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: 7242607
• 负责人: Edward Brice Stephens
• 金额: $ 62.22万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7242607
• 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，使用猕猴评估HIV疫苗的功效表明，尽管多种类型的疫苗可以通过致病性挑战病毒来束缚急性感染，但没有疫苗可以预测地预测感染和不可避免地建立伴随感染的病毒潜伏期。因此，疫苗的负担是维持保护性反应，以防止病毒从潜在感染细胞中反弹。经过多年的保护后，病毒突破的发生率的增加表明，可能有必要定期进行暴露后提升，以无限期地保持预防病毒反弹。考虑到这一点，我们研究了使用一种新型的DNA疫苗的可行性，该疫苗可以预防性使用并在暴露于致病性病毒后继续使用。我们选择了Shivku2 DNA作为表达几种HIV基因的慢病毒载体，其中可以量身定制以匹配任何特定HIV亚型的基因。疫苗主链由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，从中删除了RT，Integrase，VIF和3'LTR（Delta4），Rev和Rev和Tat保留。概念证明表明，表达SIV GAG和X4 HIV ENV的DELTA4 DNA诱导了针对异源X4 SHIV的保护，而无需促进病毒蛋白的益处，并且在挑战挑战后可以继续进行免疫接种。但是，针对不同亚型的R5病毒的疗效证明将需要表达这些病毒的ENV/GAG的致病性SHIV。在该提案的目标1中，我们将开发新的致病性SHIV，通过将这些基因纳入高度致病性Shivku2的基因组中来表达亚型B和C的患者分离株的ENV/GAG。然后，这些病毒将在目标3中用作测试新的Delta4 SHIV DNA疫苗的挑战，表达HIV亚型的Env和gag b andC的堵嘴。我们将使用细胞因子GM-CSF和IL-15的DNA作为辅助物质的DNA，以增强已经成功的DNA效果的长期降低和持续时间，以促进DNA液的长度和持续时间。这些潜在的辅助作用。然后，我们将在AIM 4中扩展研究参数，在那里我们将确定可能使用细胞因子辅助剂加强的DNA疫苗可用于在抗逆转录病毒疗法的覆盖范围内免疫长期感染的动物，以重新诱导治疗期间会减弱的免疫力。撤离药物治疗后，疫苗将继续促进。这些研究将适用于HAART领导下的艾滋病毒感染者。