Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals

Abstract

HIV-specific CD8+ T cells demonstrate an exhausted phenotype associated with increased expression of inhibitory receptors, decreased functional capacity, and a skewed transcriptional profile, which are only partially restored by antiretroviral treatment (ART). Expression levels of the inhibitory receptor, T cell immunoglobulin and ITIM domain (TIGIT), the co-stimulatory receptor CD226 and their ligand PVR are altered in viral infections and cancer. However, the extent to which the TIGIT/CD226/PVR-axis is affected by HIV-infection has not been characterized. Here, we report that TIGIT expression increased over time despite early initiation of ART. HIV-specific CD8+ T cells were almost exclusively TIGIT+, had an inverse expression of the transcription factors T-bet and Eomes and co-expressed PD-1, CD160 and 2B4. HIV-specific TIGIThi cells were negatively correlated with polyfunctionality and displayed a diminished expression of CD226. Furthermore, expression of PVR was increased on CD4+ T cells, especially T follicular helper (Tfh) cells, in HIV-infected lymph nodes. These results depict a skewing of the TIGIT/CD226 axis from CD226 co-stimulation towards TIGIT-mediated inhibition of CD8+ T cells, despite early ART. These findings highlight the importance of the TIGIT/CD226/PVR axis as an immune checkpoint barrier that could hinder future “cure” strategies requiring potent HIV-specific CD8+ T cells.

Sugar or Fat?—Metabolic Requirements for Immunity to Viral Infections

“…Markers of T cell activation, such as CD38 and HLADR, remain elevated above normal in HIV positive individuals with durable viral suppression on ART ( 76 ). Moreover, elevated expression of co-inhibitory receptors, such as PD-1, TIGIT, CD160, and 2B4, is associated with functionally exhausted HIV-specific and non-specific CD8 + T cells with reduced proliferative capacity and impaired effector functions ( 77 – 80 ).…”

Immune checkpoint blockade in infectious diseases

“…Expression of T cell immunoreceptor with Ig and ITIM domains (TIGIT) is also increased on CD8 + T cells in untreated and treated HIV infection compared to HIV-negative controls 38 even following early initiation of ART 60 . HIV-specific CD8 + T cells were almost exclusively TIGIT + , and co-expressed PD-1, CD160 and 2B4 60 . HIV-specific TIGIT hi cells were also negatively correlated with polyfunctionality and had reduced expression of the co-stimulatory receptor CD226.…”

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

“…The TIGIT inhibitory signal is mediated by ligation with its high affinity ligand, the poliovirus receptor (CD155 or PVR), and its low affinity ligand CD112 (Nectin-2 or PVRL2) [30,32,33]. TIGIT has been previously associated with CD4 + T cell, CD8 + T cell and NK cell exhaustion both in the setting of chronic viral infections and malignancy [31,[34][35][36][37][38][39][40]. Blockade of the TIGIT/CD155/CD112 pathway to improve the function of T cells and NK cells against solid cancers is currently under investigation [41,42].…”

“…In HIV-1 infection, TIGIT marks exhausted T cells, correlates with disease progression and is decreased on CD4 + T cells from elite controllers [43,44]. Early initiation of antiretroviral treatment (ART) in HIV infected individuals does not return TIGIT/CD115 to normal levels on CD8 + T cells [37]. Additionally, the co-expression of TIGIT with immune checkpoint inhibitor PD-1 marks CD4 + T cells harboring latent virus [45][46][47].…”