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


CONCLUSIONS
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.
Berges
Bradford K
BK
Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA. bberges@colostate.edu
Wheat
William H
WH
Palmer
Brent E
BE
Connick
Elizabeth
E
Akkina
Ramesh
R
D000818:Animals; D018952:Antigens, CD34 / Q000276:immunology; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D055316:Cystatin C; D015891:Cystatins / Q000172:deficiency*; D004268:DNA-Binding Proteins / Q000172:deficiency*; D004195:Disease Models, Animal; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008099:Liver / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D014183:Transplantation, Heterologous; D014766:Viremia / Q000276:immunology / Q000473:pathology
D018952:Antigens, CD34; C525030:CST3 protein, human; C525031:Cst3 protein, mouse; D055316:Cystatin C; D015891:Cystatins; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse