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

Abstract

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.

HIV vaccines: Unmasking myeloid derived suppressor cells

“…This vaccine expressed HIV-1 Gag p24 fused to soluble PD-1 (sPD-1) which binds to PD-L1 and/or PD-L2 on dendritic cells (DCs) and blocks the inhibitory pathway, thus promoting T-cell activation. Here, the authors reveal that similar to infection in humans, EcoHIV infection results in expansion of MDSC and Treg cells and upregulation of inhibitory molecules (PD-1, Tim-3) on T-cells, resulting in decreased T-cell function and chronic infection [4]. In contrast, prophylactic DNA vaccination with sPD1-p24 fc reduced viral burden and restored some anti-viral CD8 + T-cell activity, however, was unable to reduce Treg and MDSC frequency, nor prevent immune exhaustion.…”

“…This study begins to unmask the complex and Janus-like nature of MDSCs during HIV viral infection: reducing antiviral CD8 + T cell responses or limiting CD4 + proliferation and HIV viral targets. The results by Li et al, [4] further suggest the need to deplete, block or reduce MDSC activity, expansion, and/or recruitment in order to enhance T-cell responses generated by therapeutic or prophylactic HIV vaccine strategies. Beyond directly targeting CD8 + T-cells in the context of primary vaccination/booster immunizations, the effects of regulating MDSC suppressive effects on CD4 + Th/T follicular (Tfh) cells and various antigen presenting cells (APCs) should be further examined.…”

“…In this article of EBioMedicine, Li et al, [4] investigate the role of MDSC, Treg and immune checkpoint blockade on T-cell function during prophylactic and therapeutic DNA vaccination in a murine model of chronic HIV infection (EcoHIV). Previously [5] the authors reported amplification of anti-viral T-cell responses generated by a DNA vaccine (sPD1-p24 fc ).…”

Protective and pathological roles of regulatory immune cells in human cytomegalovirus infection following hematopoietic stem cell transplantation

“…48,49 These cells suppress both innate and adaptive immune responses via a multitude of mechanisms and help resolve inflammation. 50,51 However, the existing evidences indicate the doubleedged role of MDSCs in HCMV.…”

“…Based on their surface markers, MDSCs can be divided into two major groups: monocytic MDSCs (Mo‐MDSCs), which express CD14, and granulocytic MDSCs (GR‐MDSC)—which express granulocytic markers like CD66b and/or CD15 48,49 . These cells suppress both innate and adaptive immune responses via a multitude of mechanisms and help resolve inflammation 50,51 . However, the existing evidences indicate the double‐edged role of MDSCs in HCMV.…”