title: Humanized Rag1-/- γc-/- mice support multilineage hematopoiesis and are susceptible to HIV-1 infection via systemic and vaginal routes.
abstract: Several new immunodeficient mouse models for human cell engraftment have recently been introduced that include the Rag2(-/-)γc(-/-), NOD/SCID, NOD/SCIDγc(-/-) and NOD/SCIDβ2m(-/-) strains. Transplantation of these mice with CD34(+) human hematopoietic stem cells leads to prolonged engraftment, multilineage hematopoiesis and the capacity to generate human immune responses against a variety of antigens. However, the various mouse strains used and different methods of engrafting human cells are beginning to illustrate strain specific variations in engraftment levels, duration and longevity of mouse life span. In these proof-of-concept studies we evaluated the Balb/c-Rag1(-/-)γ(-/-) strain for engraftment by human fetal liver derived CD34(+) hematopoietic cells using the same protocol found to be effective for Balb/c-Rag2(-/-)γc(-/-) mice. We demonstrate that these mice can be efficiently engrafted and show multilineage human hematopoiesis with human cells populating different lymphoid organs. Generation of human cells continues beyond a year and production of human immunoglobulins is noted. Infection with HIV-1 leads to chronic viremia with a resultant CD4 T cell loss. To mimic the predominant sexual viral transmission, we challenged humanized Rag1(-/-)γc(-/-) mice with HIV-1 via vaginal route which also resulted in chronic viremia and helper T cell loss. Thus these mice can be further exploited for studying human pathogens that infect the human hematopoietic system in an in vivo setting.
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America. akkina@colostate.edu
authors.forename: Ramesh
authors.initials: R
authors.lastname: Akkina
authors.forename: Bradford K
authors.initials: BK
authors.lastname: Berges
authors.forename: Brent E
authors.initials: BE
authors.lastname: Palmer
authors.forename: Leila
authors.initials: L
authors.lastname: Remling
authors.forename: C Preston
authors.initials: CP
authors.lastname: Neff
authors.forename: Jes
authors.initials: J
authors.lastname: Kuruvilla
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Connick
authors.forename: Joy
authors.initials: J
authors.lastname: Folkvord
authors.forename: Kathy
authors.initials: K
authors.lastname: Gagliardi
authors.forename: Afework
authors.initials: A
authors.lastname: Kassu
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Akkina
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D018952:Antigens, CD34 / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D007150:Immunohistochemistry; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency* / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008221:Lymphoid Tissue / Q000166:cytology; D051379:Mice; D009092:Mucous Membrane / Q000821:virology; D010537:Peritoneum / Q000821:virology; D014621:Vagina / Q000821:virology*
chemical_list: D018952:Antigens, CD34; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007136:Immunoglobulins; D053631:Interleukin Receptor Common gamma Subunit; C499308:Rag2 protein, mouse; C064658:RAG-1 protein; D017493:Leukocyte Common Antigens