AIDS Institute and Department of Microbiology, State Key Laboratory of Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, P.R. China; HKU-AIDS Institute Shenzhen Research Laboratory and AIDS Clinical Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Key Clinical Department of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, P.R. China.
AIDS Institute and Department of Microbiology, State Key Laboratory of Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, P.R. China.
EBioMedicine. 2020 Oct;60:103008. doi: 10.1016/j.ebiom.2020.103008. Epub 2020 Sep 24.
Memory CD8T cell responses play an essential role in protection against persistent infection. However, HIV-1 evades vaccine-induced memory CD8T cell response by mechanisms that are not fully understood.
We analyzed the temporal dynamics of CD8T cell recall activity and function during EcoHIV infection in a potent PD1-based vaccine immunized immunocompetent mice.
Upon intraperitoneal EcoHIV infection, high levels of HIV-1 GAG-specific CD8T lymphocytes recall response reduced EcoHIV-infected cells significantly. However, this protective effect diminished quickly after seven days, followed by a rapid reduction of GAG-specific CD8T cell number and activity, and viral persistence. Mechanistically, EcoHIV activated dendritic cells (DCs) and myeloid cells. Myeloid cells were infected and rapidly expanded, exhibiting elevated PD-L1/-L2 expression and T cell suppressive function before day 7, and were resistant to CD8T cell-mediated apoptosis. Depletion of myeloid-derived suppressor cells (MDSCs) reduced EcoHIV infection and boosted T cell responses.
This study provides an overview of the temporal interplay of persistent virus, DCs, MDSCs and antigen-specific CD8T cells during acute infection. We identify MDSCs as critical gatekeepers that restrain antiviral T cell memory responses, and highlight MDSCs as an important target for developing effective vaccines against chronic human infections.
Hong Kong Research Grant Council (T11-709/18-N, HKU5/CRF/13G), General Research Fund (17122915 and 17114114), Hong Kong Health and Medical Research Fund (11100752, 14130582, 16150662), Grant RGC-ANR A-HKU709/14, the San-Ming Project of Medicine (SZSM201512029), University Development Fund of the University of Hong Kong and Li Ka Shing Faculty of Medicine Matching Fund to HKU AIDS Institute.
记忆性 CD8T 细胞应答在抵抗持续性感染中发挥着重要作用。然而，HIV-1 通过尚未完全阐明的机制来逃避疫苗诱导的记忆性 CD8T 细胞应答。
我们分析了在 PD1 为基础的有效疫苗免疫的免疫功能正常的小鼠中，EcoHIV 感染期间 CD8T 细胞回忆活性和功能的时间动态。
腹腔内感染 EcoHIV 后，高水平的 HIV-1 GAG 特异性 CD8T 淋巴细胞的回忆应答显著减少了 EcoHIV 感染的细胞。然而，这种保护作用在七天后迅速减弱，随后 GAG 特异性 CD8T 细胞数量和活性迅速下降，病毒持续存在。从机制上讲，EcoHIV 激活了树突状细胞（DCs）和髓样细胞。髓样细胞被感染并迅速扩增，在第 7 天之前表达上调 PD-L1/-L2 和 T 细胞抑制功能，并对 CD8T 细胞介导的细胞凋亡有抗性。髓源性抑制细胞（MDSCs）的耗竭减少了 EcoHIV 感染并增强了 T 细胞应答。
本研究概述了急性感染期间持续性病毒、DCs、MDSCs 和抗原特异性 CD8T 细胞之间的时间相互作用。我们确定 MDSCs 是抑制抗病毒 T 细胞记忆应答的关键调控者，并强调 MDSCs 是开发针对慢性人类感染的有效疫苗的重要靶点。
香港研究资助局（T11-709/18-N，HKU5/CRF/13G）、一般研究基金（17122915 和 17114114）、香港卫生和医学研究基金（11100752、14130582、16150662）、GRGC-ANR A-HKU709/14、深圳市医学科技计划项目（SZSM201512029）、香港大学发展基金和李嘉诚医学院配套基金。
