How did a vaccine enhance HIV acquisition

疫苗如何促进艾滋病毒感染

基本信息

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
项目类别：
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

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

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项目摘要

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（由适用提供）：迄今为止，已经完成了六项对候选HIV疫苗的人类有效试验。这些试验评估了四种不同的疫苗策略。在RV144试验中，评估了CanaryPox Prime，然后评估了CanaryPox和GP120包膜蛋白的增强。 RV144是唯一证明疫苗候选者可以预防艾滋病毒收购的试验，尽管保护是适度的。其他试验未能证明对艾滋病毒收购的任何保护。此外，在步骤和phambili试验中，接受疫苗的人比安慰剂感染更多的人更多，这表明HIV疫苗有可能增强对HIV感染的易感性。类似地，与未免疫化的恒河猕猴更容易受到Penile SIV感染感染的鼠尾草猕猴长期感染了AD5，然后免疫抑制AD5 SIVMAC239 GAG-POL-NEF疫苗更容易受到Penile SIV感染的影响。我们将使用这种动物模型来了解HIV疫苗如何增强HIV的获取。特别是我们将确定1）AD5在Forestkin的组织中是否持久导致T细胞募集增加并保留在3 AD5载体免疫中的扩增； 2）如果AD5感染的RM在免疫抑制至AD5-RM后，森林金的活化CD4+ T细胞/Th17细胞数量增加； 3）与AD5-RM相比，IFAD5感染的RM具有更多的AD5特异性CD4+ T细胞和SIV特异性的CD4+ T细胞。 4）如果被AD5感染的RM具有更多的先天免疫信号，这些信号来自上皮细胞，DC和森林中的其他人，则在免疫抑制至AD5-RM后驱动T细胞募集和生存。了解跨步道中疫苗增强的HIV敏感性背后的基本机制将使该领域避免测试人中有害的HIV疫苗。