Science：可积极控制艾滋病病毒的干细胞疗法及三种新抗体

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在找到艾滋病疫苗或治愈方法方面失望多年以后，几个研究组已经报告了一些有希望的进展。

南加州大学的科学家Paula Cannon在7月2日的《自然—生物技术》（Nature Biotechnology）上描述了一种利用改造的干细胞控制艾滋病病毒感染的新方法。

她的研究组利用了来自人类干细胞的CCR5基因，该基因在正常情况下能让艾滋病病毒进入人类细胞。携带有该基因突变版本的人天然地可以抵御最常见的艾滋病病毒的感染。

他们用病毒感染了两组实验室小鼠：一组拥有经过修改的CCR5的细胞，另一组没有。

在经过12周之后，经过干细胞疗法治疗的小鼠可以抑制艾滋病病毒感染。

“我们如今证明了可以制造出抗艾滋病病毒的人类血干细胞——而且这些细胞生长并增殖，制造出了所有人类免疫细胞类型的‘女儿细胞’——这包括艾滋病病毒攻击的T细胞。”Cannon说。

“干细胞疗法令人激动之处在于它有可能成为一种‘一针’的疗法，因为干细胞可能在患者体内终身存在，持续制造这类抗艾滋病病毒的细胞……因此患者可以利用他们自己的细胞应对艾滋病病毒。” 她说。

与此同时，《科学》杂志发表的两份报告称发现了3种新的抗体，可以积极地对抗一大批艾滋病病毒毒株，其中两种抗体可以消灭90%以上的艾滋病毒株。

美国国立卫生研究院疫苗研究中心主任、其中一份报告的作者Gary J. Nabel说，这些发现为艾滋病疫苗的设计提供了重要的见解。

“对于艾滋病疫苗设计而言，我们使用这些抗体发现了疫苗要保留的蛋白质的部分，去除了不必要的部分，让免疫系统可以把重点放在相关结构上。”他说。

“这个分子生物学的进展很重要，”联合国艾滋病规划署哥伦比亚办事处主任Luis ángel Moreno Díaz说。但是他也指出，“在这些新技术能够进行人体试验之前，仍然缺乏一些步骤”。

根据全球艾滋病疫苗计划即将于2010年9月在美国亚特兰大举行的艾滋病疫苗会议上发布的一份题为《预防之路》的报告，自从1981年以来，艾滋病已经夺去了2500多万人的生命，每年新发感染270多万人。（生物谷Bioon.com）

生物谷推荐摘要1：

Nature Biotechnology  doi:10.1038/nbt.1663

Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo
Nathalia Holt1, Jianbin Wang2, Kenneth Kim2, Geoffrey Friedman2, Xingchao Wang3, Vanessa Taupin3, Gay M Crooks4, Donald B Kohn4, Philip D Gregory2, Michael C Holmes2 & Paula M Cannon1

CCR5 is the major HIV-1 co-receptor, and individuals homozygous for a 32-bp deletion in CCR5 are resistant to infection by CCR5-tropic HIV-1. Using engineered zinc-finger nucleases (ZFNs), we disrupted CCR5 in human CD34+ hematopoietic stem/progenitor cells (HSPCs) at a mean frequency of 17% of the total alleles in a population. This procedure produces both mono- and bi-allelically disrupted cells. ZFN-treated HSPCs retained the ability to engraft NOD/SCID/IL2rγnull mice and gave rise to polyclonal multi-lineage progeny in which CCR5 was permanently disrupted. Control mice receiving untreated HSPCs and challenged with CCR5-tropic HIV-1 showed profound CD4+ T-cell loss. In contrast, mice transplanted with ZFN-modified HSPCs underwent rapid selection for CCR5?/? cells, had significantly lower HIV-1 levels and preserved human cells throughout their tissues. The demonstration that a minority of CCR5?/? HSPCs can populate an infected animal with HIV-1-resistant, CCR5?/? progeny supports the use of ZFN-modified autologous hematopoietic stem cells as a clinical approach to treating HIV-1.

生物谷推荐摘要2：

Science DOI: 10.1126/science.1187659

Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1
Xueling Wu,1,* Zhi-Yong Yang,1,* Yuxing Li,1,* Carl-Magnus Hogerkorp,1, William R. Schief,4 Michael S. Seaman,5 Tongqing Zhou,1 Stephen D. Schmidt,1 Lan Wu,1 Ling Xu,1 Nancy S. Longo,1 Krisha McKee,1 Sijy O’Dell,1 Mark K. Louder,1 Diane L. Wycuff,1 Yu Feng,1, Martha Nason,2 Nicole Doria-Rose,3 Mark Connors,3 Peter D. Kwong,1 Mario Roederer,1 Richard T. Wyatt,1, Gary J. Nabel,1, John R. Mascola1,

Cross-reactive neutralizing antibodies (NAbs) are found in the sera of many HIV-1–infected subjects, but the virologic basis of their neutralization remains poorly understood. We used knowledge of HIV-1 envelope (Env) structure to develop antigenically resurfaced glycoproteins specific for the structurally conserved site of CD4 receptor binding. These probes were used to identify sera with NAbs to the CD4-binding site (CD4bs) and to isolate individual B cells from such an HIV-1–infected donor. By expressing immunoglobulin genes from individual cells, we identified three monoclonal antibodies, including a pair of somatic variants that neutralized over 90% of circulating HIV-1 isolates. Exceptionally broad HIV-1 neutralization can be achieved with individual antibodies targeted to the functionally conserved CD4bs of gp120, an important insight for future HIV-1 vaccine design.

生物谷推荐摘要3：

Science DOI: 10.1126/science.1192819

Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01
Tongqing Zhou,1 Ivelin Georgiev,1,* Xueling Wu,1,* Zhi-Yong Yang,1,* Kaifan Dai,1 Andrés Finzi,2 Young Do Kwon,1 Johannes Scheid,3 Wei Shi,1 Ling Xu,1 Yongping Yang,1 Jiang Zhu,1 Michel C. Nussenzweig,3 Joseph Sodroski,2,4 Lawrence Shapiro,1,5 Gary J. Nabel,1 John R. Mascola,1 Peter D. Kwong1,

During HIV-1 infection, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves broad neutralization of diverse viral strains. Here, we determine the crystal structure of VRC01 in complex with an HIV-1 gp120 core. VRC01 partially mimics CD4 interaction with gp120. A shift from the CD4-defined orientation, however, focuses VRC01 onto the vulnerable site of initial CD4 attachment, allowing it to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through V-gene–derived regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies.