title: Diverse repertoire of HIV-1 p24-specific, IFN-gamma-producing CD4+ T cell clones following immune reconstitution on highly active antiretroviral therapy.
abstract: HIV-1 Ag-specific CD4(+) T cell proliferative responses in human subjects with advanced, untreated HIV-1 disease are often weak or undetectable. Conversely, HIV-1-specific CD4(+) T cell proliferation is occasionally detected following suppression of HIV-1 replication with highly active antiretroviral therapy (HAART). These observations suggest that unchecked HIV-1 replication may lead to depletion or dysfunction of HIV-1-specific CD4(+) T cells, and that these defects may be partially corrected by viral suppression and subsequent immune reconstitution. However, the impact of this immune reconstitution on the repertoire of HIV-1-specific CD4(+) T cells has not been thoroughly evaluated. To examine the HIV-1-specific CD4(+) T cell repertoire in this clinical setting, we established HIV-1 p24-specific CD4(+) T cell clones from a successfully HAART-treated subject whose pretreatment peripheral CD4 count was 0 cells/ micro l. Eleven different p24-specific CD4(+) T cell clonotypes were distinguished among 13 clones obtained. Most clones produced both IFN-gamma and IL-4 upon Ag stimulation. Clones targeted eight distinct epitopes that varied in their conservancy among HIV-1 strains, and responses were restricted by one of three MHC II molecules. Clones showed a range of functional avidities for both protein and peptide Ags. Additional studies confirmed that multiple HIV-1 p24-derived epitopes were targeted by IFN-gamma-producing CD4(+) cells from subjects first treated with HAART during advanced HIV-1 disease (median, 4.5 peptides/subject; range, 3-6). These results suggest that in HAART-treated subjects whose peripheral CD4(+) T cell pools were once severely depleted, the HIV-1-specific CD4(+) T cell repertoire may include a diverse array of clonotypes targeting multiple HIV-1 epitopes.
authors.affiliation: Department of Immunology, University of Colorado Health Sciences Center, Denver 80262, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Boritz
authors.forename: Brent E
authors.initials: BE
authors.lastname: Palmer
authors.forename: Brian
authors.initials: B
authors.lastname: Livingston
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Cara C
authors.initials: CC
authors.lastname: Wilson
mesh_terms: D000483:Alleles; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D002999:Clone Cells; D017124:Conserved Sequence / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D016655:HIV Core Protein p24 / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006684:HLA-DR Antigens / Q000378:metabolism; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis*; D008297:Male; D011485:Protein Binding / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis / Q000096:biosynthesis; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D016655:HIV Core Protein p24; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007371:Interferon-gamma