title: Activation associated ERK1/2 signaling impairments in CD8+ T cells co-localize with blunted polyclonal and HIV-1 specific effector functions in early untreated HIV-1 infection.
abstract: We recently observed that a large proportion of activated (CD38(+)HLA-DR(+)) CD8(+) T cells from recently HIV-1-infected adults are refractory to phosphorylation of ERK1/2 kinases (p-ERK1/2-refractory). Given that the ERK1/2 pathway mediates intracellular signaling critical for multiple T cell functions, including key effector functions, the loss of ERK1/2 responsiveness may have broad consequences for CD8(+) T cell function. In the current study, we hypothesized that the p-ERK1/2-refractory population, localized largely within the activated CD38(+)HLA-DR(+) CD8(+) T cell population, would display impairments in CD8(+) T cell effector functions, such as cytokine production and degranulation, compared to CD8(+) p-ERK1/2-responsive cells. We further hypothesized that the p-ERK1/2-refractory phenotype is persistent over time during untreated infection, and would correlate with poorer virologic control, in a manner independent of CD8(+) T cell activation level. We performed single-cell resolution, flow cytometric assays of phospho-kinase responses paired to intracellular cytokine staining in one assay to examine IFN-γ, perforin and CD107α responses in CD8(+) T cells by ERK1/2 signaling profile. On a per cell basis, p-ERK1/2-refractory cells, which fall predominantly within the activated CD8(+) T cell compartment, produced less IFN-γ in response to polyclonal or HIV-1 antigen-specific stimulation, and expressed lower levels of perforin and CD107α. The p-ERK1/2 refractory cell population displayed minimal overlap with the PD-1 and Tim-3 inhibitory exhaustion markers and predicted high viral load independent of activation, suggesting that ERK1/2 may be a unique marker and point of intervention for improving CD8(+) T cell function. Blunted effector functions, secondary to ERK1/2 signaling deficits concentrated within activated CD8(+) T cells, may contribute to immunodeficiency and underlie the predictive capacity of CD8(+) T cell activation on HIV-1 disease progression. (270/300).
authors.affiliation: Hawaii Center for HIV/AIDS, John A. Burns School of Medicine, Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
authors.forename: Timothy Q
authors.initials: TQ
authors.lastname: Crawford
authors.forename: Fredrick M
authors.initials: FM
authors.lastname: Hecht
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Pilcher
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
authors.forename: Jason D
authors.initials: JD
authors.lastname: Barbour
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D013045:Species Specificity; D013997:Time Factors; D019562:Viral Load / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D010750:Phosphoproteins; D054301:gag Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3