title: 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 TIGIThicells 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.
authors.affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Tauriainen
authors.affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Lydia
authors.initials: L
authors.lastname: Scharf
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Juliet
authors.initials: J
authors.lastname: Frederiksen
authors.affiliation: Division of Transplantation, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Hans-Gustaf
authors.initials: HG
authors.lastname: Ljunggren
authors.affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.|Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Sönnerborg
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Lund
authors.affiliation: Centre for Infectious Diseases Research, National Institute of Respiratory Diseases, Mexico City, Mexico.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Reyes-Terán
authors.affiliation: Department of Medicine, University of California, San Francisco Positive Health Program, San Francisco General Hospital, San Francisco, CA, United States of America.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.affiliation: Department of Medicine, University of California, San Francisco Positive Health Program, San Francisco General Hospital, San Francisco, CA, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Marcus
authors.initials: M
authors.lastname: Buggert
authors.affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Annika C
authors.initials: AC
authors.lastname: Karlsson
mesh_terms: D000328:Adult; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D023241:Antiretroviral Therapy, Highly Active; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006678:HIV / Q000472:pathogenicity; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000235:genetics*; D011991:Receptors, Virus / Q000235:genetics*; D015398:Signal Transduction; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C534712:TIGIT protein, human; C066100:poliovirus receptor