Development of a Vaccine for HIVAIDS: Cellular Immunity

我们的艾滋病毒疫苗方法是基于携带艾滋病毒基因(S)的复制型腺病毒(Ad)载体的初始免疫，然后用艾滋病毒包膜蛋白加强免疫。Ad-HIV疫苗在黏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激发强大的、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能刺激抗HIV抗体的产生。总而言之，这种疗法可以诱导强烈而持久的保护性反应。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，肠道是HIV感染的主要部位。因此，疫苗方法在对预防或控制艾滋病毒感染至关重要的位置引起细胞免疫。对使用HIV DNA疫苗和细胞因子佐剂，然后是Ad-HIV疫苗和包膜蛋白增强的组合疫苗方法的研究表明，它们具有免疫原性。这项研究强调了几个可以优化的领域，以更好地预防艾滋病毒感染。一项对起源于毛里求斯的食蟹猴的临床前研究确定了MHC I类单倍型与抵抗猴免疫缺陷病毒(SIV)-艾滋病毒嵌合病毒(SHIV)攻击的自然保护相关。这些结果将使在该动物模型中更好地设计疫苗研究成为可能。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战略提供新的途径。

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.