Background:
HIV-1 specific CD8 T cells play an important role in controlling HIV infection. However, during chronic HIV infection, HIV-specific CD8 T cells undergo functional exhaustion, lose effector function and fail to control viral infection.Leukocyte-associated Ig-like receptor-1 (LAIR-1), a 32 kDa transmembrane glycoprotein, is a surface molecule expressed on human peripheral blood mononuclear leukocytes and act as an inhibitory receptor many immune cells. However, the role of LAIR-1 on CD8 T cells during SIV/HIV infection remains unknown.
Methods:
A total of 14 macaques were infected with simian immunodeficiency virus(SIVmac251) and studied the temporal dynamics of LAIR-1+ SIV-specific CD8 T cells for their phenotypic and functional profiles using multicolor flow cytometry. We performed immunohistochemistry IHC to stain for LAIR-1 in LN tissues and used RNA sequencing to study the transcriptomic profile of LAIR-1+ CD8 T cells.
Results:
Here, we report on the expression of LAIR-1 on virus-specific CD8+ T cells during chronic SIV infection and the effect of LAIR-1 blockade on the proliferation and cytokine function of these cells. LAIR-1 expression was found to be low on naive CD8+ T cells and increased on total and SIV-specific effector memory CD8+ T cells during chronic infection. In addition, the level of LAIR-1 expression in the lymph node during chronic infection was higher compared to naïve animals. Transcriptionally, these LAIR-1+ CD8 T cells exhibited a unique transcriptome characterized by with heightened type I IFN-signaling coupled with reduced TCR signaling, cell cycling and cell metabolism pathways. Importantly the expression of LAIR-1 on SIV-specific effector memory CD8 T cells correlated directly with the SIV viral RNA levels in plasma. 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.
Conclusions:
These results serve as a foundation for future in vivotrials of the use of LAIR-1 blockade to potentially enhance and/or restore antiviral SIV-specific CD8 T cells, especially in secondary lymphoid tissues which may be important for the HIV cure strategy.
LAIR-1 mediated inhibition of CD8 T cells during chronic SIV/HIV infection