Deng Jing, Mitsuki Yu-Ya, Shen Guomiao, Ray Jocelyn C, Cicala Claudia, Arthos James, Dustin Michael L, Hioe Catarina E
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.
Department of Pathology, New York University School of Medicine, New York, New York, USA.
J Virol. 2016 Nov 14;90(23):10513-10526. doi: 10.1128/JVI.01532-16. Print 2016 Dec 1.
HIV is transmitted most efficiently from cell to cell, and productive infection occurs mainly in activated CD4 T cells. It is postulated that HIV exploits immunological synapses formed between CD4 T cells and antigen-presenting cells to facilitate the targeting and infection of activated CD4 T cells. This study sought to evaluate how the presence of the HIV envelope (Env) in the CD4 T cell immunological synapse affects synapse formation and intracellular signaling to impact the downstream T cell activation events. CD4 T cells were applied to supported lipid bilayers that were reconstituted with HIV Env gp120, anti-T cell receptor (anti-TCR) monoclonal antibody, and ICAM-1 to represent the surface of HIV Env-bearing antigen-presenting cells. The results showed that the HIV Env did not disrupt immunological synapse formation. Instead, the HIV Env accumulated with TCR at the center of the synapse, altered the kinetics of TCR recruitment to the synapse and affected synapse morphology over time. The HIV Env also prolonged Lck phosphorylation at the synapse and enhanced TCR-induced CD69 upregulation, interleukin-2 secretion, and proliferation to promote virus infection. These results suggest that HIV uses the immunological synapse as a conduit not only for selective virus transmission to activated CD4 T cells but also for boosting the T cell activation state, thereby increasing its likelihood of undergoing productive replication in targeted CD4 T cells.
There are about two million new HIV infections every year. A better understanding of how HIV is transmitted to susceptible cells is critical to devise effective strategies to prevent HIV infection. Activated CD4 T cells are preferentially infected by HIV, although how this is accomplished is not fully understood. This study examined whether HIV co-opts the normal T cell activation process through the so-called immunological synapse. We found that the HIV envelope is recruited to the center of the immunological synapse together with the T cell receptor and enhances the T cell receptor-induced activation of CD4 T cells. Heightened cellular activation promotes the capacity of CD4 T cells to support productive HIV replication. This study provides evidence of the exploitation of the normal immunological synapse and T cell activation process by HIV to boost the activation state of targeted CD4 T cells and promote the infection of these cells.
HIV在细胞间的传播效率最高，且有效感染主要发生在活化的CD4 T细胞中。据推测，HIV利用CD4 T细胞与抗原呈递细胞之间形成的免疫突触，促进对活化CD4 T细胞的靶向和感染。本研究旨在评估CD4 T细胞免疫突触中HIV包膜（Env）的存在如何影响突触形成和细胞内信号传导，从而影响下游T细胞活化事件。将CD4 T细胞应用于用HIV Env gp120、抗T细胞受体（抗TCR）单克隆抗体和ICAM-1重构的支持脂质双层，以代表携带HIV Env的抗原呈递细胞表面。结果表明，HIV Env不会破坏免疫突触形成。相反，HIV Env与TCR在突触中心聚集，改变了TCR募集到突触的动力学，并随时间影响突触形态。HIV Env还延长了突触处Lck的磷酸化，并增强了TCR诱导的CD69上调、白细胞介素-2分泌和增殖，以促进病毒感染。这些结果表明，HIV不仅将免疫突触用作选择性病毒传播至活化CD4 T细胞的通道，还用作增强T细胞活化状态的通道，从而增加其在靶向CD4 T细胞中进行有效复制的可能性。
每年约有200万新发HIV感染病例。更好地了解HIV如何传播至易感细胞对于制定有效的HIV感染预防策略至关重要。活化的CD4 T细胞优先被HIV感染，尽管其具体机制尚不完全清楚。本研究探讨了HIV是否通过所谓的免疫突触来利用正常的T细胞活化过程。我们发现，HIV包膜与T细胞受体一起被募集到免疫突触中心，并增强T细胞受体诱导的CD4 T细胞活化。细胞活化增强促进了CD4 T细胞支持HIV有效复制的能力。本研究提供了证据，证明HIV利用正常的免疫突触和T细胞活化过程来增强靶向CD4 T细胞的活化状态并促进这些细胞的感染。
