How did a vaccine enhance HIV acquisition

疫苗如何促进艾滋病毒感染

• 批准号: 9089944
• 负责人: CHRISTOPHER James MILLER
• 金额: $ 69.2万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089944
• 关键词: Acquired Immunodeficiency Syndrome; Adenovirus Vector; Adenoviruses; Animal Model; Animals; Antigens; Antiviral Agents; Biological Markers; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Dose; Enrollment; Epithelial Cells; Equilibrium; Futility; Goals; HIV; HIV Antigens; HIV Envelope Protein gp120; HIV Infections; HIV Vaccine Trials Network; HIV vaccine; HIV-1; Health; Heterosexuals; Homing; Human; Immune; Immune response; Immunity; Immunization; Infection; Irrigation; Macaca mulatta; Mediating; Modeling; Monkeys; Participant; Placebos; Population; Predisposition; Proteome; Risk; Role; SIV; SIV Vaccines; Sampling; Serotyping; Signal Transduction; Subgroup; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; Vaccinated; Vaccination; Vaccines; Viral Load result; Virus; efficacy trial; env Gene Products; follow-up; male; meetings; men; men who have sex with men; nonhuman primate; pandemic disease; penis foreskin; plasmid DNA; prevent; recombinant adenovirus; research study; seropositive; transmission process; vaccine candidate; vector

 DESCRIPTION (provided by applicant): To date, six human efficacy trials of candidate HIV vaccines have been completed. These trials have evaluated four different vaccine strategies have been completed. In the RV144 Thai trial a canarypox prime followed by boosts with canarypox and gp120 envelope protein were evaluated. Rv144 is the only trial to demonstrate that a vaccine candidate can protect against HIV acquisition, although protection was modest. The other trials failed to demonstrate any protection against HIV acquisition. Further, in the STEP and Phambili trials more people receiving the vaccine than the placebo became infected, demonstrating that the HIV vaccines have the potential to enhance susceptibility to HIV infection. Similarly, rhesus macaques chronically infected with Ad5 and then immunized with a replication defective Ad5 SIVmac239 Gag-Pol-Nef vaccine were more susceptible to penile SIV infection than unimmunized rhesus macaques. We will use this animal model to understand how an HIV vaccine enhanced HIV acquisition. In particular we will determine 1) if Ad5 persistence in tissues of the foreskin leads to increased T cell recruitment to, and retention in, that is amplifid by 3 Ad5 vector immunizations; 2) if Ad5 infected RM have increased numbers of activated CD4+ T cells/TH17 cells in the foreskin after immunization compared to Ad5- RM; 3) ifAd5 infected RM have more Ad5 specific CD4+ T cells and SIV-specific CD4+ T cells in the foreskin after immunization compared to Ad5- RM; 4) if Ad5 infected RM have more innate immune signals emanating from epithelial cells, DC and others in the foreskin that drive T cell recruitment and survival after immunization compared to Ad5- RM. Understanding the underlying mechanisms behind the vaccine-enhanced HIV susceptibility in the STEP trail will allow the field to avoid testing harmful HIV vaccines in people.

 描述(由申请人提供)：到目前为止，已经完成了六项候选艾滋病毒疫苗的人体功效试验。这些试验评估了四种不同的疫苗策略已经完成。在RV144泰国试验中，评估了金丝雀痘原液，然后是金丝雀痘和gp120包膜蛋白的强化接种。RV144是唯一一项证明候选疫苗可以预防艾滋病毒感染的试验，尽管保护力度不大。其他试验未能证明对感染艾滋病毒有任何保护作用。此外，在STEP和Phambili试验中，接受疫苗接种的人比服用安慰剂的人更多被感染，这表明艾滋病毒疫苗有可能增加对艾滋病毒感染的易感性。类似地，长期感染Ad5的恒河猴，然后用复制缺陷的Ad5 SIVmac239 Gag-Pol-Nef疫苗免疫的恒河猴比未免疫的恒河猴更容易感染阴茎SIV。我们将使用这个动物模型来了解艾滋病毒疫苗是如何促进艾滋病毒感染的。特别是，我们将确定1)Ad5在包皮组织中的持续存在是否导致T细胞在包皮组织中的募集和滞留增加，即通过3次Ad5载体免疫而扩增；2)与Ad5-RM相比，Ad5感染的RM在包皮中是否有更多激活的CD4+T细胞/TH17细胞；3)与Ad5-RM相比，Ad5感染的RM在包皮中是否有更多的Ad5特异性的CD4+T细胞和SIV特异性的CD4+T细胞；4)与Ad5-RM相比，Ad5感染的RM是否有更多的天然免疫信号来自包皮中的上皮细胞、DC和其他细胞，从而推动T细胞的招募和存活。在STEP试验中了解疫苗增强艾滋病毒易感性背后的潜在机制将使该领域能够避免在人体内测试有害的艾滋病毒疫苗。