title: A transcriptome-based model of central memory CD4 T cell death in HIV infection.
abstract: Human central memory CD4 T cells are characterized by their capacity of proliferation and differentiation into effector memory CD4 T cells. Homeostasis of central memory CD4 T cells is considered a key factor sustaining the asymptomatic stage of Human Immunodeficiency Virus type 1 (HIV-1) infection, while progression to acquired immunodeficiency syndrome is imputed to central memory CD4 T cells homeostatic failure. We investigated if central memory CD4 T cells from patients with HIV-1 infection have a gene expression profile impeding proliferation and survival, despite their activated state.
  
  
  
  Using gene expression microarrays, we analyzed mRNA expression patterns in naive, central memory, and effector memory CD4 T cells from healthy controls, and naive and central memory CD4 T cells from patients with HIV-1 infection. Differentially expressed genes, defined by Log2Fold Change (FC) ≥ |0.5| and Log (odds) > 0, were used in pathway enrichment analyses.
  
  
  
  Central memory CD4 T cells from patients and controls showed comparable expression of differentiation-related genes, ruling out an effector-like differentiation of central memory CD4 T cells in HIV infection. However, 210 genes were differentially expressed in central memory CD4 T cells from patients compared with those from controls. Expression of 75 of these genes was validated by semi quantitative RT-PCR, and independently reproduced enrichment results from this gene expression signature. The results of functional enrichment analysis indicated movement to cell cycle phases G1 and S (increased CCNE1, MKI67, IL12RB2, ADAM9, decreased FGF9, etc.), but also arrest in G2/M (increased CHK1, RBBP8, KIF11, etc.). Unexpectedly, the results also suggested decreased apoptosis (increased CSTA, NFKBIA, decreased RNASEL, etc.). Results also suggested increased IL-1β, IFN-γ, TNF, and RANTES (CCR5) activity upstream of the central memory CD4 T cells signature, consistent with the demonstrated milieu in HIV infection.
  
  
  
  Our findings support a model where progressive loss of central memory CD4 T cells in chronic HIV-1 infection is driven by increased cell cycle entry followed by mitotic arrest, leading to a non-apoptotic death pathway without actual proliferation, possibly contributing to increased turnover.
authors.affiliation: Department of Research in Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calzada de Tlalpan 4502, Mexico City, Mexico.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Olvera-García
authors.affiliation: Department of Research in Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calzada de Tlalpan 4502, Mexico City, Mexico.
authors.forename: Tania
authors.initials: T
authors.lastname: Aguilar-García
authors.affiliation: Department of Research in Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calzada de Tlalpan 4502, Mexico City, Mexico.
authors.forename: Fany
authors.initials: F
authors.lastname: Gutiérrez-Jasso
authors.affiliation: Computational Genomics Department, Instituto Nacional de Medicina Genómica, Periferico Sur 4809, Mexico City, Mexico.
authors.forename: Iván
authors.initials: I
authors.lastname: Imaz-Rosshandler
authors.affiliation: Computational Genomics Department, Instituto Nacional de Medicina Genómica, Periferico Sur 4809, Mexico City, Mexico.
authors.forename: Claudia
authors.initials: C
authors.lastname: Rangel-Escareño
authors.affiliation: Laboratory of Immunogenomics and Metabolic Diseases, Instituto Nacional de Medicina Genómica, Periferico Sur 4809, Mexico City, Mexico.
authors.forename: Lorena
authors.initials: L
authors.lastname: Orozco
authors.affiliation: Laboratory of Immunogenomics and Metabolic Diseases, Instituto Nacional de Medicina Genómica, Periferico Sur 4809, Mexico City, Mexico.
authors.forename: Irma
authors.initials: I
authors.lastname: Aguilar-Delfín
authors.affiliation: Department of Virology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calzada de Tlalpan 4502, Mexico City, Mexico.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Vázquez-Pérez
authors.affiliation: Department of Research in Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calzada de Tlalpan 4502, Mexico City, Mexico.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Zúñiga
authors.affiliation: Infectious Immunopathogenesis Laboratory, Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Avenida Vasco de Quiroga 15, Mexico City, Mexico.
authors.forename: Santiago
authors.initials: S
authors.lastname: Pérez-Patrigeon
authors.affiliation: Department of Research in Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calzada de Tlalpan 4502, Mexico City, Mexico. espinosa@iner.gob.mx.
authors.forename: Enrique
authors.identifier: 0000-0002-3231-1626
authors.initials: E
authors.lastname: Espinosa
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D002453:Cell Cycle / Q000235:genetics; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D015497:HIV-1; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000821:virology; D059467:Transcriptome
keywords: CD4-Positive T-Lymphocytes; Cell Cycle; Cell Death; HIV; Homeostasis; Immunologic Memory; Transcriptome