Characterization of human antiviral adaptive immune responses during hepatotropic virus infection in HLA-transgenic human immune system mice

Eva K. Billerbeck, Joshua A. Horwitz, Rachael N. Labitt, Bridget M. Donovan, Kevin Vega, William C. Budell, Gloria C. Koo, Charles M. Rice, Alexander Ploss

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Humanized mice have emerged as a promising model to study human immunity in vivo. Although they are susceptible to many pathogens exhibiting an almost exclusive human tropism, human immune responses to infection remain functionally impaired. It has recently been demonstrated that the expression of HLA molecules improves human immunity to lymphotropic virus infections in humanized mice. However, little is known about the extent of functional human immune responses in nonlymphoid tissues, such as in the liver, and the role of HLA expression in this context. Therefore, we analyzed human antiviral immunity in humanized mice during a hepatotropic adenovirus infection. We compared immune responses of conventional humanized NOD SCID IL-2Rγ-deficient (NSG) mice to those of a novel NOD SCID IL-2Rγ-deficient strain transgenic for both HLA-A*0201 and a chimeric HLA-DR*0101 molecule. Using a firefly luciferase-expressing adenovirus and in vivo bioluminescence imaging, we demonstrate a human T cell-dependent partial clearance of adenovirus-infected cells from the liver of HLA-transgenic humanized mice. This correlated with liver infiltration and activation of T cells, as well as the detection of Ag-specific humoral and cellular immune responses. When infected with a hepatitis C virus NS3-expressing adenovirus, HLA-transgenic humanized mice mounted an HLA-A*0201-restricted hepatitis C virus NS3-specific CD8 + T cell response. In conclusion, our study provides evidence for the generation of partial functional antiviral immune responses against a hepatotropic pathogen in humanized HLA-transgenic mice. The adenovirus reporter system used in our study may serve as simple in vivo method to evaluate future strategies for improving human intrahepatic immune responses in humanized mice.

Original languageEnglish (US)
Pages (from-to)1753-1764
Number of pages12
JournalJournal of Immunology
Volume191
Issue number4
DOIs
StatePublished - Aug 15 2013
Externally publishedYes

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Adaptive Immunity
Virus Diseases
Antiviral Agents
Immune System
Adenoviridae
Transgenic Mice
Immunity
T-Lymphocytes
Hepacivirus
Liver
Firefly Luciferases
Adenoviridae Infections
Tropism
HLA-DR Antigens
Humoral Immunity
Cellular Immunity
Infection

ASJC Scopus subject areas

  • Immunology

Cite this

Characterization of human antiviral adaptive immune responses during hepatotropic virus infection in HLA-transgenic human immune system mice. / Billerbeck, Eva K.; Horwitz, Joshua A.; Labitt, Rachael N.; Donovan, Bridget M.; Vega, Kevin; Budell, William C.; Koo, Gloria C.; Rice, Charles M.; Ploss, Alexander.

In: Journal of Immunology, Vol. 191, No. 4, 15.08.2013, p. 1753-1764.

Research output: Contribution to journalArticle

Billerbeck, Eva K. ; Horwitz, Joshua A. ; Labitt, Rachael N. ; Donovan, Bridget M. ; Vega, Kevin ; Budell, William C. ; Koo, Gloria C. ; Rice, Charles M. ; Ploss, Alexander. / Characterization of human antiviral adaptive immune responses during hepatotropic virus infection in HLA-transgenic human immune system mice. In: Journal of Immunology. 2013 ; Vol. 191, No. 4. pp. 1753-1764.
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