HIV-1 infection and CD4 T cell depletion in the humanized Rag2-/-gamma c-/- (RAG-hu) mouse model

Retrovirology. 2006 Nov 1;3:76. doi: 10.1186/1742-4690-3-76.

Abstract

Background: The currently well-established humanized mouse models, namely the hu-PBL-SCID and SCID-hu systems played an important role in HIV pathogenesis studies. However, despite many notable successes, several limitations still exist. They lack multi-lineage human hematopoiesis and a functional human immune system. These models primarily reflect an acute HIV infection with rapid CD4 T cell loss thus limiting pathogenesis studies to a short-term period. The new humanized Rag2-/-gamma c-/- mouse model (RAG-hu) created by intrahepatic injection of CD34 hematopoietic stem cells sustains long-term multi-lineage human hematopoiesis and is capable of mounting immune responses. Thus, this model shows considerable promise to study long-term in vivo HIV infection and pathogenesis.

Results: Here we demonstrate that RAG-hu mice produce human cell types permissive to HIV-1 infection and that they can be productively infected by HIV-1 ex vivo. To assess the capacity of these mice to sustain long-term infection in vivo, they were infected by either X4-tropic or R5-tropic HIV-1. Viral infection was assessed by PCR, co-culture, and in situ hybridization. Our results show that both X4 and R5 viruses are capable of infecting RAG-hu mice and that viremia lasts for at least 30 weeks. Moreover, HIV-1 infection leads to CD4 T cell depletion in peripheral blood and thymus, thus mimicking key aspects of HIV-1 pathogenesis. Additionally, a chimeric HIV-1 NL4-3 virus expressing a GFP reporter, although capable of causing viremia, failed to show CD4 T cell depletion possibly due to attenuation.

Conclusion: The humanized RAG-hu mouse model, characterized by its capacity for sustained multi-lineage human hematopoiesis and immune response, can support productive HIV-1 infection. Both T cell and macrophage tropic HIV-1 strains can cause persistent infection of RAG-hu mice resulting in CD4 T cell loss. Prolonged viremia in the context of CD4 T cell depletion seen in this model mirrors the main features of HIV infection in the human. Thus, the RAG-hu mouse model of HIV-1 infection shows great promise for future in vivo pathogenesis studies, evaluation of new drug treatments, vaccines and novel gene therapy strategies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD34 / immunology
  • CD4 Lymphocyte Count
  • CD4-Positive T-Lymphocytes* / immunology
  • Cystatin C
  • Cystatins / deficiency*
  • DNA-Binding Proteins / deficiency*
  • Disease Models, Animal*
  • HIV Infections / immunology*
  • HIV Infections / pathology
  • HIV Infections / virology*
  • HIV-1 / physiology*
  • Hematopoiesis
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Liver / cytology
  • Mice
  • Mice, Inbred BALB C
  • Transplantation, Heterologous
  • Viremia / immunology
  • Viremia / pathology

Substances

  • Antigens, CD34
  • CST3 protein, human
  • Cst3 protein, mouse
  • Cystatin C
  • Cystatins
  • DNA-Binding Proteins
  • Rag2 protein, mouse