title: CD4+ T cells from HIV-1-infected patients recognize wild-type and mutant human immunodeficiency virus-1 protease epitopes.
abstract: Human immunodeficiency virus (HIV)-1 protease is a known target of CD8+ T cell responses, but it is the only HIV-1 protein in which no fully characterized HIV-1 protease CD4 epitopes have been identified to date. We investigated the recognition of HIV-1 protease by CD4+ T cells from 75 HIV-1-infected, protease inhibitor (PI)-treated patients, using the 5,6-carboxyfluorescein diacetate succinimidyl ester-based proliferation assay. In order to identify putative promiscuous CD4+ T cell epitopes, we used the TEPITOPE algorithm to scan the sequence of the HXB2 HIV-1 protease. Protease regions 4-23, 45-64 and 73-95 were identified; 32 sequence variants of the mentioned regions, encoding frequent PI-induced mutations and polymorphisms, were also tested. On average, each peptide bound to five of 15 tested common human leucocyte antigen D-related (HLA-DR) molecules. More than 80% of the patients displayed CD4+ as well as CD8+ T cell recognition of at least one of the protease peptides. All 35 peptides were recognized. The response was not associated with particular HLA-DR or -DQ alleles. Our results thus indicate that protease is a frequent target of CD4+ along with CD8+ proliferative T cell responses by the majority of HIV-1-infected patients under PI therapy. The frequent finding of matching CD4(+) and CD8+ T cell responses to the same peptides may indicate that CD4+ T cells provide cognate T cell help for the maintenance of long-living protease-specific functional CD8+ T cells.
authors.affiliation: Division of Clinical Immunology and Allergy, Department of Medicine, School of Medicine Heart Institute (InCor) Institute of Tropical Medicine, University of São Paulo, São Paulo, SP 01246-000, Brazil.
authors.forename: N G
authors.initials: NG
authors.lastname: Muller
authors.forename: R
authors.initials: R
authors.lastname: Alencar
authors.forename: L
authors.initials: L
authors.lastname: Jamal
authors.forename: J
authors.initials: J
authors.lastname: Hammer
authors.forename: J
authors.initials: J
authors.lastname: Sidney
authors.forename: A
authors.initials: A
authors.lastname: Sette
authors.forename: R M
authors.initials: RM
authors.lastname: Brindeiro
authors.forename: J
authors.initials: J
authors.lastname: Kalil
authors.forename: E
authors.initials: E
authors.lastname: Cunha-Neto
authors.forename: S L
authors.initials: SL
authors.lastname: Moraes
mesh_terms: D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018604:Epitope Mapping / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016333:HIV Protease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding
chemical_list: D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D010455:Peptides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1