Development of a Vaccine for HIVAIDS: Cellular Immunity

我们正在寻求一种基于复制能力腺病毒（Ad）重组的HIV疫苗方法。其基本原理是基于这样一个事实，即减毒活疫苗历来是最具保护性的，基本上可以产生终身免疫。例子包括天花、脊髓灰质炎、麻疹和黄热病疫苗。我们在恒河猴中进行临床前疫苗研究，并用SIV或SHIV（一种含有HIV包膜的嵌合SIV病毒）进行挑战，这些系统模拟人类HIV感染。我们采用一种启动-增强策略，首先用携带HIV/SIV基因的复制腺病毒（Ad）载体进行免疫，然后用HIV/SIV包膜蛋白进行增强。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引发强烈、持久的细胞免疫。我们目前正在猕猴中进行临床前疫苗研究，并正在调查疫苗方案引起的细胞免疫反应。特别令人感兴趣的问题是，雌性和雄性猕猴是否对疫苗成分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功效。虽然在其他疫苗中发现了性别差异，但这是第一次描述艾滋病候选疫苗的这种差异。我们还合作进行了一项研究，调查先天和适应性细胞对复制能力强的Ad载体的反应，并发现先天免疫在一定程度上受到抑制，而cd4阳性T细胞在免疫后被短暂激活。由于非中和抗体反应已被证明是保护功效的贡献者，我们正在研究介导这些反应的效应细胞。我们继续探索cd4依赖的自然杀伤（NK）细胞，以前显示在控制SIV感染中发挥作用。目前，我们正在研究在抗逆转录病毒治疗过程中，包膜免疫是否能增强这种反应，以及疫苗接种是否能引起这种反应。NK细胞本身是抗体介导的细胞毒性的关键效应细胞，这种活性与疫苗引起的保护功效有关。目前的研究包括确定NK细胞在恒河猴模型中是否有助于粘膜免疫保护以及它们是否表现出记忆。γ - δ T细胞，在粘膜免疫保护方面特别重要的效应细胞，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些细胞发育的影响，这些细胞应该导致记忆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.