: Edward Brice Stephens
• 金额: $ 48.44万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7433286
• 关键词: Acute; Adjuvant; Animals; Appearance; Automobile Driving; Cells; DNA; DNA Fingerprinting; DNA Vaccines; Disease; Enhancers; Exposure to; Gagging; Genes; Genome; Granulocyte-Macrophage Colony-Stimulating Factor; HIV; HIV vaccine; Highly Active Antiretroviral Therapy; Immune response; Immunity; Immunization; Incidence; Infection; Infection prevention; Integrase; Interleukin-15; Lentivirus Vector; Macaca; Mind; Mus; Numbers; Pathogenicity; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmacotherapy; Prevention; Protocols documentation; SIV; Signal Transduction; Specificity; Staging; Testing; Therapeutic; Vaccination; Vaccines; Vertebral column; Viral Proteins; Virus; Virus Latency; Virus Replication; antiretroviral therapy; concept; cytokine; drug withdrawal; indexing; latent infection; pinacolyl methylphosphonic acid; prevent; programs; promoter; response; simian human immunodeficiency virus; time interval

DESCRIPTION (provided by applicant): Currently, use of macaques to evaluate efficacy of HIV vaccines has shown that although numerous types of vaccines can blunt acute infections by pathogenic challenge viruses, no vaccine can predictably prevent infection and the inevitable establishment of viral latency that accompanies the infection. The burden on the vaccine therefore is to maintain protective responses to prevent rebound of the virus from latently infected cells. The increasing incidence of virus breakthroughs after years of protection suggests that it may be necessary to administer post-exposure boosts at regular intervals in order to indefinitely maintain prevention of virus rebound. With this in mind, we investigated the feasibility of using a new type of DNA vaccine that could be used prophylactically and continued after exposure to pathogenic virus. We chose SHIVku2 DNA as a lentiviral vector that expresses several HIV genes, among which are the env and gag that can be tailored to match the genes of any particular subtype of HIV. The vaccine backbone consists of SIV promoter/enhancer sequences driving expression of the high-replication-competent SHIVku2 genome from which the rt, integrase, vif, and 3 'LTR were deleted (delta4), and the rev and tat retained. Proof of concept has shown that the delta4 DNA expressing SIV gag and X4 HIV env induced protection against heterologous X4 SHIV without the benefit of viral protein boosts and that immunization could be continued following challenge. However, proof of efficacy against R5 viruses of different subtypes would require availability of pathogenic SHIVs expressing the env/gag of these viruses. In Aim 1 of this proposal, we will develop new pathogenic SHIVs that express the env/gag of patient isolates of subtypes B and C by incorporating these genes into the genome of highly pathogenic SHIVku2. These viruses will then be used in Aim 3 as challenge to test the efficacy of new delta4 SHIV DNA vaccines expressing env and gag of HIV subtypes B and C. We will use DNAs of cytokines GM-CSF and IL-15 as adjuvants to boost the magnitude and duration of long term immunity induced by the already successful DNA vaccine, depending on results of studies in Aim 2, in which mice will be used to assess these potential adjuvanting effects. We will then extend the study parameters in Aim 4, where we will determine whether the DNA vaccine, possibly strengthened with the cytokine adjuvants, can be used to immunize chronically infected animals under the cover of antiretroviral therapy, to re-induce immunity that would have waned during therapy. Vaccine boosts will continue after drug therapy had been withdrawn. These studies will be applicable to HIV infected persons under HAART.

描述（由申请人提供）：目前，使用猕猴来评估 HIV 疫苗的功效表明，尽管多种类型的疫苗可以减弱致病性攻击病毒的急性感染，但没有疫苗可以预测性地预防感染以及随之而来的不可避免的病毒潜伏期的建立感染。因此，疫苗的负担是维持保护性反应，以防止病毒从潜伏感染的细胞中反弹。经过多年的保护后，病毒突破的发生率不断增加，这表明可能有必要定期进行暴露后加强，以无限期地维持对病毒反弹的预防。考虑到这一点，我们研究了使用新型 DNA 疫苗的可行性，这种疫苗可以预防性使用，并在接触致病病毒后继续使用。我们选择 SHIVku2 DNA 作为表达多个 HIV 基因的慢病毒载体，其中包括可定制以匹配任何特定 HIV 亚型基因的 env 和 gag。疫苗骨架由 SIV 启动子/增强子序列组成，驱动具有高复制能力的 SHIVku2 基因组的表达，其中删除了 rt、整合酶、vif 和 3'LTR (delta4)，并保留了 rev 和 tat。概念验证表明，表达 SIV gag 和 X4 HIV env 的 delta4 DNA 诱导针对异源 X4 SHIV 的保护，而无需病毒蛋白增强的益处，并且在攻击后可以继续免疫。然而，要证明针对不同亚型的 R5 病毒的功效，需要获得表达这些病毒的 env/gag 的致病性 SHIV。在本提案的目标 1 中，我们将开发新的致病性 SHIV，通过将这些基因整合到高致病性 SHIVku2 的基因组中，表达 B 和 C 亚型患者分离株的 env/gag。然后，这些病毒将在目标 3 中用作挑战，以测试表达 HIV B 和 C 亚型的 env 和 gag 的新型 delta4 SHIV DNA 疫苗的功效。我们将使用细胞因子 GM-CSF 和 IL-15 的 DNA 作为佐剂来增强已经成功的 DNA 疫苗诱导的长期免疫的强度和持续时间，取决于目标 2 的研究结果，其中将使用小鼠来评估这些潜在的佐剂效应。然后，我们将扩展目标 4 中的研究参数，其中我们将确定 DNA 疫苗（可能用细胞因子佐剂增强）是否可用于在抗逆转录病毒治疗的掩护下对慢性感染动物进行免疫，以重新诱导免疫力治疗期间减弱。药物治疗取消后，疫苗加强接种仍将继续。这些研究将适用于HAART 治疗下的HIV 感染者。