title: TB-IRIS, T-cell activation, and remodeling of the T-cell compartment in highly immunosuppressed HIV-infected patients with TB.
abstract: OBJECTIVE
  To investigate the impact of tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) upon immunological recovery and the T-cell compartment after initiation of TB and antiretroviral therapy (ART).
  
  
  METHODS
  We prospectively evaluated T-cell immunophenotypes by flow cytometry and cytokines by Luminex assays in a subset (n = 154) of highly immunosuppressed HIV-infected patients with TB from the Cambodian Early versus Late Introduction of Antiretrovirals randomized clinical trial. We compared findings from patients who developed TB-IRIS with findings from patients who did not develop TB-IRIS. Data were evaluated with mixed-effect linear regression, Kaplan-Meier estimates, and Wilcoxon rank-sum tests, and q-values were calculated to control for multiple comparisons.
  
  
  RESULTS
  Development of TB-IRIS was associated with significantly greater pre-ART frequencies of HLA-DRCD45ROCD4, CCR5CD4, OX40CD4, and Fas effector memory CD8 T cells, and significantly elevated levels of plasma interleukin (IL)-6, IL-1β, IL-8, and IL-10, and viral load. Post-ART initiation, effector memory CD4 and Fas effector memory CD4 T-cell frequencies significantly expanded, and central memory CD4 T-cell frequencies significantly contracted in patients who experienced TB-IRIS. By week 34 post-TB treatment initiation, effector memory/central memory CD4 T-cell ratios were markedly higher in TB-IRIS versus non-TB-IRIS patients.
  
  
  CONCLUSIONS
  A distinct pattern of pre-ART T-cell and cytokine markers appear to poise the immune response of certain patients to develop TB-IRIS. Experience of TB-IRIS is then associated with long-term remodeling of the CD4 T-cell memory compartment towards an effector memory-dominated phenotype. We speculate that these pre and post-ART TB-IRIS-associated immune parameters may contribute to superior immune control of TB/HIV co-infection and better clinical outcome.
authors.affiliation: aProgram in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA bImmunology Platform, Institut Pasteur du Cambodge, Phnom Penh, Cambodia cInstitut Pasteur, Emerging Diseases Epidemiology Unit, Paris, France dCambodian Health Committee, Phnom Penh, Cambodia eInstitut Pasteur du Cambodge, Epidemiology and Public Health Unit, Phnom Penh, Cambodia fDepartment of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA gFrench National Agency for Research on AIDS and Viral Hepatitis (ANRS), Paris hAssistance Publique - Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France. *Viraga Haridas, Polidy Pean, and Luke D. Jasenosky contributed equally to the writing of this article. †Current address: Univ. Montpellier, INSERM U1058, Department of Infectious and Tropical Diseases, CHRU Nimes, Nimes, France. ‡Current Address: Univ. Bordeaux, Centre INSERM U897, Epidemiologie-Biostatisque, Bordeaux, France. §Current address: Calmette Hospital, Phnom Penh, Cambodia. ¶Current address: UMR INSERM 1087, CNRS UMR_6291, l'Institut du Thorax, Nantes University, Nantes, France.
authors.forename: Viraga
authors.initials: V
authors.lastname: Haridas
authors.forename: Polidy
authors.initials: P
authors.lastname: Pean
authors.forename: Luke D
authors.initials: LD
authors.lastname: Jasenosky
authors.forename: Yoann
authors.initials: Y
authors.lastname: Madec
authors.forename: Didier
authors.initials: D
authors.lastname: Laureillard
authors.forename: Thim
authors.initials: T
authors.lastname: Sok
authors.forename: Sun
authors.initials: S
authors.lastname: Sath
authors.forename: Laurence
authors.initials: L
authors.lastname: Borand
authors.forename: Olivier
authors.initials: O
authors.lastname: Marcy
authors.forename: Sarin
authors.initials: S
authors.lastname: Chan
authors.forename: Erdyni
authors.initials: E
authors.lastname: Tsitsikov
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Delfraissy
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Blanc
authors.forename: Anne E
authors.initials: AE
authors.lastname: Goldfeld
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000627:therapeutic use*; D002160:Cambodia; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000276:immunology / Q000473:pathology*; D016130:Immunophenotyping; D008297:Male; D011446:Prospective Studies; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology
chemical_list: D044966:Anti-Retroviral Agents; D000995:Antitubercular Agents; D016207:Cytokines