RESUMO
The viral diversity of HIV-1 is likely to require a vaccine strategy that induces broad cellular and humoral anti-HIV-1 immunity. Our strategy is based on multiple HIV-1 DNA immunogens together with adjuvant recombinant granulocyte-macrophage stimulating factor. This article describes pre-clinical and clinical work preceding the initiation of clinical HIV-1 phase I/II trials.
Assuntos
Vacinas contra a AIDS/genética , Vacinas contra a AIDS/imunologia , Antígenos HIV/genética , Antígenos HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Vacinas de DNA/imunologia , Animais , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Modelos Animais de Doenças , Produtos do Gene gag/genética , Produtos do Gene gag/imunologia , Produtos do Gene nef/genética , Produtos do Gene nef/imunologia , Produtos do Gene rev/genética , Produtos do Gene rev/imunologia , Produtos do Gene tat/genética , Produtos do Gene tat/imunologia , Proteína gp160 do Envelope de HIV/genética , Proteína gp160 do Envelope de HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/terapia , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/imunologia , HIV-1/genética , Humanos , Vírus da Leucemia Murina , Camundongos , Camundongos Endogâmicos C57BL , Vacinas Combinadas/genética , Vacinas Combinadas/imunologia , Vacinas de DNA/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana , Produtos do Gene rev do Vírus da Imunodeficiência Humana , Produtos do Gene tat do Vírus da Imunodeficiência HumanaRESUMO
A highly desirable feature for an human immunodeficiency virus type 1 (HIV-1) vaccine is the ability to induce broadly reactive anti-envelope antibodies that can neutralize primary HIV-1 isolates. Two immunizations with an HIV-1 envelope-encoding plasmid together with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) resulted in high antibody titers in mice. The antibody induction was further enhanced after immunization with genes encoding HIV-1 envelopes originating from subtypes A, B and C. The sera from these animals were able to neutralize A, B and C viral isolates, whereas the sera from animals immunized solely with subtype B DNA neutralized only subtype B virus. The combined DNA vaccine gave serum antibodies with broad recognition of HIV-1 envelope epitopes as determined by peptide mapping. Cell-mediated immunity was not compromised by the increased humoral immunity. This demonstrates the ability of multiple envelope genes to induce the desired antibody response against several subtypes. Moreover, it documents the ability of rGM-CSF to enhance the potency of such a vaccine when given simultaneously. The strategy may be useful for making an HIV vaccine more potent and broadly effective against strains of different clades.
Assuntos
Vacinas contra a AIDS/uso terapêutico , Anticorpos Antivirais/imunologia , Proteína gp160 do Envelope de HIV/genética , Infecções por HIV/terapia , Imunoterapia Ativa/métodos , Vacinas de DNA/uso terapêutico , Animais , Ensaio de Imunoadsorção Enzimática/métodos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/imunologia , Humanos , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes , Linfócitos T/imunologiaRESUMO
To improve immune responses induced by DNA immunization, murine polyomavirus major capsid protein (VP1) pseudocapsids were complexed with a DNA plasmid encoding the p37 (p24 and p17) nucleocapsid proteins of the human immunodeficiency virus type 1 (HIV-1). A 10-fold increase in antibody titer was noted in mice given DNA plasmid together with VP1 pseudocapsids in comparison to animals that received DNA plasmid alone. Cell mediated responses to HIV-1 p24 occurred, but were not significantly augmented by delivering the DNA as a VP1 complex. We have consequently for the first time shown a carrier/adjuvant effect of polyomavirus pseudocapsids that strongly increased the humoral immune response in DNA immunization.
Assuntos
Proteínas do Capsídeo/imunologia , Infecções por Polyomavirus/imunologia , Polyomavirus/imunologia , Vacinas de DNA/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/sangue , Formação de Anticorpos , Proteínas do Capsídeo/genética , Clonagem Molecular , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Clinical and experimental studies of HIV-1 subcomponents were made in order to increase their immunogenicity. HIV subtype envelopes A, B and C have been compared and a detailed analysis made by peptides of the coreceptor-ligand interactions. We identified a direct interaction between HIV-1 envelope and a cellular receptor at the amino acid level. Both the viral subtype and its tropism appeared to influence inhibition of infection. Genetic immunization induced new cytotoxic responses while proteins appeared to efficiently boost previous responses. One HIV-1 subtype B antigen was strongly immunogenic in a human immunotherapeutic trial and permitted better survival at 2 years of the study in patients with poor prognosis.