Development of a Vaccine for HIVAIDS: Cellular Immunity

我们正在寻求一种基于复制型腺病毒(Ad)重组体的HIV疫苗方法。这一理由是基于这样一个事实，即从历史上看，减毒活疫苗一直是最具保护性的，基本上可以诱导终身免疫。例子包括针对天花、小儿麻痹症、麻疹和黄热病的疫苗。我们在恒河猴身上进行临床前疫苗研究，并用SIV或SIV(一种包含HIV包膜的嵌合SIV病毒)挑战SIV或SIV，这是模拟人类感染HIV的系统。我们使用初始-增强策略，首先用携带HIV/SIV基因的复制型腺病毒(Ad)载体(S)免疫，然后用HIV/SIV包膜蛋白加强免疫。AD在粘膜诱导部位的上皮细胞中复制，因此在粘膜效应部位和血液中都能引起强烈的、持久的细胞免疫。我们目前正在对猕猴进行临床前疫苗研究，并正在研究疫苗方案引发的细胞免疫反应。特别令人感兴趣的问题是，雌性猕猴和雄性猕猴对疫苗成分是否产生了不同的细胞免疫反应，因为雌性猕猴比雄性猕猴表现出更好的保护效果。虽然在其他疫苗中也发现了性别差异，但这是第一次描述候选艾滋病疫苗的性别差异。我们还合作了一项研究，研究了复制能力强的Ad载体对先天和适应性细胞的反应，并发现免疫后先天免疫受到一定程度的抑制，而CD4+T细胞则被瞬时激活。由于非中和抗体反应已被证明是保护性疗效的贡献者，我们正在研究介导其中一些反应的效应细胞。我们继续探索之前被证明在控制SIV感染中发挥作用的CD4依赖的自然杀伤(NK)细胞。目前，我们正在研究在抗逆转录病毒治疗过程中是否可以通过包膜免疫来增强这种反应，以及接种疫苗是否会引起这种反应。NK细胞本身是抗体介导的细胞毒性的关键效应细胞，这种活性与疫苗诱导的保护效果有关。目前的研究包括确定恒河猴模型中的NK细胞是否有助于粘膜免疫保护，以及它们是否表现出记忆力。在粘膜免疫保护方面特别重要的效应细胞--伽马-德尔塔T细胞也在研究中。最后，T滤泡辅助细胞(TFH细胞)对于促进B细胞的发育和成熟以及诱导有效的抗体反应至关重要。我们正在研究疫苗接种对这类细胞发育的影响，这应该会导致记忆B细胞和更持久的抗体反应。

We are pursuing an HIV vaccine approach based on replication-competent Adenovirus (Ad)-recombinants. The rationale is based on the fact that live attenuated vaccines historically have been the most protective, eliciting essentially life-long immunity. Examples include vaccines for small pox, polio, measles, and yellow fever. We conduct pre-clinical vaccine studies in rhesus macaques and challenge with SIV or SHIV (a chimeric SIV virus containing an HIV envelope), systems that model HIV-infection of humans. We use a prime-boost strategy, first immunizing with a replicating adenovirus (Ad) vector carrying an HIV/SIV gene(s) followed by a boosting with HIV/SIV envelope protein. Ad replicates in epithelial cells that line mucosal inductive sites, and therefore elicits strong, persistent cellular immunity at mucosal effector sites as well as in the blood. We are currently conducting a pre-clinical vaccine study in macaques and are investigating cellular immune responses elicited by the vaccine regimen. Of particular interest is the question of whether female and male macaques developed different cellular immune responses to the vaccine components, as female macaques exhibited better protective efficacy compared to males. While sex differences have been seen with other vaccines, this is the first description of such a difference with a candidate AIDS vaccine. We have also collaborated on a study investigating innate and adaptive cellular responses to the replication-competent Ad vector, and have seen that innate immunity is somewhat suppressed while CD4-positive T cells are transiently activated following immunization. Because non-neutralizing antibody responses have been shown to be contributors to protective efficacy, we are studying effector cells which mediate some of these responses. We continue to explore CD4-dependent natural killer (NK) cells, previously shown to play a role in controlling SIV infection. Currently we are examining whether such responses can be boosted by envelope immunizations during the course of anti-retroviral therapy, and also whether vaccination elicits such responses. NK cells themselves are key effector cells in antibody-mediated cellular cytotoxicity, an activity that has been asociated with vaccine-elicited protective efficacy. Current studies include determining if NK cells in the rhesus macaque model contribute to mucosal immune protection and whether they exhibit memory. Gamma-delta T cells, effector cells that are especially important with regard to mucosal immune protection, are also under study. Finally T follicular helper cells (Tfh cells) are critical for promoting B cell development and maturation and induction of potent antibody responses. We are examining the effects of vaccination on development of such cells which should lead to memory B cells and more persistent antibody responses.