title: Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome.
abstract: Immune reconstitution inflammatory syndrome (IRIS) is a considerable problem in the treatment of HIV-infected patients. To identify immunologic correlates of IRIS, we characterized T-cell phenotypic markers and serum cytokine levels in HIV patients with a range of different AIDS-defining illnesses, before and at regular time points after initiation of antiretroviral therapy. Patients developing IRIS episodes displayed higher frequencies of effector memory, PD-1(+), HLA-DR(+), and Ki67(+) CD4(+) T cells than patients without IRIS. Moreover, PD-1(+) CD4(+) T cells in IRIS patients expressed increased levels of LAG-3, CTLA-4, and ICOS and had a Th1/Th17 skewed cytokine profile upon polyclonal stimulation. Elevated PD-1 and Ki67 expression was also seen in regulatory T cells of IRIS patients. Furthermore, IRIS patients displayed higher serum interferon-γ, compared with non-IRIS patients, near the time of their IRIS events and higher serum interleukin-7 levels, suggesting that the T-cell populations are also exposed to augmented homeostatic signals. In conclusion, our findings indicate that IRIS appears to be a predominantly CD4-mediated phenomenon with reconstituting effector and regulatory T cells showing evidence of increased activation from antigenic exposure. These studies are registered online at http://clinicaltrials.gov as NCT00557570 and NCT00286767.
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lis R V
authors.initials: LR
authors.lastname: Antonelli
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Mahnke
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Hodge
authors.forename: Brian O
authors.initials: BO
authors.lastname: Porter
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Barber
authors.forename: Rebecca
authors.initials: R
authors.lastname: DerSimonian
authors.forename: Jamieson H
authors.initials: JH
authors.lastname: Greenwald
authors.forename: Gregg
authors.initials: G
authors.lastname: Roby
authors.forename: Joann
authors.initials: J
authors.lastname: Mican
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.forename: Irini
authors.initials: I
authors.lastname: Sereti
mesh_terms: D019380:Anti-HIV Agents / Q000009:adverse effects*; D015703:Antigens, CD / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000209:etiology* / Q000276:immunology*; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D061026:Programmed Cell Death 1 Receptor; D012189:Retrospective Studies; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D019380:Anti-HIV Agents; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor