本帖最后由 marine0425030 于 2015-4-28 18:13 编辑
多谢ipsvirus 兄发帖，我也来个锦上添花之举吧。
那么就先来说说这个VIP(vectored immunoprophylaxis)的概念吧。利用腺伴随病毒（adeno associated virus,AAV）作为载体将表达HIV中和抗体的基因运送到肌肉组织中，让其不断的产生抗体从而可以中和前来进犯的病毒们。
这个概念很多人都说是诺贝尔奖获得者加州理工的David Baltimore教授开发的，也有一部分说不是，这个是由费城儿童医院的Phillip Johnson开发的。
好吧，反正不是我开发的。目前，费城儿童医院和美国NIAID也正在进行临床一期试验的，他们用AAV1表达一种光谱抗体PG9。不过目前还没发布任何试验结果，网页上写着预期2016年吧。
咱就看看回顾下之前发过的主要文章吧。
1. Nature Medicine 15, 901 - 906 (2009)
Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys
Philip R Johnson1, Bruce C Schnepp1, Jianchao Zhang2, Mary J Connell1, Sean M Greene1, Eloisa Yuste3, Ronald C Desrosiers3 & K Reed Clark2
AbstractThe key to an effective HIV vaccine is development of an immunogen that elicits persisting antibodies with broad neutralizing activity against field strains of the virus. Unfortunately, very little progress has been made in finding or designing such immunogens. Using the simian immunodeficiency virus (SIV) model, we have taken a markedly different approach: delivery to muscle of an adeno-associated virus gene transfer vector expressing antibodies or antibody-like immunoadhesins having predetermined SIV specificity. With this approach, SIV-specific molecules are endogenously synthesized in myofibers and passively distributed to the circulatory system. Using such an approach in monkeys, we have now generated long-lasting neutralizing activity in serum and have observed complete protection against intravenous challenge with virulent SIV. In essence, this strategy bypasses the adaptive immune system and holds considerable promise as a unique approach to an effective HIV vaccine.
2.Nature,481,81–84 (05 January 2012) Antibody-based protection against HIV infection by vectored immunoprophylaxis
Alejandro B. Balazs, Joyce Chen,Christin M. Hong,Dinesh S. Rao,Lili Yang & David Baltimore
Despite tremendous efforts, development of an effective vaccine against human immunodeficiency virus (HIV) has proved an elusive goal. Recently, however, numerous antibodies have been identified that are capable of neutralizing most circulating HIV strains1, 2, 3, 4, 5. These antibodies all exhibit an unusually high level of somatic mutation6, presumably owing to extensive affinity maturation over the course of continuous exposure to an evolving antigen7. Although substantial effort has focused on the design of immunogens capable of eliciting antibodies de novo that would target similar epitopes8, 9,10, it remains uncertain whether a conventional vaccine will be able to elicit analogues of the existing broadly neutralizing antibodies. As an alternative to immunization, vector-mediated gene transfer could be used to engineer secretion of the existing broadly neutralizing antibodies into the circulation. Here we describe a practical implementation of this approach, which we call vectored immunoprophylaxis (VIP), which in mice induces lifelong expression of these monoclonal antibodies at high concentrations from a single intramuscular injection. This is achieved using a specialized adeno-associated virus vector optimized for the production of full-length antibody from muscle tissue. We show that humanized mice receiving VIP appear to be fully protected from HIV infection, even when challenged intravenously with very high doses of replication-competent virus. Our results suggest that successful translation of this approach to humans may produce effective prophylaxis against HIV.
原文链接：http://pathology.ucla.edu/workfiles/Research/nature10660.pdf
论坛链接：Nature：艾滋病基因疗法在动物体内效果显著 http://bbs.virology.com.cn/thread-379-1-1.html
3. Nature Medicine 20, 296–300 (2014)
Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission
Alejandro B Balazs,Yong Ouyang,Christin M Hong,Joyce Chen,Steven M Nguyen,Dinesh S Rao,Dong Sung An& David Baltimore
The vast majority of new HIV infections result from relatively inefficient transmission1, 2 of the virus across mucosal surfaces during sexual intercourse3. A consequence of this inefficiency is that small numbers of transmitted founder viruses initiate most heterosexual infections4. This natural bottleneck to transmission has stimulated efforts to develop interventions that are aimed at blocking this step of the infection process5. Despite the promise of this strategy, clinical trials of preexposure prophylaxis have had limited degrees of success in humans, in part because of lack of adherence to the recommended preexposure treatment regimens6, 7. In contrast, a number of existing vaccines elicit systemic immunity that protects against mucosal infections, such as the vaccines for influenza8 and human papilloma virus9. We recently demonstrated the ability of vectored immunoprophylaxis (VIP) to prevent intravenous transmission of HIV in humanized mice using broadly neutralizing antibodies10. Here we demonstrate that VIP is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse HIV strains despite repeated exposures. Moreover, animals receiving VIP that expresses a modified VRC07 antibody were completely resistant to repetitive intravaginal challenge by a heterosexually transmitted founder HIV strain11, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans.
原文链接：http://balazslab.mgh.harvard.edu/pdfs/Nat.%20Med.-Balazs,2014.pdf
论坛链接：诺奖得主Nature子刊发表艾滋病研究重要成果 http://www.ebiotrade.com/newsf/2014-2/2014211163547833.htm
4. Nature Biotechnology 31, 647–652 (2013)
Broad protection against influenza infection by vectored immunoprophylaxis in mice
Alejandro B Balazs,Jesse D Bloom,Christin M Hong,Dinesh S Rao& David Baltimore
Neutralizing antibodies that target epitopes conserved among many strains of influenza virus have been recently isolated from humans. Here we demonstrate that adeno-associated viruses (AAV) encoding two such broadly neutralizing antibodies are protective against diverse influenza strains. Serum from mice that received a single intramuscular AAV injection efficiently neutralized all H1, H2 and H5 influenza strains tested. After infection with diverse strains of H1N1 influenza, treated mice showed minimal weight loss and lung inflammation. Protection lasted for at least 11 months after AAV injection. Notably, even immunodeficient and older mice were protected by this method, suggesting that expression of a monoclonal antibody alone is sufficient to protect mice from illness. If translated to humans, this prophylactic approach may be uniquely capable of protecting immunocompromised or elderly patient populations not reliably protected by existing vaccines.
原文链接：http://balazslab.mgh.harvard.edu/pdfs/Nat.%20Biotech.-Balazs,2013.pdf
论坛链接：VIP，诺奖得主打造对抗疾病的新利器 http://www.ebiotrade.com/newsf/2014-9/2014919141841733.htm
5.Sci Transl Med 17 September 2014
Broadly neutralizing antibodies abrogate established hepatitis C virus infection
Ype P. de Jong1,2,*,Marcus Dorner2,†,Michiel C. Mommersteeg2,Jing W. Xiao2,Alejandro B. Balazs3,Justin B. Robbins4,Benjamin Y. Winer5,Sherif Gerges5,Kevin Vega2,Rachael N. Labitt2,Bridget M. Donovan2,Erick Giang4,Anuradha Krishnan6,Luis Chiriboga7,Michael R. Charlton6,Dennis R. Burton3,4,David Baltimore8,Mansun Law4,Charles M. Rice2 andAlexander Ploss2,5,*
In most exposed individuals, hepatitis C virus (HCV) establishes a chronic infection; this long-term infection in turn contributes to the development of liver diseases such as cirrhosis and hepatocellular carcinoma. The role of antibodies directed against HCV in disease progression is poorly understood. Neutralizing antibodies (nAbs) can prevent HCV infection in vitro and in animal models. However, the effects of nAbs on an established HCV infection are unclear. We demonstrate that three broadly nAbs—AR3A, AR3B, and AR4A—delivered with adeno-associated viral vectors can confer protection against viral challenge in humanized mice. Furthermore, we provide evidence that nAbs can abrogate an ongoing HCV infection in primary hepatocyte cultures and in a human liver chimeric mouse model. These results showcase a therapeutic approach to interfere with HCV infection by exploiting a previously unappreciated need for HCV to continuously infect new hepatocytes to sustain a chronic infection.
原文链接：http://stm.sciencemag.org/content/6/254/254ra129.abstract
论坛链接：VIP，诺奖得主打造对抗疾病的新利器http://science.bio1000.com/sciencecover/201409/86.html
6.Nature Immunology 14, 1–5 (2013) Review
Antibody gene transfer for HIV immunoprophylaxis
原文链接：http://balazslab.mgh.harvard.edu/pdfs/Nat.%20Immunol.-Balazs,2012.pdf
7. PNAS,August 26, 2014 Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice
AbstractMalaria caused by Plasmodium falciparum kills nearly one million children each year and imposes crippling economic burdens on families and nations worldwide. No licensed vaccine exists, but infection can be prevented by antibodies against the circumsporozoite protein (CSP), the major surface protein of sporozoites, the form of the parasite injected by mosquitoes. We have used vectored immunoprophylaxis (VIP), an adeno-associated virus-based technology, to introduce preformed antibody genes encoding anti-P. falciparum CSP mAb into mice. VIP vector-transduced mice exhibited long-lived mAb expression at up to 1,200 µg/mL in serum, and up to 70% were protected from both i.v. and mosquito bite challenge with transgenic Plasmodium berghei rodent sporozoites that incorporate the P. falciparum target of the mAb in their CSP. Serum antibody levels and protection from mosquito bite challenge were dependent on the dose of the VIP vector. All individual mice expressing CSP-specific mAb 2A10 at 1 mg/mL or more were completely protected, suggesting that in this model system, exceeding that threshold results in consistent sterile protection. Our results demonstrate the potential of VIP as a path toward the elusive goal of immunization against malaria.
|
发表于 2015-4-28 17:28:26
