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。尽管经过了30多年的共同努力，迄今为止没有一种艾滋病毒候选疫苗显示出有意义的能力来预防每年近200万新感染。由于药物滥用对整体健康的负面影响以及与成瘾有关的高风险行为，药物滥用者感染艾滋病毒的危险更大。因此，显然需要采取革命性的方法来研制一种预防性艾滋病毒疫苗，以减轻药物滥用造成的艾滋病负担。尽管对HIV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细胞介导的细胞毒性（ADCC）的抗体被广泛认为是成功的HIV预防性疫苗的关键组成部分。然而，广泛中和抗体（bnAbs）在hiv感染人群中相对罕见，并且通常在感染的很晚才出现。此外，对hiv特异性bnAbs的详细分析揭示了生殖系免疫球蛋白序列的大量突变，表明持续、确定的生发中心反应可能需要促进hiv特异性抗男孩反应的充分亲和成熟。一个有效的生发中心反应依赖于卵泡辅助CD4 T细胞（TFH）的一个特殊亚群，它支持B细胞增殖和体细胞超突变。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。自然杀伤细胞（NK）通常被认为主要通过裂解病毒感染细胞来促进抗病毒免疫。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细胞介导的杀伤活化的CD4 T细胞使病毒特异性CD8 T细胞变得功能衰竭，从而有利于宿主生存和持续的病毒感染，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，并显著促进了病毒特异性中和抗体的延迟和弱诱导。综上所述，我们的研究结果支持了组织假说，即规避NK细胞免疫调节活性的创造性策略代表了开发有效HIV疫苗的根本创新方法。该应用程序的目的是获得一个明确的机制理解的贡献，一种新的NK细胞免疫调节功能，以控制疫苗接种后保护性免疫的发展。从长远来看，在这项建议中获得的发现应该对设计控制艾滋病毒/艾滋病流行的下一代疫苗具有变革性。

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.