Persistent lentivirus infection induces early myeloid suppressor cells expansion to subvert protective memory CD8 T cell response(✰,✰✰)

Liu, Li; Lin, Qingqing; Peng, Jie; Fang, Jun; Tan, Zhiwu; Tang, Hangying; Kwan, Kayi; Nishiura, Kenji; Liang, Jianguo; Kwok, Hauyee; Du, Zhenglong; Sun, Jiaze; Liu, Kang; Yuen, Kwok-Yung; Wang, Hui; Chen, Zhiwei

BACKGROUND: Memory CD8(+)T cell responses play an essential role in protection against persistent infection. However, HIV-1 evades vaccine-induced memory CD8(+)T cell response by mechanisms that are not fully understood. METHODS: We analyzed the temporal dynamics of CD8(+)T cell recall activity and function during EcoHIV infection in a potent PD1-based vaccine immunized immunocompetent mice. FINDINGS: Upon intraperitoneal EcoHIV infection, high levels of HIV-1 GAG-specific CD8(+)T 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 CD8(+)T 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 CD8(+)T cell-mediated apoptosis. Depletion of myeloid-derived suppressor cells (MDSCs) reduced EcoHIV infection and boosted T cell responses. INTERPRETATION: This study provides an overview of the temporal interplay of persistent virus, DCs, MDSCs and antigen-specific CD8(+)T 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. FUNDING: 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.