title: Infection of CD127+ (interleukin-7 receptor+) CD4+ cells and overexpression of CTLA-4 are linked to loss of antigen-specific CD4 T cells during primary human immunodeficiency virus type 1 infection.
abstract: We recently found that human immunodeficiency virus (HIV)-specific CD4+ T cells express coreceptor CCR5 and activation antigen CD38 during early primary HIV-1 infection (PHI) but then rapidly disappear from the circulation. This cell loss may be due to susceptibility to infection with HIV-1 but could also be due to inappropriate apoptosis, an expansion of T regulatory cells, trafficking out of the circulation, or dysfunction. We purified CD38+++CD4+ T cells from peripheral blood mononuclear cells, measured their level of HIV-1 DNA by PCR, and found that about 10% of this population was infected. However, a small subset of HIV-specific CD4+) T cells also expressed CD127, a marker of long-term memory cells. Purified CD127+CD4+ lymphocytes contained fivefold more copies of HIV-1 DNA per cell than did CD127-negative CD4+ cells, suggesting preferential infection of long-term memory cells. We observed no apoptosis of antigen-specific CD4+ T cells in vitro and only a small increase in CD45RO+CD25+CD127dimCD4+ T regulatory cells during PHI. However, 40% of CCR5+CD38+++ CD4+ T cells expressed gut-homing integrins, suggesting trafficking through gut-associated lymphoid tissue (GALT). Furthermore, 80% of HIV-specific CD4+ T cells expressed high levels of the negative regulator CTLA-4 in response to antigen stimulation in vitro, which was probably contributing to their inability to produce interleukin-2 and proliferate. Taken together, the loss of HIV-specific CD4+ T cells is associated with a combination of an infection of CCR5+ CD127+ memory CD4+ T cells, possibly in GALT, and a high expression of the inhibitory receptor CTLA-4.
authors.affiliation: Centre for Immunology, St. Vincent's Hospital, Victoria Street, Darlinghurst, NSW 2010, Australia. j.zaunders@cfi.unsw.edu.au
authors.forename: John J
authors.initials: JJ
authors.lastname: Zaunders
authors.forename: Susanna
authors.initials: S
authors.lastname: Ip
authors.forename: Mee Ling
authors.initials: ML
authors.lastname: Munier
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.forename: Kazuo
authors.initials: K
authors.lastname: Suzuki
authors.forename: Choechoe
authors.initials: C
authors.lastname: Brereton
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Sasson
authors.forename: Nabila
authors.initials: N
authors.lastname: Seddiki
authors.forename: Kersten
authors.initials: K
authors.lastname: Koelsch
authors.forename: Alan
authors.initials: A
authors.lastname: Landay
authors.forename: Pat
authors.initials: P
authors.lastname: Grey
authors.forename: Robert
authors.initials: R
authors.lastname: Finlayson
authors.forename: John
authors.initials: J
authors.lastname: Kaldor
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Barbara
authors.initials: B
authors.lastname: Fazekas de St Groth
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D000328:Adult; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D060908:CTLA-4 Antigen; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006801:Humans; D017493:Leukocyte Common Antigens / Q000032:analysis; D008297:Male; D016133:Polymerase Chain Reaction; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D019713:Receptors, CCR5 / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000032:analysis; D020395:Receptors, Interleukin-7 / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000821:virology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D004279:DNA, Viral; D019713:Receptors, CCR5; D015375:Receptors, Interleukin-2; D020395:Receptors, Interleukin-7; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D051997:ADP-ribosyl Cyclase 1