LAIR-1 expression on SIV-specific CD8 T cells is associated with T cell impairment and disease progression

Abstract

Abstract Functional impairment of CD8 T cells is characteristic of chronic HIV infection. HIV-specific CD8 T cells undergo exhaustion, lose effector function and fail to control the virus. Leukocyte-associated Ig-like receptor-1 (LAIR-1), a transmembrane glycoprotein, expressed on human blood mononuclear leukocytes and act as an inhibitory receptor of cytotoxic cells. However, the role of LAIR-1 expression on virus-specific CD8 T cells during SIV/HIV infection remains unknown. We examined a total of 14 macaques infected with the Simian Immunodeficiency Virus (SIVmac251) and studied the dynamics of LAIR-1+ SIV-specific CD8 T cells for their phenotype and function using flow cytometry. We performed immunohistochemistry to stain for LAIR-1 in lymph nodes and used RNA seq to study the transcriptomic profile of LAIR-1+ CD8 T cells. Here we report that LAIR-1 is significantly up regulated on SIV-specific CD8 +T cells during chronic SIV infection. and the expression of LAIR-1 on total and SIV-specific effector memory CD8 T cells correlated directly with the SIV viral RNA levels. In addition, the level of LAIR-1 in the lymph node was higher compared to naïve animals. Transcriptionally, the LAIR-1+ CD8 T cells exhibited an heightened type I IFN-signaling coupled with reduced TCR signaling, cell cycling and cell metabolism pathways. Indeed, In vitroblockade of LAIR-1 using LAIR-1-Fc/anti-LAIR-1 antibody resulted in enhanced proliferation of SIV-specific CD8 T cells with cytotoxic function. These data indicate that the immunoregulatory LAIR-1/Collagen pathway is operative during SIV infection and serve as a foundation in vivotrials of LAIR-1 blockade to potentially enhance/restore antiviral SIV-specific CD8 T cells for the HIV cure strategy. This work was supported in part by NIH grants CFAR ERASE AIDS-R03, R01AI148377 (to VV), U19 AI109633 (to RRA, macaque core to VV),