title: CD25+ FoxP3+ Memory CD4 T Cells Are Frequent Targets of HIV Infection In Vivo.
abstract: Interleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates HIV replication in vitro and facilitates homeostatic proliferation of CD25(+) FoxP3(+) CD4(+) T cells. CD25(+) FoxP3(+) CD4(+) T cells may therefore constitute a suitable subset for HIV infection and plasma virion production. CD25(+) FoxP3(+) CD4(+) T cell frequencies, absolute numbers, and the expression of CCR5 and cell cycle marker Ki67 were studied in peripheral blood from HIV(+) and HIV(-) study volunteers. Different memory CD4(+) T cell subsets were then sorted for quantification of cell-associated HIV DNA and phylogenetic analyses of the highly variable EnvV1V3 region in comparison to plasma-derived virus sequences. In HIV(+) subjects, 51% (median) of CD25(+) FoxP3(+) CD4(+) T cells expressed the HIV coreceptor CCR5. Very high frequencies of Ki67(+) cells were detected in CD25(+) FoxP3(+) memory CD4(+) T cells (median, 27.6%) in comparison to CD25(-) FoxP3(-) memory CD4(+) T cells (median, 4.1%; P < 0.0001). HIV DNA content was 15-fold higher in CD25(+) FoxP3(+) memory CD4(+) T cells than in CD25(-) FoxP3(-) T cells (P = 0.003). EnvV1V3 sequences derived from CD25(+) FoxP3(+) memory CD4(+) T cells did not preferentially cluster with plasma-derived sequences. Quasi-identical cell-plasma sequence pairs were rare, and their proportion decreased with the estimated HIV infection duration. These data suggest that specific cellular characteristics of CD25(+) FoxP3(+) memory CD4(+) T cells might facilitate efficient HIV infection in vivo and passage of HIV DNA to cell progeny in the absence of active viral replication. The contribution of this cell population to plasma virion production remains unclear.
  
  
  
  Despite recent advances in the understanding of AIDS virus pathogenesis, which cell subsets support HIV infection and replication in vivo is incompletely understood. In vitro, the IL-2 signaling pathway and IL-2-dependent cell cycle induction are essential for HIV infection of stimulated T cells. CD25(+) FoxP3(+) memory CD4 T cells, often referred to as regulatory CD4 T cells, depend on IL-2 signaling for homeostatic proliferation in vivo Our results show that CD25(+) FoxP3(+) memory CD4(+) T cells often express the HIV coreceptor CCR5, are significantly more proliferative, and contain more HIV DNA than CD25(-) FoxP3(-) memory CD4 T cell subsets. The specific cellular characteristics of CD25(+) FoxP3(+) memory CD4(+) T cells probably facilitate efficient HIV infection in vivo and passage of HIV DNA to cell progeny in the absence of active viral replication. However, the contribution of this cell subset to plasma viremia remains unclear.
authors.affiliation: NIMR Mbeya Medical Research Centre, Mbeya, Tanzania mchachage@nimr-mmrc.org geldmacher@lrz.uni-muenchen.de.
authors.forename: Mkunde
authors.initials: M
authors.lastname: Chachage
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Georgios
authors.initials: G
authors.lastname: Pollakis
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Dusseldorf, Germany.
authors.forename: Edmund Osei
authors.initials: EO
authors.lastname: Kuffour
authors.affiliation: Department of Genome Oriented Bioinformatics, Technische Universität München, Freising, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Haase
authors.affiliation: NIMR Mbeya Medical Research Centre, Mbeya, Tanzania Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany.
authors.forename: Asli
authors.initials: A
authors.lastname: Bauer
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nadai
authors.affiliation: NIMR Mbeya Medical Research Centre, Mbeya, Tanzania Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany.
authors.forename: Lilli
authors.initials: L
authors.lastname: Podola
authors.affiliation: NIMR Mbeya Medical Research Centre, Mbeya, Tanzania Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Clowes
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Helmholtz Center Munich, Technische Universität München, Munich, Germany Clinical Cooperation Groups Antigen-Specific Immunotherapy and Immune-Monitoring, Helmholtz Center Munich, Technische Universität München, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schiemann
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Helmholtz Center Munich, Technische Universität München, Munich, Germany.
authors.forename: Lynette
authors.initials: L
authors.lastname: Henkel
authors.affiliation: Institute of Virology, Helmholtz Center Munich, Technische Universität München, Munich, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoffmann
authors.affiliation: MRC Clinical Trials Unit at UCL, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Joseph
authors.affiliation: Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Sabin
authors.initials: S
authors.lastname: Bhuju
authors.affiliation: NIMR Mbeya Medical Research Centre, Mbeya, Tanzania.
authors.forename: Leonard
authors.initials: L
authors.lastname: Maboko
authors.affiliation: Kwame Nkrumah University of Science & Technology, Kumasi, Ghana.
authors.forename: Fred Stephen
authors.initials: FS
authors.lastname: Sarfo
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Eberhardt
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Dusseldorf, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Feldt
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Saathoff
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany mchachage@nimr-mmrc.org geldmacher@lrz.uni-muenchen.de.
authors.forename: Christof
authors.initials: C
authors.lastname: Geldmacher
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000821:virology*; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006678:HIV / Q000145:classification / Q000235:genetics / Q000302:isolation & purification*; D015658:HIV Infections / Q000821:virology*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis*; D019394:Ki-67 Antigen / Q000032:analysis; D010802:Phylogeny; D019713:Receptors, CCR5 / Q000032:analysis*; D017422:Sequence Analysis, DNA; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000821:virology*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: C584933:CCR5 protein, human; D004279:DNA, Viral; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D019394:Ki-67 Antigen; D019713:Receptors, CCR5; D054299:env Gene Products, Human Immunodeficiency Virus