title: Concurrent loss of co-stimulatory molecules and functional cytokine secretion attributes leads to proliferative senescence of CD8(+) T cells in HIV/TB co-infection.
abstract: The role of T-cell immunosenescence and functional CD8(+) T-cell responses in HIV/TB co-infection is unclear. We examined and correlated surrogate markers of HIV disease progression with immune activation, immunosenescence and differentiation using T-cell pools of HIV/TB co-infected, HIV-infected and healthy controls. Our investigations showed increased plasma viremia and reduced CD4/CD8 T-cell ratio in HIV/TB co-infected subjects relative to HIV-infected, and also a closer association with changes in the expression of CD38, a cyclic ADP ribose hydrolase and CD57, which were consistently expressed on late-senescent CD8(+) T cells. Up-regulation of CD57 and CD38 were directly proportional to lack of co-stimulatory markers on CD8(+) T cells, besides diminished expression of CD127 (IL-7Rα) on CD57(+)CD4(+) T cells. Notably, intracellular IFN-γ, perforin and granzyme B levels in HIV-specific CD8(+) T cells of HIV/TB co-infected subjects were diminished. Intracellular CD57 levels in HIV gag p24-specific CD8(+) T cells were significantly increased in HIV/TB co-infection. We suggest that HIV-TB co-infection contributes to senescence associated with chronic immune activation, which could be due to functional insufficiency of CD8(+) T cells.
authors.affiliation: Tropical Infectious Disease Research and Education Center (TIDREC), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Alireza
authors.initials: A
authors.lastname: Saeidi
authors.affiliation: Department of Biomedical Science, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Yee K
authors.initials: YK
authors.lastname: Chong
authors.affiliation: Center of Excellence for Research in AIDS (CERiA), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Yean K
authors.initials: YK
authors.lastname: Yong
authors.affiliation: Center of Excellence for Research in AIDS (CERiA), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Hong Y
authors.initials: HY
authors.lastname: Tan
authors.affiliation: Tropical Infectious Disease Research and Education Center (TIDREC), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Muttiah
authors.initials: M
authors.lastname: Barathan
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Rajarajeswaran
authors.affiliation: Faculty of Medicine, SEGi University, Kota Damansara, 47810 Selangor, Malaysia.
authors.forename: Negar S
authors.initials: NS
authors.lastname: Sabet
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Shamala D
authors.initials: SD
authors.lastname: Sekaran
authors.affiliation: Center of Excellence for Research in AIDS (CERiA), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Sasheela
authors.initials: S
authors.lastname: Ponnampalavanar
authors.affiliation: Institute for Environmental Medicine, Karolinska Institute, Solna, 17 177 Stockholm, Sweden.
authors.forename: Karlhans F
authors.initials: KF
authors.lastname: Che
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Vijayakumar
authors.initials: V
authors.lastname: Velu
authors.affiliation: Center of Excellence for Research in AIDS (CERiA), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Adeeba
authors.initials: A
authors.lastname: Kamarulzaman
authors.affiliation: Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Larsson
authors.affiliation: Tropical Infectious Disease Research and Education Center (TIDREC), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia; Center of Excellence for Research in AIDS (CERiA), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia; Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia. Electronic address: shankarem@um.edu.my.
authors.forename: Esaki M
authors.initials: EM
authors.lastname: Shankar
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000328:Adult; D016516:CD4-CD8 Ratio; D018959:CD57 Antigens / Q000096:biosynthesis / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000276:immunology*; D060085:Coinfection / Q000276:immunology; D018450:Disease Progression; D005260:Female; D053804:Granzymes / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology*; D059805:HLA-DR alpha-Chains / Q000276:immunology; D006801:Humans; D000068884:Immunosenescence / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D054353:Perforin / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
chemical_list: D018959:CD57 Antigens; D059805:HLA-DR alpha-Chains; D053699:Interleukin-7 Receptor alpha Subunit; D008562:Membrane Glycoproteins; D054353:Perforin; D007371:Interferon-gamma; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D053804:Granzymes
keywords: Co-stimulation; HIV/TB co-infection; Immune activation; Immunosenescence; T-cell activation