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1.
Vaccine ; 29(18): 3465-75, 2011 Apr 18.
Article in English | MEDLINE | ID: mdl-21382480

ABSTRACT

Virus-like particles (VLPs) are excellent tools for vaccines against pathogens and tumors. They can accommodate foreign polypeptides whose incorporation efficiency and immunogenicity however decrease strongly with the increase of their size. We recently described the CD8(+) T cell immune response against a small foreign antigen (i.e., the 98 amino acid long human papilloma virus E7 protein) incorporated in human immunodeficiency virus (HIV)-1 based VLPs as product of fusion with an HIV-1 Nef mutant (Nef(mut)). Here, we extended our previous investigations by testing the antigenic/immunogenic properties of Nef(mut)-based VLPs incorporating much larger heterologous products, i.e., human hepatitis C virus (HCV) NS3 and influenza virus NP proteins, which are composed of 630 and 498 amino acids, respectively. We observed a remarkable cross-presentation of HCV NS3 in dendritic cells challenged with Nef(mut)-NS3 VLPs, as detected using a NS3 specific CD8(+) T cell clone as well as PBMCs from HCV infected patients. On the other hand, when injected in mice, Nef(mut)-NP VLPs elicited strong anti-NP CD8(+) T cell and CTL immune responses. In addition, we revealed the ability of Nef(mut) incorporated in VLPs to activate and mature primary human immature dendritic cells (iDCs). This phenomenon correlated with the activation of Src tyrosine kinase-related intracellular signaling, and can be transmitted from VLP-challenged to bystander iDCs. Overall, these results prove that Nef(mut)-based VLPs represent a rather flexible platform for the design of innovative CD8(+) T cell vaccines.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Vaccines, Virus-Like Particle/immunology , Animals , Antigen Presentation , Cross-Priming , HEK293 Cells , HIV-1/immunology , Humans , Immunity, Cellular , Interferon-gamma/immunology , Mice , Mice, Inbred C57BL , Nucleocapsid Proteins , RNA-Binding Proteins/immunology , Viral Core Proteins/immunology , Viral Nonstructural Proteins/immunology , nef Gene Products, Human Immunodeficiency Virus/immunology , src-Family Kinases/immunology
2.
Arch Virol ; 153(3): 463-72, 2008.
Article in English | MEDLINE | ID: mdl-18080858

ABSTRACT

Simian-human immunodeficiency virus (SHIV) 89.6P is considered to be one of the most pathogenic chimeric viruses in rhesus macaques. However, when crossing from one to another species of monkeys the pathogenicity of this virus may be affected. By using SHIV-89.6P(cy243), a virus obtained by passaging SHIV-89.6P in cynomolgus macaques, we investigated the dynamics of viral replication and the impact of the inoculum size (from 10 up to 50 monkey infectious dose) on the progression of the infection in 22 cynomolgus macaques. SHIV-89.6P(cy243 )caused massive depletion of CD4+ T-cells within 4 weeks of the inoculum, followed by an irreversible immune deficiency in a high proportion of the infected monkeys. This study demonstrates that SHIV-89.6P(cy243) is pathogenic in cynomolgus macaques and that the dynamics of the viral replication and the rate of clinical progression depend on the size of the inoculum. Our findings provide unique and relevant data, particularly with regard to the value of the in vivo titration used to select the most appropriate infectious dose to study the "virus-host" interplay.


Subject(s)
HIV/genetics , Macaca fascicularis/virology , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/genetics , Animals , CD4 Lymphocyte Count , Disease Progression , Genome, Viral , HIV/isolation & purification , HIV/pathogenicity , HIV/physiology , Humans , Kaplan-Meier Estimate , Mutation , Simian Immunodeficiency Virus/isolation & purification , Simian Immunodeficiency Virus/pathogenicity , Simian Immunodeficiency Virus/physiology , Viral Load , Virus Replication
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