Research

T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+T Cells in HIV Infection

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Abstract

CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation.

DNA and RNA Reverse Transcribing Viruses Viruses Microorganisms (DNA and RNA Reverse Transcribing Viruses Microorganisms Viruses) - Retroviridae [03305] HIV common Human immunodeficiency virus species pathogen Primates Mammalia Vertebrata Chordata Animalia (Animals Chordates Humans Mammals Primates Vertebrates) - Hominidae [86215] human common adult middle age host female male 2B4 CD160 Eomes expression inhibitory receptors PD-1 T-bet expression transcription factors 02506 Cytology - Animal 02508 Cytology - Human 10060 Biochemistry studies - General 12512 Pathology - Therapy 22002 Pharmacology - General 22005 Pharmacology - Clinical pharmacology 33502 Virology - General and methods 34502 Immunology - General and methods 34508 Immunology - Immunopathology tissue immunology 36006 Medical and clinical microbiology - Virology Biochemistry and Molecular Biophysics Clinical Immunology Infection Pharmacology HIV infection human immunodeficiency virus infection viral disease immune system disease drug therapy viral replication Human Medicine Medical Sciences CD8 positive T cell immune system antiretroviral therapy ART therapeutic and prophylactic techniques clinical techniques MICROBIOLOGY PARASITOLOGY VIROLOGY CHRONIC VIRAL-INFECTION TRANSCRIPTION FACTOR EOMESODERMIN HIGHLY PATHOGENIC SIV C VIRUS-INFECTION DISEASE PROGRESSION PD-1 EXPRESSION CUTTING EDGE EFFECTOR FUNCTION MEMORY IMMUNE