title: Broad and cross-clade CD4+ T-cell responses elicited by a DNA vaccine encoding highly conserved and promiscuous HIV-1 M-group consensus peptides.
abstract: T-cell based vaccine approaches have emerged to counteract HIV-1/AIDS. Broad, polyfunctional and cytotoxic CD4(+) T-cell responses have been associated with control of HIV-1 replication, which supports the inclusion of CD4(+) T-cell epitopes in vaccines. A successful HIV-1 vaccine should also be designed to overcome viral genetic diversity and be able to confer immunity in a high proportion of immunized individuals from a diverse HLA-bearing population. In this study, we rationally designed a multiepitopic DNA vaccine in order to elicit broad and cross-clade CD4(+) T-cell responses against highly conserved and promiscuous peptides from the HIV-1 M-group consensus sequence. We identified 27 conserved, multiple HLA-DR-binding peptides in the HIV-1 M-group consensus sequences of Gag, Pol, Nef, Vif, Vpr, Rev and Vpu using the TEPITOPE algorithm. The peptides bound in vitro to an average of 12 out of the 17 tested HLA-DR molecules and also to several molecules such as HLA-DP, -DQ and murine IA(b) and IA(d). Sixteen out of the 27 peptides were recognized by PBMC from patients infected with different HIV-1 variants and 72% of such patients recognized at least 1 peptide. Immunization with a DNA vaccine (HIVBr27) encoding the identified peptides elicited IFN-γ secretion against 11 out of the 27 peptides in BALB/c mice; CD4(+) and CD8(+) T-cell proliferation was observed against 8 and 6 peptides, respectively. HIVBr27 immunization elicited cross-clade T-cell responses against several HIV-1 peptide variants. Polyfunctional CD4(+) and CD8(+) T cells, able to simultaneously proliferate and produce IFN-γ and TNF-α, were also observed. This vaccine concept may cope with HIV-1 genetic diversity as well as provide increased population coverage, which are desirable features for an efficacious strategy against HIV-1/AIDS.
authors.affiliation: Laboratory of Clinical Immunology and Allergy-LIM60, Division of Clinical Immunology and Allergy, Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Rafael Ribeiro
authors.initials: RR
authors.lastname: Almeida
authors.forename: Daniela Santoro
authors.initials: DS
authors.lastname: Rosa
authors.forename: Susan Pereira
authors.initials: SP
authors.lastname: Ribeiro
authors.forename: Vinicius Canato
authors.initials: VC
authors.lastname: Santana
authors.forename: Esper Georges
authors.initials: EG
authors.lastname: Kallás
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Jorge
authors.initials: J
authors.lastname: Kalil
authors.forename: Edecio
authors.initials: E
authors.lastname: Cunha-Neto
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000465:Algorithms; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016384:Consensus Sequence; D003429:Cross Reactions; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D011485:Protein Binding; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D019444:Vaccines, DNA
chemical_list: D016915:AIDS Vaccines; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D054298:Human Immunodeficiency Virus Proteins; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D019444:Vaccines, DNA; D007371:Interferon-gamma