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Persistent lentivirus infection induces early myeloid suppressor cells expansion to subvert protective memory CD8 T cell response(?,??) #MMPMID32979832
Liu L; Lin Q; Peng J; Fang J; Tan Z; Tang H; Kwan K; Nishiura K; Liang J; Kwok H; Du Z; Sun J; Liu K; Yuen KY; Wang H; Chen Z
EBioMedicine 2020[Oct]; 60 (?): 103008 PMID32979832show ga
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.
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EBioMedicine 2020 ; 60 (?): 103008
