A revolutionary vaccine approach to prevent HIV infection in substance abuse

描述：持续的艾滋病毒/艾滋病大流行已导致全球6000多万人感染，3000多万人死亡。尽管经过30多年的共同努力，迄今为止还没有任何艾滋病毒候选疫苗显示出有意义的能力来预防每年近200万的新感染。由于药物滥用对总体健康的负面影响以及与成瘾相关的高风险行为，药物滥用者感染艾滋病毒的风险更高。因此，显然需要采取革命性的方法来开发预防性艾滋病毒疫苗，以减轻药物滥用中艾滋病的负担。尽管针对HIV的有效免疫的确切相关性仍然难以捉摸，但可以介导广泛中和活性或抗体依赖性细胞介导的细胞毒性（ADCC）的抗体被广泛认为是成功的针对HIV的预防性疫苗的关键组分。然而，广泛中和抗体（bnAb）在HIV感染人群中相对罕见，通常在感染后期出现。此外，对HIV特异性bnAb的详细分析揭示了生殖系免疫球蛋白序列的大量突变，表明可能需要持续的、确定的生殖细胞中心应答来促进HIV特异性抗boy应答的充分亲和力成熟。有效的生发中心应答依赖于支持B细胞增殖和体细胞超变的滤泡辅助性CD 4 T细胞（TFH）的特化亚群。因此，对限制生发中心效率的宿主和病毒机制的更好理解应该能够设计出更有效的HIV疫苗。自然杀伤（NK）细胞被经典地认为主要通过裂解病毒感染的细胞而有助于抗病毒免疫。然而，我们最近证明，NK细胞在小鼠慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染的背景下发挥重要的调节作用。NK细胞介导的活化的CD 4 T细胞的杀伤使病毒特异性CD 8 T细胞倾向于功能耗尽，从而有利于宿主存活和持续的病毒感染，而不是致命的免疫病理。最近，我们发现NK细胞也限制了急性LCMV感染后的生发中心反应，并显著导致病毒特异性中和抗体的延迟和弱诱导。总之，我们的研究结果支持了组织假设，即规避NK细胞的这种免疫调节活性的发明策略代表了开发有效HIV疫苗的根本创新方法。本申请的目的是获得对新型NK细胞免疫调节功能对控制疫苗接种后保护性免疫发展的贡献的明确机制理解。从长远来看，该提案中获得的研究结果对于设计控制艾滋病毒/艾滋病流行病的下一代疫苗应该是变革性的。

DESCRIPTION: The ongoing HIV/AIDS pandemic has resulted in more than 60 million infections worldwide and left more than 30 million people dead. Despite more than 30 years of concerted efforts, no HIV vaccine candidate to date has demonstrated a meaningful capacity to prevent the nearly 2 million new infections each year. Drug abusers are at heightened peril for acquisition of HIV by virtue of the negative consequences of drug abuse on overall health and the high risk behaviors associated with addiction. Thus, there is a clear need for revolutionary approaches to the development of a preventative HIV vaccine to reduce the burden of AIDS in drug abuse. Although the exact correlates of effective immunity against HIV remain elusive, antibodies that can mediate broad neutralizing activity or antibody-dependent cell-mediated cytotoxicity (ADCC) are widely considered to be critical components of a successful preventative vaccine against HIV. However, broadly neutralizing antibodies (bnAbs) are relatively rare in the HIV-infected population, and usually appear very late in infection. Moreover, a detailed analysis of HIV-specific bnAbs reveals substantial mutation from the germ line immunoglobulin sequence, indicating that a sustained, determined germinal center response is likely required to facilitate sufficient affinity maturation of the HIV-specific antiboy response. An efficient germinal center response depends upon a specialized subset of follicular helper CD4 T cells (TFH), which support B cell proliferation and somatic hypermutation. Thus, an improved understanding of host and viral mechanisms that limit germinal center efficiency should enable design of more efficacious HIV vaccines. Natural killer (NK) cells are classically thought to primarily contribute to antiviral immunity through lysis of virus- infected cells. However, we recently demonstrated that NK cells play a vital regulatory role in the context of chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. NK cell-mediated killing of activated CD4 T cells predisposed virus-specific CD8 T cell to become functionally exhausted, thereby favoring host survival and persistent virus infection rather than fatal immune pathology. More recently, we found that NK cells also restrict the germinal center response after acute LCMV infection and significantly contribute to the delayed and weak induction of virus-specific neutralizing antibodies. Taken together, our findings support the organizing hypothesis that inventive strategies to circumvent this immunoregulatory activity of NK cells represent a radically innovative approach to the development of an efficacious HIV vaccine. The goal of this application is to gain a clear mechanistic understanding of the contribution of a novel NK cell immunoregulatory function to controlling development of protective immunity after vaccination. In the long-term, the findings obtained in this proposal should be transformative with regards to the design of a next-generation vaccine to control the HIV/AIDS epidemic.