title: Innate and adaptive immune responses both contribute to pathological CD4 T cell activation in HIV-1 infected Ugandans.
abstract: HIV-1 disease progression is associated with persistent immune activation. However, the nature of this association is incompletely understood. Here, we investigated immune activation in the CD4 T cell compartment of chronically HIV-1 infected individuals from Rakai, Uganda. Levels of CD4 T cell activation, assessed as co-expression of PD-1, CD38 and HLA-DR, correlated directly to viral load and inversely to CD4 count. Deeper characterization of these cells indicated an effector memory phenotype with relatively frequent expression of Ki67 despite their PD-1 expression, and levels of these cells were inversely associated with FoxP3+ regulatory T cells. We therefore use the term deregulated effector memory (DEM) cells to describe them. CD4 T cells with a DEM phenotype could be generated by antigen stimulation of recall responses in vitro. Responses against HIV-1 and CMV antigens were enriched among the DEM CD4 T cells in patients, and the diverse Vβ repertoire of DEM CD4 T cells suggested they include diverse antigen-specificities. Furthermore, the levels of DEM CD4 T cells correlated directly to soluble CD14 (sCD14) and IL-6, markers of innate immune activation, in plasma. The size of the activated DEM CD4 T cell subset was predictive of the rate of disease progression, whereas IL-6 was only weakly predictive and sCD14 was not predictive. Taken together, these results are consistent with a model where systemic innate immune activation and chronic antigen stimulation of adaptive T cell responses both play important roles in driving pathological CD4 T cell immune activation in HIV-1 disease.
authors.affiliation: Makerere University Walter Reed Project, Kampala, Uganda.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eller
authors.forename: Kim G
authors.initials: KG
authors.lastname: Blom
authors.forename: Veronica D
authors.initials: VD
authors.lastname: Gonzalez
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Eller
authors.forename: Prossy
authors.initials: P
authors.lastname: Naluyima
authors.forename: Oliver
authors.initials: O
authors.lastname: Laeyendecker
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Quinn
authors.forename: Noah
authors.initials: N
authors.lastname: Kiwanuka
authors.forename: David
authors.initials: D
authors.lastname: Serwadda
authors.forename: Nelson K
authors.initials: NK
authors.lastname: Sewankambo
authors.forename: Boonrat
authors.initials: B
authors.lastname: Tasseneetrithep
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Wawer
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Gray
authors.forename: Mary A
authors.initials: MA
authors.lastname: Marovich
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Michael
authors.forename: Mark S
authors.initials: MS
authors.lastname: de Souza
authors.forename: Fred
authors.initials: F
authors.lastname: Wabwire-Mangen
authors.forename: Merlin L
authors.initials: ML
authors.lastname: Robb
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Currier
authors.forename: Johan K
authors.initials: JK
authors.lastname: Sandberg
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D056704:Adaptive Immunity / Q000276:immunology*; D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D000956:Antigens, Viral / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D049109:Cell Proliferation; D002908:Chronic Disease; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000276:immunology*; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood; D018950:Lipopolysaccharide Receptors / Q000097:blood; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D014454:Uganda; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D000956:Antigens, Viral; D051017:Apoptosis Regulatory Proteins; D006684:HLA-DR Antigens; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051997:ADP-ribosyl Cyclase 1