Human hepatocyte depletion in the presence of HIV-1 infection in dual reconstituted humanized mice

Raghubendra Singh Dagur, Weimin Wang, Yan Cheng, Edward Makarov, Murali Ganesan, Hiroshi Suemizu, Catherine L Gebhart, Santhi Gorantla, Natalia Osna, Larisa Y. Poluektova

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection impairs liver function, and liver diseases have become a leading cause of morbidity in infected patients. The immunopathology of liver damage caused by HIV-1 remains unclear. We used chimeric mice dually reconstituted with a human immune system and hepatocytes to address the relevance of the model to pathobiology questions related to human hepatocyte survival in the presence of systemic infection. TK-NOG males were transplanted with mismatched human hematopoietic stem/ progenitor cells and hepatocytes, human albumin concentration and the presence of human immune cells in blood were monitored for hepatocytes and immune reconstitution, and mice were infected with HIV-1. HIV-1-infected animals showed a decline in human albumin concentration with a significant reduction in percentage of human hepatocytes compared to uninfected mice. The decrease in human albumin levels correlated with a decline in CD4+ cells in the liver and with an increase in HIV-1 viral load. HIV-1 infection elicited proinflammatory response in the immunological milieu of the liver in HIV-infected mice compared to uninfected animals, as determined by upregulation of IL23, CXCL10 and multiple toll-like receptor expression. The inflammatory reaction associated with HIV-1 infection in vivo could contribute to the depletion and dysfunction of hepatocytes. The dual reconstituted TK-NOG mouse model is a feasible platform to investigate hepatocyte-related HIV-1 immunopathogenesis.

Original languageEnglish (US)
Article numberbio029785
JournalBiology Open
Volume7
Issue number2
DOIs
StatePublished - 2018

Keywords

  • Hematopoietic stem/progenitor cells
  • Hepatocytes
  • Human immune system
  • Human immunodeficiency virus-1
  • Humanized mouse model
  • Liver reconstitution
  • Toll-like receptors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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