P10. Sustained expression of the inhibitory receptor TIGIT is linked to CD8 T cell exhaustion despite successful ART.

Johanna Tauriainen1, Noor Salam1, Bo Hejdeman2, Anders Sönnerborg1,3, Hans-Gustaf Ljunggren4, Frederick M Hecht5, Steven G Deeks5, Michael R Betts6, Marcus Buggert1,6, Annika C Karlsson1

Affiliates: Div of Clin Microbiology, Karolinska Institutet, Stockholm, Sweden1, Dept of Infectious Diseases, South General Hospital, Stockholm, Sweden2, Unit of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden3, Center for, Infectious Medicine, Karolinska Institutet, Stockholm, Sweden4, University of California San Francisco, CA, USA5, Dept of Microbiology, University of Pennsylvania, Philadelphia, PA, USA6

Background
HIV-1 infection is associated with a state of CD8 T cell dysfunction despite antiretroviral treatment (ART). These dysfunctional, or exhausted cells display a loss of functions such as proliferation, cytotoxicity and production of antiviral cytokines as well as an increased expression of inhibitory receptors such as PD-1, 2B4 and CD160. Recently the inhibitory receptor, T cell immunoglobulin and ITIM domain (TIGIT), was shown to inhibit T cell functionality in mouse models and in human melanoma patients. Therefore, we set out to investigate if TIGIT expression on CD8 T cells was related to CD8 T cell function, activation, exhaustion and differentiation in HIV-positive treated and untreated subjects.

Methods
Multi-color flow cytometry was used to investigate TIGIT expression on CD8 T cells in HIV-1 infected ART naïve individuals (n=39), individuals on long-term ART (n=20), elite controllers (n=14) and healthy controls (n=31).

Results
The frequency of TIGIT+ CD8 T cells was increased during chronic HIV-1 infection and decreased after long-term ART, however it did not reach the levels seen in healthy controls. Expression of TIGIT on bulk and HIV-specific CD8 T cells was correlated with a higher level of T cell activation and single-and triple expression of the inhibitory markers PD-1, CD160 and 2B4. Furthermore, HIV-specific CD8 T cells with a TIGIThi phenotype had a limited virus-specific functionality (IFN-γ, TNF, Granzyme B, CD107a) compared to TIGITdim and TIGITneg cells. In elite controllers the frequencies of TIGIThi cells were significantly lower compared to untreated and long-term treated individuals.

Conclusions
We show that TIGIT was up-regulated on CD8 T cells during chronic HIV infection even after successful ART and that CD8 T cells expressing a TIGIThi phenotype had a limited functional capacity compared to TIGITdim and TIGIT neg cells. The TIGIThi cells were more common in untreated and long-term treated subjects compared to elite controllers, suggesting a role for TIGIT in CD8 T cell dysfunction during HIV-infection. Future shock-and-kill approaches involving CD8 effector T cells likely need to overcome the barrier of sustained expression of inhibitory receptors, including TIGIT, on CD8 T cells in ART+ subjects.