Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>HIV-specific CD8 T cells display an accumulation of inhibitory receptors that are associated with poor effector functions. Expression of the inhibitory receptor, T cell immunoglobulin and ITIM domain (TIGIT), its co-stimulatory receptor CD226 and their ligand poliovirus receptor (PVR) are altered during chronic viral infections and cancer. Here we show that the TIGIT/CD226/PVR axis is dysregulated during HIV infection and linked to poor polyfunctional activity, increased expression of inhibitory receptors and an altered effector transcriptional programming. We report that TIGIT expression is increased on CD8 T cells in untreated HIV infection. Additionally, a longitudinal increase in TIGIT expression was demonstrated despite early initiation of antiretroviral therapy during acute HIV infection. The HIV-specific TIGIT+ CD8 T cells co-expressed PD-1, CD160 and 2B4 and had an inverse expression profile of the T-box transcription factors T-bet and Eomes. The HIV-specific CD8 T cells were almost exclusively TIGIThiCD226neg/dim and the frequency of TIGIThi cells was inversely correlated with polyfunctionality. Furthermore, the TIGIT/CD226 ligand PVR was increased on CD4 T cells, especially T follicular helper (Tfh) cells in HIV-infected lymph nodes. These results demonstrate a preferential skewing of the TIGIT/CD226 axis towards the inhibitory receptor TIGIT on CD8 T cells during HIV-1 infection, which is linked to severe T cell dysfunction. The findings highlight the importance of the TIGIT/CD226/PVR axis as an immune checkpoint barrier that potentially could hinder future therapeutic “cure” strategies that require potent HIV-specific CD8 T cells and/or the clearance of HIV-1 infected Tfh cells.</jats:p>