title: Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies.
abstract: Cytolytic CD8 T cells play a crucial role in the control and elimination of virus-infected cells and are a major focus of HIV cure efforts. However, it has been shown that HIV-specific CD8 T cells are infrequently found within germinal centers (GCs), a predominant site of active and latent HIV infection. We demonstrate that HIV infection induces marked changes in the phenotype, frequency, and localization of CD8 T cells within the lymph node (LN). Significantly increased frequencies of CD8 T cells in the B cell follicles and GCs were found in LNs from treated and untreated HIV-infected individuals. This profile was associated with persistent local immune activation but did not appear to be directly related to local viral replication. Follicular CD8 (fCD8) T cells, despite compromised cytokine polyfunctionality, showed good cytolytic potential characterized by high ex vivo expression of granzyme B and perforin. We used an anti-HIV/anti-CD3 bispecific antibody in a redirected killing assay and found that fCD8 T cells had better killing activity than did non-fCD8 T cells. Our results indicate that CD8 T cells with potent cytolytic activity are recruited to GCs during HIV infection and, if appropriately redirected to kill HIV-infected cells, could be an effective component of an HIV cure strategy.
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA. petrovasc@mail.nih.gov.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Petrovas
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Ferrando-Martinez
authors.affiliation: Laboratory of Systems Biology, Lymphocyte Biology Section, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Gerner
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Casazza
authors.affiliation: Virology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Amarendra
authors.initials: A
authors.lastname: Pegu
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, BG 535, Post Office Box B, Frederick, MD 21702, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Deleage
authors.affiliation: Virology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Arik
authors.initials: A
authors.lastname: Cooper
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Hataye
authors.affiliation: Immunology Core Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Andrews
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ambrozak
authors.affiliation: Departamento de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.
authors.forename: Perla M
authors.initials: PM
authors.lastname: Del Río Estrada
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Boritz
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Paris
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Eirini
authors.initials: E
authors.lastname: Moysi
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Boswell
authors.affiliation: Laboratory of Immunovirology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Consejo Superior de Investigaciones Cientificas, Sevilla 41013, Spain.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Ruiz-Mateos
authors.affiliation: Department of Histopathology, Venizeleio Hospital, Iraklion, Crete, Greece.
authors.forename: Ilias
authors.initials: I
authors.lastname: Vagios
authors.affiliation: Laboratory of Immunovirology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Consejo Superior de Investigaciones Cientificas, Sevilla 41013, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Leal
authors.affiliation: Departamento de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.
authors.forename: Yuria
authors.initials: Y
authors.lastname: Ablanedo-Terrazas
authors.affiliation: Departamento de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.
authors.forename: Amaranta
authors.initials: A
authors.lastname: Rivero
authors.affiliation: Departamento de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.
authors.forename: Luz Alicia
authors.initials: LA
authors.lastname: Gonzalez-Hernandez
authors.affiliation: Immunology Core Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Adrian B
authors.initials: AB
authors.lastname: McDermott
authors.affiliation: Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Moir
authors.affiliation: Departamento de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Reyes-Terán
authors.affiliation: Laboratory of Immunovirology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Consejo Superior de Investigaciones Cientificas, Sevilla 41013, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Docobo
authors.affiliation: Service of Immunology and Allergy, Service of Infectious Diseases, Department of Medicine and Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pantaleo
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.affiliation: Department of Microbiology, Center for AIDS Research, and Institute for Immunology Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, BG 535, Post Office Box B, Frederick, MD 21702, USA.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.affiliation: Laboratory of Systems Biology, Lymphocyte Biology Section, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Germain
authors.affiliation: Virology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
mesh_terms: D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D016207:Cytokines / Q000276:immunology; D005260:Female; D053804:Granzymes / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D008198:Lymph Nodes / Q000166:cytology; D008297:Male; D008875:Middle Aged; D014066:Palatine Tonsil / Q000166:cytology; D054353:Perforin / Q000276:immunology; D010641:Phenotype
chemical_list: D018033:Antibodies, Bispecific; D016207:Cytokines; D015483:HIV Antibodies; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes