Cytolytic antibodies:Bridging the gap between the innate and adaptive immune resp

描述（由申请人提供）：我们对HIV感染中的体液和细胞免疫反应的理解取得了重大进展，但预防疾病进展的相关因素仍未确定。一些证据表明，尽管CD8+ T细胞和中和抗体似乎在体外抑制病毒复制中发挥关键作用，但诱导这些反应的疫苗似乎不能诱导保护性免疫。HIV-1感染与显著的高γ -球蛋白血症有关。尽管诱导了这些大量的抗体，但广泛中和的抗体似乎只在感染数年后才产生，而且似乎总是落后于同时感染的病毒，并且很难中和。然而，少数研究表明，除了中和抗体外，可以诱导细胞溶解活性的非中和抗体，例如那些诱导抗体依赖性细胞毒性（ADCC）的抗体，也可能在控制HIV-1感染中发挥保护作用。ADCC诱导抗体早在急性HIV-1感染时就可以检测到，可以从粘膜部位分离出来，并且独立于其他效应功能与更好的疾病预后相关。此外，来自猿类感染模型的新数据表明，中和抗体可能主要通过诱导ADCC活性在体内发挥其保护作用。然而，旨在确定ADCC在控制HIV-1感染中的作用的人体研究，已经在少数特征不明确的患者群体中进行，使用了多种和无与伦比的测定方法。鉴于ADCC与HIV-1疾病进展缓慢的关联，来自SIV模型的数据表明，ADCC可能在预防感染、ADCC诱导抗体引发和聚焦先天免疫系统细胞效应功能的能力、非中和抗体具有灵活性并可靶向HIV包膜基因产物中的多个表位的事实、它们在其他感染和癌症模型背景下的免疫反应中的关键性质等方面发挥重要作用。而且通过接种疫苗诱导抗体很容易，因此具有细胞溶解功能的保护性抗体可能在抑制HIV-1复制中发挥关键作用。因此，我们必须开始确定细胞溶解抗体的作用，以确定这些免疫反应的诱导是否可以改善体内HIV-1复制的控制。因此，本应用旨在全面定义细胞溶解ADCC在HIV-1感染中诱导抗体反应的作用，并确定在我们设计有效疫苗的努力中是否应优先诱导这些反应。公共卫生相关性：杀伤T细胞和阻断病毒感染的抗体（中和抗体）似乎在体外抑制病毒复制中发挥关键作用，但诱导这些反应的疫苗并不能诱导对HIV-1疾病进展的保护。相比之下，非中和抗体通过抗体依赖性细胞毒性（ADCC）诱导固有免疫系统细胞的细胞溶解活性，将适应性（B细胞）与先天免疫应答连接起来，早在急性HIV-1感染患者中就已被发现，并与更好的疾病预后显著相关。鉴于非中和抗体在减缓HIV-1疾病进展中的关键性质，它们在靶向HIV包膜蛋白上多个区域的灵活性，以及它们在防止其他致病性感染和癌症方面的关键作用，具有细胞溶解功能的抗体可能在控制HIV-1复制中也发挥核心作用。因此，本提案旨在确定ADCC在HIV- 1感染中的作用，以确定在我们设计有效的预防性或治疗性疫苗的努力中，是否应该优先考虑这些反应的产生。

DESCRIPTION (provided by applicant): Significant advances have been achieved in our understanding of both the humoral and cellular immune response in HIV infection, however the correlates of protection against disease progression have still not been defined. Several lines of evidence suggest that although both CD8+ T cells and neutralizing antibodies seem to play a critical role in suppressing viral replication in vitro, vaccines that induce these responses do not seem to induce protective immunity. HIV-1 infection is associated with a dramatic hypergammaglobulinemia. Despite the induction of these large quantities of antibodies, broadly neutralizing antibodies only seem to develop following years of infection, and always seem to lag behind and poorly neutralize the contemporaneous infecting virus. However a small number of studies have demonstrated that in addition to neutralizing antibodies, non-neutralizing antibodies that can induce cytolytic activity, such as those that induce antibody-dependent cellular cytotoxicity (ADCC), may also play a protective role in the control of HIV-1 infection. ADCC inducing antibodies are detectable as early as acute HIV-1 infection, can be isolated from mucosal sites, and correlate independently of other effector functions with better disease outcome. Furthermore, novel data from the simian model of infection suggests that neutralizing antibodies may largely elicit their protective role in vivo via the induction of ADCC activity. However human studies, aimed at defining the role of ADCC in the control of HIV-1 infection, have been performed on small numbers of poorly characterized patient populations, using varied and incomparable assays. Given the association of ADCC with slower HIV-1 disease progression, data from the SIV model demonstrating that ADCC may be important in preventing infection, the capacity of ADCC inducing antibodies to elicit and focus the effector functions of cells of the innate immune system, the fact that non-neutralizing Abs are flexible and can target multiple epitopes in the HIV envelope gene products, their critical nature in the immune response in the context of other infections and cancer models, and the ease with which antibodies can be induced via vaccination, it is plausible that protective antibodies with cytolytic functions could play a critical role in containing HIV-1 replication. It is therefore imperative that we begin to define the role of cytolytic antibodies to determine whether the induction of these immune responses can improve control of HIV-1 replication in vivo. Thus this application aims to comprehensively define the role of cytolytic ADCC inducing antibody responses in HIV-1 infection and to determine whether the induction of these responses should be a priority in our efforts to design an effective vaccine. PUBLIC HEALTH RELEVANCE: Both killer- T cells and antibodies that block viral infection (neutralizing antibodies) seem to play a critical role in suppressing viral replication in vitro, but vaccines that induce these responses do not induce protection against HIV-1 disease progression. In contrast, non-neutralizing antibodies that bridge the adaptive (B cells) to the innate immune response, via the induction of cytolytic activity by cells of the innate immune system by antibody dependent cellular cytotoxicity (ADCC), have been identified in patients as early as acute HIV-1 infection and correlate significantly with better disease outcome. Given the critical nature of non-neutralizing antibodies in slower HIV-1 disease progression, their flexibility in targeting multiple regions on the HIV envelope protein, as well as their critical role in protection against other pathogenic infections and cancers, it is plausible that antibodies with cytolytic functions could play a central role in controlling HIV-1 replication as well. This proposal therefore aims to define the role of ADCC in HIV- 1 infection to determine whether the generation of these responses should be a priority in our efforts to design an effective prophylactic or therapeutic vaccine.