PNAS：通过HIV传播机制治疗艾滋病潜力巨大
2012-04-27 10:58 来源：丁香园 作者：fyc5078 波士顿大学医学院（BUSM）的研究人员在当前《美国国家科学院院刊》 (PNAS) 上非常重要的一项研究中，阐述了对最初人类1型（HIV-1）免疫缺陷病毒和树突状细胞相互作用的一种新的认识。随着每年超过250万新感染艾滋病毒患者被诊断出，以及对艾滋病毒早期检测的越来越普遍性，对早期病毒宿主之间的相互作用有更好地了解，可能对未来的研究和药物治疗有很大的影响。在这项研究中，研究人员阐述了HIV-1通过树突状细胞进行传播的一种新机制。这些处在人体粘膜表面的细胞是研究的重点，因为他们是首先与HIV-1接触并诱导免疫系统的细胞之一。以前的工作主要集中在HIV-1包膜糖蛋白相互作用方式上，而这项研详细阐述了一种称作GM3的分子作用，其来自宿主本身，被病毒用于粘附和传播。
由于这种病毒的入侵方式依赖于宿主自身的分子，“这是一种隐形的输入机制，可能不会被细胞检测到，所以艾滋病毒能够迅速传播，”RahmGummuluru博士说，他是波士顿大学医学院微生物学系副教授，也是这项研究主要作者。
尽管病毒聪明，但HIV-1和树突状细胞之间的这种独特的接触，可能会为抗病毒治疗提供一种新的方向。“治疗抵抗，对医生来说通常是挑战，但这种情况不太可能发生在以HIV-1和树突状细胞之间接触为作用靶点的药物身上，因为这些药物的优点是作用于宿主，而不是病毒，” Gummuluru说。这个领域的进一步研究可能会证实特定的靶点，并为阻止艾滋病毒感染带来希望。
相关文献HIV-1 incorporation of host-cell-derived glycosphingolipid GM3 allows for capture by mature dendritic cells. Proc Natl Acad Sci U S A 2012 Apr;: Puryear WB Yu X Ramirez NP Reinhard BM Gummuluru S Department of Microbiology, Boston University School of Medicine, Boston, MA 02118. Abstract
The interaction between HIV and dendritic cells (DCs) is an important early event in HIV-1 pathogenesis that leads to efficient viral dissemination. Here we demonstrate a HIV gp120-independent DC capture mechanism that uses virion-incorporated host-derived gangliosides with terminal α2-3-linked sialic acid linkages. Using exogenously enriched virus and artificial liposome particles, we demonstrate that both α2-3 gangliosides GM1 and GM3 are capable of mediating this interaction when present in the particle at high levels. In the absence of overexpression, GM3 is the primary ligand responsible for this capture mechanism, because siRNA depletion of GM3 but not GM1 from the producer cell and hence virions, resulted in a dramatic decrease in DC capture. Furthermore, HIV-1 capture by DCs was competitively inhibited by targeting virion-associated GM3, but was unchanged by targeting GM1. Finally, virions were derived from monocytoid THP-1 cells that constitutively display low levels of GM1 and GM3, or from THP-1 cells induced to express high surface levels of GM1 and GM3 upon stimulation with the TLR2/1 ligand Pam3CSK4. Compared with untreated THP-1 cells, virus produced from Pam3CSK4-stimulated THP-1 cells incorporated higher levels of GM3, but not GM1, and showed enhanced DC capture and trans-infection. Our results identify a unique HIV-1 DC attachment mechanism that is dependent on a host-cell-derived ligand, GM3, and is a unique example of pathogen mimicry of host-cell recognition pathways that drive virus capture and dissemination in vivo.
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