Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome.
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.
Antonelli
Lis R V
LR
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Mahnke
Yolanda
Y
Hodge
Jessica N
JN
Porter
Brian O
BO
Barber
Daniel L
DL
DerSimonian
Rebecca
R
Greenwald
Jamieson H
JH
Roby
Gregg
G
Mican
Joann
J
Sher
Alan
A
Roederer
Mario
M
Sereti
Irini
I
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
D019380:Anti-HIV Agents; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor