Development of a Vaccine for HIVAIDS: Cellular Immunity

我们的HIV疫苗方法是基于携带HIV基因的复制腺病毒（Ad）载体的初始免疫，然后是HIV包膜蛋白的加强免疫。Ad-HIV疫苗在粘膜诱导部位的上皮细胞中复制，从而在粘膜效应部位和血液中引发强烈、持久的细胞免疫。我们已经证明，用Ad-HIV疫苗进行初始免疫也会刺激抗hiv抗体的产生。总之，这一疗法会引起强烈而持久的保护反应。我们已经证明，将Ad-HIV疫苗注射到上呼吸道和肠道（通过口服免疫）会引起具有“归巢受体”的记忆T细胞，使它们进入肠道，这是HIV感染的主要部位。因此，疫苗方法在预防或控制HIV感染的关键部位引发细胞免疫。对HIV DNA疫苗联合细胞因子佐剂、Ad-HIV疫苗和包膜蛋白增强联合疫苗的研究表明，它们具有免疫原性。这项研究强调了几个可以优化的领域，以提高对艾滋病毒感染的保护功效。一项针对毛里求斯原产食蟹猴的临床前研究发现，MHC I类单倍型与猴免疫缺陷病毒(SIV)-HIV嵌合病毒（SHIV）的自然保护作用相关。这些结果将有助于在这种动物模型中更好地设计疫苗研究。此外，对这种天然宿主防御机制的研究可能为预防艾滋病毒的策略提供新的途径。

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.