title: Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.
abstract: Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART.
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987;
authors.forename: Rafael
authors.initials: R
authors.lastname: Cubas
authors.affiliation: Institut National de la Recherche Scientifique, Institut Armand-Frappier, Laval H7V 1B7, Quebec, Canada;
authors.forename: Julien
authors.identifier: http://orcid.org/0000-0002-2952-4081
authors.initials: J
authors.lastname: van Grevenynghe
authors.affiliation: Department of Immunology and the Duke Human Vaccine Institute, Duke University, Durham, NC 27710;
authors.forename: Saintedym
authors.identifier: http://orcid.org/0000-0003-2379-8679
authors.initials: S
authors.lastname: Wills
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Lela
authors.identifier: http://orcid.org/0000-0001-9135-6026
authors.initials: L
authors.lastname: Kardava
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Brian H
authors.identifier: http://orcid.org/0000-0001-5869-3661
authors.initials: BH
authors.lastname: Santich
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Clarisa M
authors.identifier: http://orcid.org/0000-0002-8178-8076
authors.initials: CM
authors.lastname: Buckner
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987;
authors.forename: Roshell
authors.initials: R
authors.lastname: Muir
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987;
authors.forename: Virginie
authors.initials: V
authors.lastname: Tardif
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987;
authors.forename: Carmen
authors.identifier: http://orcid.org/0000-0003-0364-9625
authors.initials: C
authors.lastname: Nichols
authors.affiliation: Service d'Immunologie et Allergie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland;
authors.forename: Francesco
authors.initials: F
authors.lastname: Procopio
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987;
authors.forename: Zhong
authors.identifier: http://orcid.org/0000-0002-7369-9989
authors.initials: Z
authors.lastname: He
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987;
authors.forename: Talibah
authors.initials: T
authors.lastname: Metcalf
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987;
authors.forename: Khader
authors.identifier: http://orcid.org/0000-0003-0548-1942
authors.initials: K
authors.lastname: Ghneim
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Michela
authors.initials: M
authors.lastname: Locci
authors.affiliation: Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada; Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada;
authors.forename: Petronella
authors.identifier: http://orcid.org/0000-0003-1922-5640
authors.initials: P
authors.lastname: Ancuta
authors.affiliation: Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec H3H 2R9, Canada; Research Institute, McGill University Health Centre, Montreal, Quebec H3H 2R9, Canada; Division of Hematology, McGill University Health Centre, Montreal, Quebec H3H 2R9, Canada;
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987;
authors.forename: Lydie
authors.initials: L
authors.lastname: Trautmann
authors.affiliation: International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Adrian B
authors.initials: AB
authors.lastname: McDermott
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Rick A
authors.initials: RA
authors.lastname: Koup
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Constantinos
authors.initials: C
authors.lastname: Petrovas
authors.affiliation: HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Steven A
authors.initials: SA
authors.lastname: Migueles
authors.affiliation: HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.affiliation: Department of Immunology and the Duke Human Vaccine Institute, Duke University, Durham, NC 27710;
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Susan
authors.initials: S
authors.lastname: Moir
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093; and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037.
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987; elias.elhaddad@drexelmed.edu.
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology; D002454:Cell Differentiation; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D002908:Chronic Disease; D006678:HIV; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000276:immunology*; D008875:Middle Aged; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000821:virology; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D007376:Interleukin-2