title: p16INK4a Expression and Immunologic Aging in Chronic HIV Infection.
abstract: Chronic HIV infection is characterized by increased immune activation and immunosenescence. p16 INK4a (p16) is a member of the cyclin-dependent kinase antagonist family that inhibits cellular proliferation, and its protein expression increases during normal chronological aging. However, some infectious diseases can increase the expression of this anti-proliferative protein, potentially accelerating immunological aging and dysfunction. In order to investigate the immunological aging in HIV patients, p16 protein expression was evaluated by flow cytometry, in T cell subsets in a cohort of chronically HIV-infected patients on and off ART as well as age-matched healthy controls. Results showed that untreated HIV-infected subjects exhibited increased per-cell p16 protein expression that was discordant with chronological aging. ART restored p16 protein expression to levels comparable with HIV-negative subjects in the CD4 compartment, but not in CD8 T cells, which can be an indicative of an irreversible activation/exhaustion status on these cells. Additionally, the frequency of activated CD4+ and CD8+ T cells was positively correlated with p16 expression in CD4+ and CD8+ T cells in untreated subjects. In contrast to healthy controls, untreated HIV-infected individuals had increased p16 levels within the effector memory (TEM) subset, indicating a possible role for this marker in impaired clonal expansion during antiviral effector function. Taken together, these data demonstrate that chronic HIV infection is associated with elevated expression of the cellular aging marker p16 in T cells. ART restored normal p16 levels in the CD4+ T cell compartment, indicating that use of therapy can be of fundamental importance to normal cell cycling and maintaining immune homeostasis.
authors.affiliation: Laboratory of Clinical Immunology and Allergy-LIM60/ University of Sao Paulo School of Medicine, São Paulo, Brazil.|Institute of Investigation in Immunology-iii-INCT, São Paulo, Brazil.|Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Susan Pereira
authors.identifier: 0000-0002-3127-3138
authors.initials: SP
authors.lastname: Ribeiro
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Milush
authors.affiliation: Laboratory of Clinical Immunology and Allergy-LIM60/ University of Sao Paulo School of Medicine, São Paulo, Brazil.|Institute of Investigation in Immunology-iii-INCT, São Paulo, Brazil.|Laboratory of Immunology, Heart Institute, University of Sao Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Edecio
authors.initials: E
authors.lastname: Cunha-Neto
authors.affiliation: Laboratory of Clinical Immunology and Allergy-LIM60/ University of Sao Paulo School of Medicine, São Paulo, Brazil.|Institute of Investigation in Immunology-iii-INCT, São Paulo, Brazil.
authors.forename: Esper G
authors.initials: EG
authors.lastname: Kallas
authors.affiliation: Laboratory of Clinical Immunology and Allergy-LIM60/ University of Sao Paulo School of Medicine, São Paulo, Brazil.|Institute of Investigation in Immunology-iii-INCT, São Paulo, Brazil.|Laboratory of Immunology, Heart Institute, University of Sao Paulo School of Medicine, São Paulo, Brazil.|Butantan Institute, Butantan, São Paulo, SP, Brazil.
authors.forename: Jorge
authors.initials: J
authors.lastname: Kalil
authors.affiliation: São Vicent Unit, Paulista Coastal Campus, São Paulo State University "Julio de Mesquita Filho", Sao Paulo, Brazil.
authors.forename: Luiz Felipe D
authors.initials: LFD
authors.lastname: Passero
authors.affiliation: HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, United States of America.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hunt
authors.affiliation: HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Department of Microbiology, Immunology & Tropical Medicine, The George Washington University, Washington DC, United States of America.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Devi
authors.initials: D
authors.lastname: SenGupta