1 Department of Systems Biology, Technical University of Denmark2 Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark3 Immunological Bioinformatics, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark4 Karolinska Institutet5 US National Institute of Health6 Stockholm South General Hospital7 University of Pennsylvania8 Karolinska Institutet9 University of Pennsylvania
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.
P L O S Pathogens, 2014, Vol 10, Issue 7
DNA and RNA Reverse Transcribing Viruses Viruses Microorganisms (DNA and RNA Reverse Transcribing Viruses, Microorganisms, Viruses) - Retroviridae  HIV common Human immunodeficiency virus species pathogen; Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae  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