CD169-mediated trafficking of HIV to plasma membrane invaginations in dendritic cells attenuates efficacy of anti-gp120 broadly neutralizing antibodies.
CD169-mediated trafficking of HIV to plasma membrane invaginations in dendritic cells attenuates efficacy of anti-gp120 broadly neutralizing antibodies.
复制标题
CD169介导的HIV对树突状细胞中质膜起伏的运输减弱了抗GP120的疗效，广泛中和抗体。
DOI：
10.1371/journal.ppat.1004751
复制
发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Gummuluru S
中科院分区：
文献类型：
--
作者：
Akiyama H;Ramirez NG;Gudheti MV;Gummuluru S
髓样树突状细胞（DC）可以通过与病毒颗粒膜中的神经节苷脂GM 3结合的受体CD 169/Siglec-1捕获HIV-1。反过来，由CD 169（一种I型凝集素，其在DC上的表达在用LPS成熟时增强）捕获的HIV-1颗粒被保护免于在含CD 169+病毒的隔室（VCC）中降解并散布到CD 4 + T细胞，这是DC介导的HIV-1转感染的机制。在这项研究中，我们描述了VCC的形成机制及其在HIV-1免疫逃避机制中的作用。我们发现HIV-1诱导的VCCs的形成仅限于骨髓细胞，并且CD 169的胞质尾区对于HIV-1在VCCs内的运输和保留以及随后的对CD 4 + T细胞的转感染是不稳定的。有趣的是，在CD 169的胞质尾区引入导致HIV-1颗粒内吞作用的二芳族内吞基序抑制了CD 169介导的HIV-1反式感染。此外，超分辨率显微镜显示CD 169和HIV-1颗粒在表面可接近但深层质膜内陷中的密切关联。有趣的是，抗gp 120广泛中和抗体VRC 01和NIH 45 -46 G54 W不能有效地接近深层VCC中的HIV-1颗粒，因此对中和作用不太敏感。我们的研究表明，通过CD 169捕获HIV-1可以提供病毒逃避先天性（吞噬）和适应性免疫应答。树突状细胞（Dendritic cells，DC）是专职的抗原提呈细胞，其哨兵作用对于诱导有效的抗病毒免疫是重要的。然而，HIV-1通过多种机制利用DC传播感染。一种这样的机制是DC介导的转感染途径，由此DC将捕获的病毒传递到CD 4 + T细胞。我们最近已经确定了I型干扰素（IFN-I）诱导蛋白，CD 169，作为介导HIV-1捕获和跨感染的DC上的受体。我们还证实了HIV-1与CD 169在DC外周非溶酶体区室中的广泛共定位，尽管区室形成的机制和生物学重要性仍不清楚。在这项研究中，我们报告了一种髓样细胞特异性辅因子在病毒捕获后与CD 169相互作用，导致隔室形成。该辅因子在DC中由IFN-I诱导TLR配体LPS诱导，但不由IFN-I本身诱导。尽管含有CD 169 + HIV-1的区室是表面可接近的，但这些区室具有相当大的深度并连接到表面，使得位于这些独特结构内的捕获的病毒颗粒被保护免于被抗gp 120广泛中和抗体检测。我们的研究表明，CD 169-HIV-1相互作用提供了一种逃避机制，通过吞噬作用和抗病毒体液反应中和降解。
Myeloid dendritic cells (DCs) can capture HIV-1 via the receptor CD169/Siglec-1 that binds to the ganglioside, GM3, in the virus particle membrane. In turn, HIV-1 particles captured by CD169, an I-type lectin, whose expression on DCs is enhanced upon maturation with LPS, are protected from degradation in CD169+ virus-containing compartments (VCCs) and disseminated to CD4+ T cells, a mechanism of DC-mediated HIV-1 trans-infection. In this study, we describe the mechanism of VCC formation and its role in immune evasion mechanisms of HIV-1. We find HIV-1-induced formation of VCCs is restricted to myeloid cells, and that the cytoplasmic tail of CD169 is dispensable for HIV-1 trafficking and retention within VCCs and subsequent trans-infection to CD4+ T cells. Interestingly, introduction of a di-aromatic endocytic motif in the cytoplasmic tail of CD169 that results in endocytosis of HIV-1 particles, suppressed CD169-mediated HIV-1 trans-infection. Furthermore, super-resolution microscopy revealed close association of CD169 and HIV-1 particles in surface-accessible but deep plasma membrane invaginations. Intriguingly, HIV-1 particles in deep VCCs were inefficiently accessed by anti-gp120 broadly neutralizing antibodies, VRC01 and NIH45-46 G54W, and thus were less susceptible to neutralization. Our study suggests that HIV-1 capture by CD169 can provide virus evasion from both innate (phagocytosis) and adaptive immune responses. Dendritic cells (DCs) are professional antigen presenting cells, and their sentinel roles are important to elicit a potent antiviral immunity. However, HIV-1 has exploited DCs to spread infection by several mechanisms. One such mechanism is the DC-mediated trans-infection pathway, whereby DCs transmit captured virus to CD4+ T cells. We have recently identified the type I interferon (IFN-I) inducible protein, CD169, as a receptor on DCs which mediates HIV-1 capture and trans-infection. We have also demonstrated extensive co-localization of HIV-1 with CD169 within peripheral non-lysosomal compartments in DCs, although the mechanism and biological importance of the compartment formation remain unclear. Here in this study, we report that a myeloid cell specific co-factor interacts with CD169 following virus capture leading to compartment formation. This co-factor is induced in DCs by an IFN-I-inducing TLR ligand LPS, but not by IFN-I itself. Though the CD169+ HIV-1 containing compartments are surface-accessible, these compartments have considerable depth and are connected to the surface, such that captured virus particles localized within these unique structures are protected from detection by anti-gp120 broadly neutralizing antibodies. Our study suggests that CD169–HIV-1 interaction provides an evasion mechanism from degradation by phagocytosis and neutralization by anti-viral humoral responses.
登录
查看更多内容
影响因子：
5.4
作者：
Frank, I;Piatak, M;Pope, M
通讯作者：
Pope, M
影响因子：
4.5
作者：
Garcia, E;Pion, M;Piguet, V
通讯作者：
Piguet, V
影响因子：
5.4
作者：
Hatch, Steven C.;Archer, Jacob;Gummuluru, Suryaram
通讯作者：
Gummuluru, Suryaram
影响因子：
4
作者：
Badieirostami, Majid;Lew, Matthew D.;Moerner, W. E.
通讯作者：
Moerner, W. E.
影响因子：
3.3
作者：
Blanchet FP;Stalder R;Czubala M;Lehmann M;Rio L;Mangeat B;Piguet V
通讯作者：
Piguet V