Immunization with Hepatitis C Virus-Like Particles Induces Humoral and Cellular Immune Responses in Nonhuman Primates

ABSTRACT We have previously reported the production of hepatitis C virus-like particles (HCV-LP) using a recombinant baculovirus containing the cDNA of the HCV structural proteins (core, E1, and E2). These particles resemble the putative HCV virions and are capable of inducing strong and broad humoral and cellular immune responses in mice. Here we present evidence on the immunogenicity of HCV-LP and the effects of novel adjuvant systems in a nonhuman primate model, the baboon. Three groups of four baboons were immunized with HCV-LP, HCV-LP and adjuvant AS01B (monophosphoryl lipid A and QS21), or HCV-LP and the combination of AS01B and CpG oligodeoxynucleotides 10105. After four immunizations over an 8-month period, all animals developed HCV-specific humoral and cellular immune responses including antibodies to HCV structural proteins and gamma interferon+ (IFN-γ+)CD4+ and IFN-γ+CD8+ T-cell responses. The immunogenicity of HCV-LP was only marginally enhanced by the use of adjuvants. The overall HCV-specific immune responses were broad and long lasting. Our results suggest that HCV-LP is a potent immunogen to induce HCV-specific humoral and cellular immune responses in primates and may be a promising approach to develop novel preventive and therapeutic modalities.

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Hepatitis C virus–like particles induce virus-specific humoral and cellular immune responses in mice

Hepatology ◽

10.1053/jhep.2001.26523 ◽

2001 ◽

Vol 34 (2) ◽

pp. 417-423 ◽

Cited By ~ 77

Author(s):

M Lechmann

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Immune Responses ◽

Virus Like Particles ◽

Cellular Immune Responses ◽

Cellular Immune

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Induction of humoral and cellular immune responses against hepatitis C virus by vaccination with replicon particles derived from Sindbis-like virus XJ-160

Archives of Virology ◽

10.1007/s00705-012-1564-8 ◽

2012 ◽

Vol 158 (5) ◽

pp. 1013-1019 ◽

Cited By ~ 6

Author(s):

Wuyang Zhu ◽

Juanjuan Fu ◽

Jian Lu ◽

Yao Deng ◽

Huanqin Wang ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Immune Responses ◽

Cellular Immune Responses ◽

Cellular Immune

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Molecular and Immunological Significance of Chimpanzee Major Histocompatibility Complex Haplotypes for Hepatitis C Virus Immune Response and Vaccination Studies

Journal of Virology ◽

10.1128/jvi.76.12.6093-6103.2002 ◽

2002 ◽

Vol 76 (12) ◽

pp. 6093-6103 ◽

Cited By ~ 22

Author(s):

Eishiro Mizukoshi ◽

Michelina Nascimbeni ◽

Joshua B. Blaustein ◽

Kathleen Mihalik ◽

Charles M. Rice ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Major Histocompatibility Complex ◽

Hepatitis C ◽

Immune Responses ◽

Cellular Immune Responses ◽

Functional Homology ◽

Histocompatibility Complex ◽

Ifn Γ ◽

Cellular Immune

ABSTRACT The chimpanzee is a critical animal model for studying cellular immune responses to infectious pathogens such as hepatitis B and C viruses, human immunodeficiency virus, and malaria. Several candidate vaccines and immunotherapies for these infections aim at the induction or enhancement of cellular immune responses against viral epitopes presented by common human major histocompatibility complex (MHC) alleles. To identify and characterize chimpanzee MHC class I molecules that are functionally related to human alleles, we sequenced 18 different Pan troglodytes (Patr) alleles of 14 chimpanzees, 2 of them previously unknown and 3 with only partially reported sequences. Comparative analysis of Patr binding pockets and binding assays with biotinylated peptides demonstrated a molecular homology between the binding grooves of individual Patr alleles and the common human alleles HLA-A1, -A2, -A3, and -B7. Using cytotoxic T cells isolated from the blood of hepatitis C virus (HCV)-infected chimpanzees, we then mapped the Patr restriction of these HCV peptides and demonstrated functional homology between the Patr-HLA orthologues in cytotoxicity and gamma interferon (IFN-γ) release assays. Based on these results, 21 HCV epitopes were selected to characterize the chimpanzees' cellular immune response to HCV. In each case, IFN-γ-producing T cells were detectable in the blood after but not prior to HCV infection and were specifically targeted against those HCV peptides predicted by Patr-HLA homology. This study demonstrates a close functional homology between individual Patr and HLA alleles and shows that HCV infection generates HCV peptides that are recognized by both chimpanzees and humans with Patr and HLA orthologues. These results are relevant for the design and evaluation of vaccines in chimpanzees that can now be selected according to the most frequent human MHC haplotypes.

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High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection

Gastroenterology ◽

10.1053/j.gastro.2004.06.015 ◽

2004 ◽

Vol 127 (3) ◽

pp. 924-936 ◽

Cited By ~ 217

Author(s):

Georg M. Lauer ◽

Eleanor Barnes ◽

Michaela Lucas ◽

Joerg Timm ◽

Kei Ouchi ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

High Resolution ◽

Virus Infection ◽

Immune Responses ◽

Hepatitis C Virus Infection ◽

Cellular Immune Responses ◽

High Resolution Analysis ◽

Resolution Analysis ◽

Cellular Immune

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Hepatitis C virus-specific cellular immune responses in individuals with no evidence of infection

Virology Journal ◽

10.1186/1743-422x-9-76 ◽

2012 ◽

Vol 9 (1) ◽

Cited By ~ 8

Author(s):

Yves Rivière ◽

Thomas Montange ◽

Geneviève Janvier ◽

Caroline Marnata ◽

Ludovic Durrieu ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Immune Responses ◽

Cellular Immune Responses ◽

Cellular Immune

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Genetic Immunization of Wild-Type and Hepatitis C Virus Transgenic Mice Reveals a Hierarchy of Cellular Immune Response and Tolerance Induction against Hepatitis C Virus Structural Proteins

Journal of Virology ◽

10.1128/jvi.75.24.12121-12127.2001 ◽

2001 ◽

Vol 75 (24) ◽

pp. 12121-12127 ◽

Cited By ~ 25

Author(s):

Jujin Satoi ◽

Kazumoto Murata ◽

Martin Lechmann ◽

Elanchezhiyan Manickan ◽

Zhensheng Zhang ◽

...

Keyword(s):

Immune Response ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Transgenic Mice ◽

Structural Proteins ◽

Dna Immunization ◽

Wild Type ◽

Genetic Immunization ◽

Cellular Immune ◽

Hcv Structural Proteins

ABSTRACT To study the effect of genetic immunization on transgenic expression of hepatitis C virus (HCV) proteins, we evaluated the immunological response of HCV transgenic mice to HCV expression plasmids. FVB/n transgenic mice expressing HCV structural proteins (core, E1, and E2) and wild-type (WT) FVB/n mice were immunized intramuscularly with plasmids expressing core (pHCVcore) or core/E1/E2 (pHCVSt). After immunization, HCV-specific humoral and cellular immune response was studied. Both WT and transgenic mice immunized with either HCV construct produced antibodies and exhibited T-cell proliferative responses against core or envelope. In WT mice immunized with pHCVSt, cytotoxic T-lymphocyte (CTL) activities were detected against E2 but not against core or E1, whereas strong CTL activities against core could be detected in WT mice immunized with pHCVcore. In pHCVSt-immunized, transgenic mice, CTL activities against the core or envelope were completely absent, but core-specific CTL activities could be detected in pHCVcore-immunized transgenic mice. A similar pattern of immune responses was also observed in other mouse strains, including a transgenic line expressing human HLA-A2.1 molecules (AAD mice). Despite the presence of a peripheral cellular immunity against HCV, no liver pathology or lymphocytic infiltrate was observed in these transgenic mice. Our study suggests a hierarchy of CTL response against the HCV structural proteins (E2 > core > E1) in vivo when the proteins are expressed as a polyprotein. The HCV transgenic mice can be induced by DNA immunization to generate anti-HCV antibodies and anticore CTLs. However, they are tolerant at the CTL level against the E2 protein despite DNA immunization.

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