title: HIV-1 conserved elements p24CE DNA vaccine induces humoral immune responses with broad epitope recognition in macaques.
abstract: To target immune responses towards invariable regions of the virus, we engineered DNA-based immunogens encoding conserved elements (CE) of HIV-1 p24gag. This conserved element vaccine is designed to avoid decoy epitopes by focusing responses to critical viral elements. We previously reported that vaccination of macaques with p24CE DNA induced robust cellular immune responses to CE that were not elicited upon wild type p55gag DNA vaccination. p24CE DNA priming followed by p55gag DNA boost provided a novel strategy to increase the magnitude and breadth of the cellular immune responses to HIV-1 Gag, including the induction of strong, multifunctional T-cell responses targeting epitopes within CE. Here, we examined the humoral responses induced upon p24CE DNA or p55gag DNA vaccination in macaques and found that although both vaccines induced robust p24gag binding antibody responses, the responses induced by p24CE DNA showed a unique broad range of linear epitope recognition. In contrast, antibodies elicited by p55gag DNA vaccine failed to recognize p24CE protein and did not recognize linear epitopes spanning the CE. Interestingly, boosting of p24CE DNA primed animals with p55gag DNA resulted in augmentation of antibodies able to recognize p24gag as well as the p24CE proteins, thereby inducing broadest immunity. Our results indicate that an effectively directed vaccine strategy that includes priming with the conserved element vaccine followed by boost with the complete immunogen induces broad cellular and humoral immunity focused on the conserved regions of the virus. This novel and effective strategy to broaden responses could be applied against other antigens of highly diverse pathogens.
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
authors.forename: Viraj
authors.initials: V
authors.lastname: Kulkarni
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
authors.forename: Antonio
authors.initials: A
authors.lastname: Valentin
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
authors.forename: Margherita
authors.initials: M
authors.lastname: Rosati
authors.affiliation: Departments of Microbiology, Medicine and Laboratory Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Morgane
authors.initials: M
authors.lastname: Rolland
authors.affiliation: Departments of Microbiology, Medicine and Laboratory Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
authors.forename: George N
authors.initials: GN
authors.lastname: Pavlakis
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Felber
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D000939:Epitopes / Q000276:immunology; D005260:Female; D016655:HIV Core Protein p24 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D056724:Immunity, Humoral; D007117:Immunization, Secondary; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D000939:Epitopes; D016655:HIV Core Protein p24; D011498:Protein Precursors; D019444:Vaccines, DNA; C514799:p24 protein, Human Immunodeficiency Virus Type 1; C059767:p55 gag precursor protein, Human immunodeficiency virus 1