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

描述（由申请人提供）：在我们对HIV感染中的体液和细胞免疫应答的理解方面已经取得了重大进展，但是尚未确定预防疾病进展的相关性。一些证据表明，尽管CD 8 + T细胞和中和抗体似乎在体外抑制病毒复制中起关键作用，但诱导这些反应的疫苗似乎不会诱导保护性免疫。HIV-1感染与严重的高丙种球蛋白血症有关。尽管诱导了这些大量的抗体，但广泛中和抗体似乎只在感染数年后才产生，并且似乎总是落后于同期感染病毒并且中和效果很差。然而，少数研究已经证明，除了中和抗体之外，可以诱导细胞溶解活性的非中和抗体，例如诱导抗体依赖性细胞毒性（ADCC）的那些抗体，也可以在控制HIV-1感染中发挥保护作用。ADCC诱导抗体早在急性HIV-1感染时就可检测到，可从粘膜部位分离，并独立于其他效应子功能与更好的疾病结局相关。此外，来自猿猴感染模型的新数据表明，中和抗体可以通过诱导ADCC活性在很大程度上引发其体内保护作用。然而，旨在确定ADCC在控制HIV-1感染中的作用的人体研究已在少数特征不明确的患者人群中进行，使用各种不同且无法比较的检测方法。考虑到ADCC与较慢的HIV-1疾病进展的关联，来自SIV模型的数据表明ADCC在预防感染中可能是重要的，ADCC诱导抗体引发和集中先天免疫系统细胞的效应子功能的能力，非中和Ab是柔性的并且可以靶向HIV包膜基因产物中的多个表位的事实，考虑到它们在其他感染和癌症模型中的免疫应答中的关键性质，以及通过疫苗接种可以容易地诱导抗体，具有细胞溶解功能的保护性抗体可能在抑制HIV-1复制中起关键作用是合理的。因此，我们必须开始确定溶细胞抗体的作用，以确定这些免疫应答的诱导是否可以改善体内HIV-1复制的控制。因此，本申请旨在全面定义溶细胞ADCC诱导抗体应答在HIV-1感染中的作用，并确定这些应答的诱导是否应该是我们设计有效疫苗的努力中的优先事项。公共卫生相关性：杀伤性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方面起着关键作用，但诱导这些反应的疫苗并不能诱导针对HIV-1疾病进展的保护。相比之下，早在急性HIV-1感染的患者中就已鉴定出非中和抗体，其通过抗体依赖性细胞毒性（ADCC）诱导先天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，并与更好的疾病结果显著相关。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包膜蛋白上的多个区域中的灵活性，以及它们在保护免受其他病原性感染和癌症中的关键作用，具有细胞溶解功能的抗体也可能在控制HIV-1复制中发挥核心作用。因此，本提案旨在确定ADCC在HIV- 1感染中的作用，以确定这些反应的产生是否应该是我们设计有效预防或治疗疫苗的优先事项。

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.