RESUMO
Feline immunodeficiency virus (FIV) DNA vaccine approaches that included a vif-deleted FIV provirus (FIV-pPPRDeltavif) and feline cytokine expression plasmids were tested for immunogenicity and efficacy by immunization of specific pathogen free cats. Vaccine protocols included FIV-pPPRDeltavif plasmid alone; a combination of FIV-pPPRDeltavif DNA and feline granulocyte macrophage-colony stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-alpha expression plasmids; or a combination of FIV-pPPRDeltavif and feline interleukin (IL)-15 plasmids. Cats immunized with FIV-pPPRDeltavif, GM-CSF and TNF-alpha plasmids demonstrated an increased frequency of FIV-specific T cell proliferation responses compared to other vaccine groups. Immunization with FIV-pPPRDeltavif and IL-15 plasmids was distinguished from other vaccine protocols by the induction of antiviral antibodies. Suppression of virus loads was not observed for any of the FIV-pPPRDeltavif DNA vaccine protocols after challenge with the FIV-PPR isolate. However, prior immunization with FIV-pPPRDeltavif, GM-CSF, and TNF-alpha plasmids resulted in preservation of CD4 T cell functions, including mitogen-induced cytokine expression and antigen-specific proliferation upon infection with FIV. These findings justify further examination of cytokine combinations as adjuvants for lentiviral DNA vaccines.
Assuntos
Adjuvantes Imunológicos/farmacologia , Produtos do Gene vif/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Vírus da Imunodeficiência Felina/imunologia , Fator de Necrose Tumoral alfa/farmacologia , Vacinas de DNA/imunologia , Vacinas Virais/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/genética , Animais , Anticorpos Antivirais/sangue , Linfócitos T CD4-Positivos/imunologia , Gatos , Proliferação de Células , Síndrome de Imunodeficiência Adquirida Felina/imunologia , Síndrome de Imunodeficiência Adquirida Felina/prevenção & controle , Deleção de Genes , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Vírus da Imunodeficiência Felina/genética , Provírus/genética , Provírus/imunologia , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/genética , Vacinas de DNA/genética , Carga Viral , Vacinas Virais/genéticaRESUMO
Simian immunodeficiency virus (SIV) infection of rhesus macaques is a valuable animal model for human immunodeficiency virus (HIV)-1 vaccine development. Our laboratory recently described the immunogenicity and limited efficacy of a vif-deleted SIVmac239 proviral DNA (SIV/CMVDelta vif) vaccine. The current report characterizes immunogenicity and efficacy for the SIV/CMVDelta vif proviral DNA vaccine when co-inoculated with an optimized rhesus interleukin (rIL)-15 expression plasmid. Macaques co-inoculated with rIL-15 and SIV/CMVDelta vif proviral plasmids showed significantly improved SIV-specific CD8 T cell immunity characterized by increased IFN-gamma ELISPOT and polyfunctional CD8 T cell responses. Furthermore, these animals demonstrated a sustained suppression of plasma virus loads after multiple low dose vaginal challenges with pathogenic SIVmac251. Importantly, SIV-specific cellular responses were greater in immunized animals compared to unvaccinated controls during the initial 12 weeks after challenge. Taken together, these findings support the use of IL-15 as an adjuvant in prophylactic anti-HIV vaccine strategies.
Assuntos
Adjuvantes Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Interleucina-15/farmacologia , Provírus/imunologia , Vacinas contra a SAIDS/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vacinas de DNA/imunologia , Adjuvantes Imunológicos/genética , Animais , Feminino , Deleção de Genes , Produtos do Gene vif/genética , Interferon gama/metabolismo , Interleucina-15/genética , Macaca mulatta , Plasmídeos , Provírus/genética , Vacinas contra a SAIDS/genética , Vacinas de DNA/genética , Carga ViralRESUMO
Studies in non-human primates, with simian immunodeficiency virus (SIV) and simian/human immunodeficiency virus (SHIV) have demonstrated that live-attenuated viral vaccines are highly effective; however these vaccine viruses maintain a low level of pathogenicity. Lentivirus attenuation associated with deletion of the viral vif gene carries a significantly reduced risk for pathogenicity, while retaining the potential for virus replication of low magnitude in the host. This report describes a vif-deleted simian immunodeficiency virus (SIV)mac239 provirus that was tested as an attenuated proviral DNA vaccine by inoculation of female rhesus macaques. SIV-specific interferon-gamma enzyme-linked immunospot responses of low magnitude were observed after immunization with plasmid containing the vif-deleted SIV provirus. However, vaccinated animals displayed strong sustained virus-specific T cell proliferative responses and increasing antiviral antibody titers. These immune responses suggested either persistent vaccine plasmid expression or low level replication of vif-deleted SIV in the host. Immunized and unvaccinated macaques received a single high dose vaginal challenge with pathogenic SIVmac251. A transient suppression of challenge virus load and a greater median survival time was observed for vaccinated animals. However, virus loads for vaccinated and unvaccinated macaques were comparable by twenty weeks after challenge and overall survival curves for the two groups were not significantly different. Thus, a vif-deleted SIVmac239 proviral DNA vaccine is immunogenic and capable of inducing a transient suppression of pathogenic challenge virus, despite severe attenuation of the vaccine virus.
