Development of a Vaccine for HIVAIDS: Cellular Immunity

HIV/艾滋病疫苗的开发：细胞免疫

• 批准号: 7733459
• 负责人: Marjorie Robert-Guroff
• 金额: $ 126.66万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733459
• 关键词: Adenovirus Vector; Adenoviruses; Adjuvant; Animal Model; Antibodies; Antibody Formation; Area; Blood; Cell Line; Cells; Cellular Immunity; Combined Vaccines; Epithelial Cells; Genes; Goals; HIV; HIV vaccine; Haplotypes; Homing; Host Defense Mechanism; Human Adenoviruses; Immune; Immune response; Immunization; Intestines; Investigation; Knowledge; Location; MHC Class I Genes; Macaca; Oral; Preventive; Production; SIV; Secondary Immunization; Site; Surface; T memory cell; Time; Treatment Protocols; Upper respiratory tract; Vaccine Design; Vaccines; Virus; Virus Diseases; base; cytokine; design; env Gene Products; immunogenic; mucosal site; preclinical study; prevent; receptor; response; simian human immunodeficiency virus; trafficking; transmission process; vaccine development; viral DNA; virus envelope

Our HIV vaccine approach is based on initial immunization with a replicating adenovirus (Ad) vector carrying an HIV gene(s) followed by a booster immunization with an HIV envelope protein. The Ad-HIV vaccine replicates in epithelial cells that line mucosal inductive sites, thus eliciting strong, persistent cellular immunity at mucosal effector sites as well as in the blood. We have shown that initial immunizations with an Ad-HIV vaccine also stimulates production of anti-HIV antibodies. Together, the regimen induces strong and durable protective responses. We have demonstrated that administration of Ad-HIV vaccine to the upper respiratory tract as well as to the gut (by oral immunization) elicits memory T cells that possess "homing receptors" leading them to traffic to the intestine, a prime site of HIV infection. Thus the vaccine approach elicits cellular immunity at a location critical for preventing or controlling HIV infection. Investigation of combination vaccine approaches using HIV DNA vaccines combined with cytokine adjuvants followed by Ad-HIV vaccine and envelope protein boosting showed them to be immunogenic. The study highlighted several areas that could be optimized for greater protective efficacy against HIV infection. A pre-clinical study in cynomolgus macaques of Mauritian origin identified MHC class I haplotypes associated with natural protection against challenge with a simian immunodeficiency virus (SIV)-HIV chimeric virus (SHIV). These results will enable better design of vaccine studies in this animal model. Further, investigation of such natural host defense mechanisms may suggest new avenues to be exploited for preventive HIV strategies.

我们的 HIV 疫苗方法基于使用携带 HIV 基因的复制腺病毒 (Ad) 载体进行初始免疫，然后使用 HIV 包膜蛋白进行加强免疫。 Ad-HIV 疫苗在粘膜诱导位点的上皮细胞中复制，从而在粘膜效应位点以及血液中引发强烈、持久的细胞免疫。我们已经证明，使用 Ad-HIV 疫苗进行初始免疫也能刺激抗 HIV 抗体的产生。总之，该方案会引起强烈而持久的保护反应。我们已经证明，对上呼吸道和肠道（通过口服免疫）注射 Ad-HIV 疫苗会引发记忆 T 细胞，这些细胞拥有“归巢受体”，导致它们运输到肠道，这是 HIV 感染的主要部位。因此，疫苗方法在预防或控制艾滋病毒感染的关键部位引发细胞免疫。使用 HIV DNA 疫苗与细胞因子佐剂相结合，然后使用 Ad-HIV 疫苗和包膜蛋白加强联合疫苗方法的研究表明，它们具有免疫原性。该研究强调了几个可以优化的领域，以提高针对艾滋病毒感染的保护效果。一项针对毛里求斯食蟹猴的临床前研究发现，MHC I 类单倍型与针对猿猴免疫缺陷病毒 (SIV)-HIV 嵌合病毒 (SHIV) 攻击的天然保护作用相关。这些结果将有助于更好地设计该动物模型中的疫苗研究。 此外，对这种自然宿主防御机制的研究可能会为预防艾滋病毒策略提供新的途径。