Human immunodeficiency virus type 1 pathobiology studied in humanized BALB/c-Rag2-/-gammac-/- mice.
The specificity of human immunodeficiency virus type 1 (HIV-1) for human cells precludes virus infection in most mammalian species and limits the utility of small animal models for studies of disease pathogenesis, therapy, and vaccine development. One way to overcome this limitation is by human cell xenotransplantation in immune-deficient mice. However, this has proved inadequate, as engraftment of human immune cells is limited (both functionally and quantitatively) following transplantation of mature human lymphocytes or fetal thymus/liver. To this end, a human immune system was generated from umbilical cord blood-derived CD34(+) hematopoietic stem cells in BALB/c-Rag2(-/-)gamma(c)(-/-) mice. Intrapartum busulfan administration followed by irradiation of newborn pups resulted in uniform engraftment characterized by human T-cell development in thymus, B-cell maturation in bone marrow, lymph node development, immunoglobulin M (IgM)/IgG production, and humoral immune responses following ActHIB vaccination. Infection of reconstituted mice by CCR5-coreceptor utilizing HIV-1(ADA) and subtype C 1157 viral strains elicited productive viral replication and lymphadenopathy in a dose-dependent fashion. We conclude that humanized BALB/c-Rag2(-/-)gamma(c)(-/-) mice represent a unique and valuable resource for HIV-1 pathobiology studies.
Gorantla
Santhi
S
Centere for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE 68198-5880, USA.
Sneller
Hannah
H
Walters
Lisa
L
Sharp
John G
JG
Pirruccello
Samuel J
SJ
West
John T
JT
Wood
Charles
C
Dewhurst
Stephen
S
Gendelman
Howard E
HE
Poluektova
Larisa
L
D000818:Animals; D000831:Animals, Newborn; D018952:Antigens, CD34 / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D002066:Busulfan / Q000494:pharmacology; D003037:Cobalt Radioisotopes; D036101:Cord Blood Stem Cell Transplantation; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005720:Gamma Rays; D006085:Graft Survival; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis; D007150:Immunohistochemistry; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency* / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019653:Myeloablative Agonists / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous; D014779:Virus Replication
D018952:Antigens, CD34; D003037:Cobalt Radioisotopes; D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; D007075:Immunoglobulin M; D053631:Interleukin Receptor Common gamma Subunit; D019653:Myeloablative Agonists; C499308:Rag2 protein, mouse; D019713:Receptors, CCR5; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002066:Busulfan