The CD8-derived chemokine XCL1/lymphotactin is a conformation-dependent, broad-spectrum inhibitor of HIV-1.
The CD8-derived chemokine XCL1/lymphotactin is a conformation-dependent, broad-spectrum inhibitor of HIV-1.
复制标题
DOI：
10.1371/journal.ppat.1003852
复制
发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Lusso P
中科院分区：
文献类型：
--
作者：
Guzzo C;Fox J;Lin Y;Miao H;Cimbro R;Volkman BF;Fauci AS;Lusso P
CD 8 + T细胞通过其细胞溶解活性以及其分泌非溶解性可溶性抑制因子的能力在体内控制HIV-1复制中起关键作用。尽管天然结合CCR 5的趋化因子（CCL 3/MIP-1α、CCL 4/MIP- 1β、CCL 5/RANTES）是CD 8衍生的抗HIV活性的主要成分，但有证据表明存在其他尚未确定的CD 8衍生的HIV抑制因子。在这里，我们报告了一种新的抗HIV趋化因子，XCL 1/approximatectin，主要由活化的CD 8 + T细胞产生的C-趋化因子家族的成员，作为一种变性蛋白，两种结构不同的构象（经典和替代）之间的相互转换的表征。我们发现，XCL 1抑制广谱的HIV-1分离株，无论其辅助受体使用表型。XCL 1稳定变体的实验表明，HIV-1抑制需要获得替代的全β构象，其与蛋白聚糖相互作用，但不结合/激活特异性XCR 1受体，而经典的XCL 1构象是无活性的。XCL 1对HIV-1的抑制作用发生在感染的早期，通过阻断病毒附着和进入宿主细胞。与最近描述的CXC趋化因子CXCL 4/PF 4的抗HIV作用类似，XCL 1介导的抑制与趋化因子与HIV-1包膜的直接相互作用有关。这些结果可能为理解HIV-1控制机制开辟新的视角，并为设计有效的HIV-1治疗和预防策略揭示新的分子靶点。虽然艾滋病的病原体HIV建立了即使有效治疗也无法根除的终身感染，但宿主免疫系统有能力在疾病保持无症状的许多年内抑制其复制。HIV控制的关键参与者是CD 8 + T细胞，这是一种专门的免疫细胞，不仅可以破坏感染的细胞，还可以分泌可溶性因子来抑制病毒而不杀死感染的细胞。CD 8 + T细胞产生多种HIV抑制因子，包括某些趋化因子（吸引免疫细胞的可溶性蛋白质），甚至在病毒进入其靶细胞之前就能阻止病毒。在本研究中，我们描述了一种新的抗HIV趋化因子，XCL 1或趋化素，它主要由CD 8 + T细胞产生。XCL 1的一个独特之处在于，与其他抗病毒趋化因子不同，它对HIV-1的不同变体具有非常广谱的活性，并直接结合病毒外壳，而不是阻断靶细胞上的特异性受体。同样独特的是，XCL 1采用两种可能的构象，其中只有一种能够抑制HIV。这些发现可能为设计有效的艾滋病毒药物或疫苗开辟新的途径。
CD8+ T cells play a key role in the in vivo control of HIV-1 replication via their cytolytic activity as well as their ability to secrete non-lytic soluble suppressive factors. Although the chemokines that naturally bind CCR5 (CCL3/MIP-1α, CCL4/MIP- 1β, CCL5/RANTES) are major components of the CD8-derived anti-HIV activity, evidence indicates the existence of additional, still undefined, CD8-derived HIV-suppressive factors. Here, we report the characterization of a novel anti-HIV chemokine, XCL1/lymphotactin, a member of the C-chemokine family that is produced primarily by activated CD8+ T cells and behaves as a metamorphic protein, interconverting between two structurally distinct conformations (classic and alternative). We found that XCL1 inhibits a broad spectrum of HIV-1 isolates, irrespective of their coreceptor-usage phenotype. Experiments with stabilized variants of XCL1 demonstrated that HIV-1 inhibition requires access to the alternative, all-β conformation, which interacts with proteoglycans but does not bind/activate the specific XCR1 receptor, while the classic XCL1 conformation is inactive. HIV-1 inhibition by XCL1 was shown to occur at an early stage of infection, via blockade of viral attachment and entry into host cells. Analogous to the recently described anti-HIV effect of the CXC chemokine CXCL4/PF4, XCL1-mediated inhibition is associated with direct interaction of the chemokine with the HIV-1 envelope. These results may open new perspectives for understanding the mechanisms of HIV-1 control and reveal new molecular targets for the design of effective therapeutic and preventive strategies against HIV-1. Although HIV, the causative agent of AIDS, establishes a lifelong infection that cannot be eradicated even with effective treatment, the host immune system has the ability to contain its replication for many years in which the disease remains asymptomatic. Key players in HIV control are CD8+ T cells, specialized immune cells that can not only destroy infected cells, but also secrete soluble factors that suppress the virus without killing infected cells. CD8+ T cells produce multiple HIV-suppressive factors, including certain chemokines (soluble proteins that attract immune cells), which block the virus even before it can gain access to its target cells. In the present study, we characterize a new anti-HIV chemokine, XCL1 or lymphotactin, which is primarily produced by CD8+ T cells. A unique feature of XCL1 is that, unlike other antiviral chemokines, it has a very broad spectrum of activity against different variants of HIV-1 and directly binds the virus outer coat, rather than blocking specific receptors on the target cell. Also unique is that fact that XCL1 adopts two possible conformations, and only one of them is capable of HIV inhibition. These findings may open new avenues for the design of effective drugs or vaccines against HIV.
登录
查看更多内容
影响因子：
56.9
作者：
COCCHI, F;DEVICO, AL;LUSSO, P
通讯作者：
LUSSO, P
DOI：
10.1073/pnas.1207314109
发表时间：
2012-06-12
影响因子：
11.1
作者：
Auerbach, David J.;Lin, Yin;Lusso, Paolo
通讯作者：
Lusso, Paolo
影响因子：
3.7
作者：
Kang, SM;Quan, FS;Compans, RW
通讯作者：
Compans, RW
影响因子：
1.5
作者：
COPELAND, KFT;MCKAY, PJ;ROSENTHAL, KL
通讯作者：
ROSENTHAL, KL
影响因子：
2.7
作者：
GRAM, GJ;HEMMING, A;HANSEN, JES
通讯作者：
HANSEN, JES