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（由申请方提供）：目前，使用猕猴评价HIV疫苗的有效性已表明，尽管许多类型的疫苗可以减弱致病性攻击病毒引起的急性感染，但没有疫苗可以可预测地预防感染以及伴随感染的病毒潜伏期的不可避免的建立。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反弹。经过多年的保护后，病毒突破的发生率越来越高，这表明可能有必要定期进行暴露后加强，以无限期地保持对病毒反弹的预防。考虑到这一点，我们研究了使用一种新型DNA疫苗的可行性，这种疫苗可以在接触致病性病毒后连续使用。我们选择SHIVku 2 DNA作为表达几种HIV基因的慢病毒载体，其中包括env和gag，可以定制以匹配任何特定HIV亚型的基因。疫苗骨架由驱动高复制能力SHIVku 2基因组表达的SIV启动子/增强子序列组成，其中rt、整合酶、vif和3 'LTR缺失（delta 4），rev和达特保留。概念验证已经显示，表达SIV gag和X4 HIV env的delta 4 DNA诱导针对异源X4 SHIV的保护，而没有病毒蛋白加强的益处，并且免疫可以在攻击后继续。然而，针对不同亚型的R5病毒的有效性的证明将需要表达这些病毒的env/gag的致病性SHIV的可用性。在本提案的目标1中，我们将通过将这些基因整合到高致病性SHIVku 2的基因组中来开发表达亚型B和C的患者分离株的env/gag的新致病性SHIV。然后，这些病毒将在目标3中用作挑战，以测试表达HIV亚型B和C的env和gag的新型delta 4 SHIV DNA疫苗的效力。我们将使用细胞因子GM-CSF和IL-15的DNA作为佐剂，以增强已经成功的DNA疫苗诱导的长期免疫的幅度和持续时间，这取决于目标2中的研究结果，其中小鼠将用于评估这些潜在的佐剂作用。然后，我们将扩展目标4中的研究参数，在目标4中，我们将确定可能用细胞因子佐剂加强的DNA疫苗是否可以在抗逆转录病毒治疗的掩护下用于免疫慢性感染的动物，以重新诱导在治疗期间减弱的免疫力。在药物治疗停止后，将继续加强疫苗接种。这些研究将适用于接受高效抗逆转录病毒疗法的艾滋病病毒感染者。