title: HIV-1 infection abrogates CD8+ T cell mitogen-activated protein kinase signaling responses.
abstract: Mitogen-activated protein kinase (MAPK) signaling pathways are dynamic and sensitive regulators of T cell function and differentiation. Altered MAPK signaling has been associated with the inflammatory and autoimmune diseases lupus and arthritis and with some pathogenic viral infections. HIV-1 infection is characterized by chronic immune inflammation, aberrantly heightened CD8(+) T cell activation levels, and altered T cell function. The relationship between MAPK pathway function, HIV-1-induced activation (CD38 and HLA-DR), and exhaustion (Tim-3) markers in circulating CD8(+) T cells remains unknown. Phosphorylation of the MAPK effector proteins ERK and p38 was examined by "phosflow" flow cytometry in 79 recently HIV-1-infected, antiretroviral-treatment-naïve adults and 21 risk-matched HIV-1-negative controls. We identified a subset of CD8(+) T cells refractory to phorbol 12-myristate 13-acetate plus ionomycin-induced ERK1/2 phosphorylation (referred to as p-ERK1/2-refractory cells) that was greatly expanded in HIV-1-infected adults. The CD8(+) p-ERK1/2-refractory cells were highly activated (CD38(+) HLA-DR(+)) but not exhausted (Tim-3 negative), tended to have low CD8 expression, and were enriched in intermediate and late transitional memory states of differentiation (CD45RA(-) CD28(-) CD27(+/-)). Targeting MAPK pathways to restore ERK1/2 signaling may normalize immune inflammation levels and restore CD8(+) T cell function during HIV-1 infection.
authors.affiliation: Hawaii Center for HIV/AIDS, John A. Burns School of Medicine, University of Hawaii Manoa, Honolulu, HI 96813, USA.
authors.forename: Timothy Q
authors.initials: TQ
authors.lastname: Crawford
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
authors.forename: Alice
authors.initials: A
authors.lastname: Tan
authors.forename: Alex
authors.initials: A
authors.lastname: Carvidi
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sinclair
authors.forename: Jason D
authors.initials: JD
authors.lastname: Barbour
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D019562:Viral Load
chemical_list: C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases