title: Induction of HIV-1-specific T cell responses by administration of cytokines in late-stage patients receiving highly active anti-retroviral therapy.
abstract: Highly active anti-retroviral therapy (HAART) is associated with reduction in the morbidity and mortality of patients with advanced HIV-1 disease. The ability of such treatment to improve immune responses against HIV-1 and opportunistic pathogens is variable and limited. Addition of cytokine immunotherapy to this treatment may improve immune responses. IL-2 with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to HIV-1+ individuals receiving HAART with undetectable viral loads, and CD4 counts < 100 cells/microl. In one patient presenting with Mycobacterium avium complex (MAC) infection, we evaluated the effect of cytokine immunotherapy on lymphocyte phenotype; plasma viral load; proliferative responses to mitogens, recall and HIV-1 antigens; cytokine production and message in response to non-specific and specific stimuli; and natural killer (NK) cell activity. Proliferation assays were performed in two similar patients. Before cytokine immunotherapy the predominant CD8+ population was mainly CD28-. No proliferation or IL-2 production was seen in response to mitogens, recall or HIV-1 antigens; and no HIV-1 peptide-specific interferon-gamma (IFN-gamma)-secreting cells were present. Low levels of IL-4 were detected in response to antigens to which patients had been exposed, associated with up-regulated expression of costimulatory molecules influenced by IL-4. Following IL-2 administration, loss of IL-4 was associated with increased NK cell activity and HIV-1 peptide-specific and non-specific IFN-gamma-producing cells. Proliferative responses associated with IL-2 production and responsiveness were only seen after subsequent concomitant administration of GM-CSF with IL-2. These changes mirrored clinical improvement. An imbalance of lymphocyte subsets may account for immune unresponsiveness when receiving HAART. Restoration of responses following immunotherapy suggests a shift towards a lymphocyte profile with anti-pathogen activity.
authors.affiliation: Department of Immunology, Imperial College School of Medicine, Chelsea & Westminster Hospital, London, UK. n.imami@ic.ac.uk
authors.forename: N
authors.initials: N
authors.lastname: Imami
authors.forename: G A
authors.initials: GA
authors.lastname: Hardy
authors.forename: M R
authors.initials: MR
authors.lastname: Nelson
authors.forename: S
authors.initials: S
authors.lastname: Morris-Jones
authors.forename: R
authors.initials: R
authors.lastname: Al-Shahi
authors.forename: C
authors.initials: C
authors.lastname: Antonopoulos
authors.forename: B
authors.initials: B
authors.lastname: Gazzard
authors.forename: F M
authors.initials: FM
authors.lastname: Gotch
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology; D004359:Drug Therapy, Combination; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D015497:HIV-1 / Q000276:immunology*; D015797:HLA-B35 Antigen / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects / Q000096:biosynthesis; D015847:Interleukin-4 / Q000172:deficiency / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D015797:HLA-B35 Antigen; D007376:Interleukin-2; D008934:Mitogens; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor