title: PD-1(+) and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals.
abstract: The mechanisms responsible for the persistence of HIV-1 after many years of suppressive antiretroviral therapy (ART) have been only partially elucidated. Most of the studies investigating HIV-1 persistence have been performed with blood, although it is well known that germinal centers (GCs) within lymph nodes (LNs) serve as primary sites for HIV-1 replication. We sought to identify the memory CD4 T cell populations in blood and LNs that are responsible for the production of replication-competent and infectious HIV-1, as well as for active and persistent virus transcription in ART-treated (for 1.5-14.0 years), aviremic (<50 HIV RNA copies/ml) HIV-infected individuals. We demonstrate that LN CD4 T cells that express programmed cell death 1 (PDCD1; also known as PD-1), which are composed of about 65% T follicular helper cells as defined by the expression of the cell surface receptors CXCR5 and PD-1, are the major source of replication-competent HIV-1 and of infectious virus, as compared to any other (CXCR5(-)PD-1(-) and CXCR5(+)PD-1(-)) blood or LN memory CD4 T cell populations. LN PD-1(+) cells accounted for 46% and 96% of the total pools of memory CD4 T cells containing inducible replication-competent or infectious virus, respectively. Notably, higher levels of cell-associated HIV-1 RNA were present in LN PD-1(+) cells after long-term (up to 12 years) ART than in other memory CD4 T cell subpopulations. These results indicate that LN PD-1(+) cells are the major CD4 T cell compartment in the blood and LNs for the production of replication-competent and infectious HIV-1, and for active and persistent virus transcription in long-term-ART-treated aviremic individuals. Thus, these cells may represent a major obstacle to finding a functional cure for HIV-1 infection.
authors.affiliation: Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Riddhima
authors.initials: R
authors.lastname: Banga
authors.affiliation: Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Francesco Andrea
authors.initials: FA
authors.lastname: Procopio
authors.affiliation: Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Noto
authors.affiliation: Department of Clinical Infection, Microbiology and Immunology (CIMI), Institute of Infection and Global Health (IGH), University of Liverpool, Liverpool, UK.
authors.forename: Georgios
authors.initials: G
authors.lastname: Pollakis
authors.affiliation: Service of Infectious Diseases, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Cavassini
authors.affiliation: Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Khalid
authors.initials: K
authors.lastname: Ohmiti
authors.affiliation: Service of Vascular Surgery, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Corpataux
authors.affiliation: Institute of Pathology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: de Leval
authors.affiliation: Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.|Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pantaleo
authors.affiliation: Service of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Perreau
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D016022:Case-Control Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008198:Lymph Nodes / Q000166:cytology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D014779:Virus Replication
chemical_list: C095085:CXCR5 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012367:RNA, Viral; D054380:Receptors, CXCR5