Human Immunodeficiency Virus Type 1 Pathobiology Studied in Humanized BALB/c-Rag2-/-gammac-/- Mice

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2006 Dec 22

PMID 17182671

Citations 87

Authors

Santhi Gorantla

Hannah Sneller

Lisa Walters

John G Sharp

Samuel J Pirruccello

John T West

Charles Wood

Stephen Dewhurst

Howard E Gendelman

Larisa Poluektova

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

A novel SIV-infection animal model based on nude mice inoculated with MT-2 cells.

Xie L, Li J, Chen X, Yin M, Huang W, Luo M Arch Virol. 2025; 170(3):56.

PMID: 39948291 DOI: 10.1007/s00705-025-06247-z.

Accelerated Neuroimmune Dysfunction in Aged HIV-1-Infected Humanized Mice.

Zhang C, Su H, Waight E, Poluektova L, Gorantla S, Gendelman H Pharmaceuticals (Basel). 2024; 17(2).

PMID: 38399364 PMC: 10892358. DOI: 10.3390/ph17020149.

Humanized Mice for Studies of HIV-1 Persistence and Elimination.

Zhang C, Zaman L, Poluektova L, Gorantla S, Gendelman H, Dash P Pathogens. 2023; 12(7).

PMID: 37513726 PMC: 10383313. DOI: 10.3390/pathogens12070879.

CRISPR editing of CCR5 and HIV-1 facilitates viral elimination in antiretroviral drug-suppressed virus-infected humanized mice.

Dash P, Chen C, Kaminski R, Su H, Mancuso P, Sillman B Proc Natl Acad Sci U S A. 2023; 120(19):e2217887120.

PMID: 37126704 PMC: 10175831. DOI: 10.1073/pnas.2217887120.

HIV-1 infected humanized DRAGA mice develop HIV-specific antibodies despite lack of canonical germinal centers in secondary lymphoid tissues.

Ollerton M, Folkvord J, Peachman K, Shashikumar S, Morrison E, Jagodzinski L Front Immunol. 2022; 13:1047277.

PMID: 36505432 PMC: 9732419. DOI: 10.3389/fimmu.2022.1047277.

References

Moffat J, Stein M, KANESHIMA H, Arvin A . Tropism of varicella-zoster virus for human CD4+ and CD8+ T lymphocytes and epidermal cells in SCID-hu mice. J Virol. 1995; 69(9):5236-42. PMC: 189355. DOI: 10.1128/JVI.69.9.5236-5242.1995. View

Aldrovandi G, Feuer G, Gao L, Jamieson B, Kristeva M, Chen I . The SCID-hu mouse as a model for HIV-1 infection. Nature. 1993; 363(6431):732-6. DOI: 10.1038/363732a0. View

Yoder M, Cumming J, Hiatt K, Mukherjee P, Williams D . A novel method of myeloablation to enhance engraftment of adult bone marrow cells in newborn mice. Biol Blood Marrow Transplant. 1996; 2(2):59-67. View

Cole K, Murphey-Corb M, Narayan O, Joag S, Shaw G, Montelaro R . Common themes of antibody maturation to simian immunodeficiency virus, simian-human immunodeficiency virus, and human immunodeficiency virus type 1 infections. J Virol. 1998; 72(10):7852-9. PMC: 110105. DOI: 10.1128/JVI.72.10.7852-7859.1998. View

Gobbi A, Stoddart C, Malnati M, Locatelli G, Santoro F, Abbey N . Human herpesvirus 6 (HHV-6) causes severe thymocyte depletion in SCID-hu Thy/Liv mice. J Exp Med. 1999; 189(12):1953-60. PMC: 2192958. DOI: 10.1084/jem.189.12.1953. View

Mazurier F, Fontanellas A, Salesse S, Taine L, Landriau S, Moreau-Gaudry F . A novel immunodeficient mouse model--RAG2 x common cytokine receptor gamma chain double mutants--requiring exogenous cytokine administration for human hematopoietic stem cell engraftment. J Interferon Cytokine Res. 1999; 19(5):533-41. DOI: 10.1089/107999099313983. View

Rozemuller H, Knaan-Shanzer S, Hagenbeek A, van Bloois L, Storm G, Martens A . Enhanced engraftment of human cells in RAG2/gammac double-knockout mice after treatment with CL2MDP liposomes. Exp Hematol. 2004; 32(11):1118-25. DOI: 10.1016/j.exphem.2004.08.002. View

Gimeno R, Weijer K, Voordouw A, Uittenbogaart C, Legrand N, Alves N . Monitoring the effect of gene silencing by RNA interference in human CD34+ cells injected into newborn RAG2-/- gammac-/- mice: functional inactivation of p53 in developing T cells. Blood. 2004; 104(13):3886-93. DOI: 10.1182/blood-2004-02-0656. View

Shultz L, Lyons B, Burzenski L, Gott B, Chen X, Chaleff S . Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol. 2005; 174(10):6477-89. DOI: 10.4049/jimmunol.174.10.6477. View

10.

Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G . Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. Blood. 2005; 106(5):1565-73. PMC: 1895228. DOI: 10.1182/blood-2005-02-0516. View

11.

Macchiarini F, Manz M, Palucka A, Shultz L . Humanized mice: are we there yet?. J Exp Med. 2005; 202(10):1307-11. PMC: 2212979. DOI: 10.1084/jem.20051547. View

12.

Zhang H, Hoffmann F, He J, He X, Kankasa C, Ruprecht R . Evolution of subtype C HIV-1 Env in a slowly progressing Zambian infant. Retrovirology. 2005; 2:67. PMC: 1308862. DOI: 10.1186/1742-4690-2-67. View

13.

Legrand N, Weijer K, Spits H . Experimental models to study development and function of the human immune system in vivo. J Immunol. 2006; 176(4):2053-8. DOI: 10.4049/jimmunol.176.4.2053. View

14.

Legrand N, Cupedo T, Van Lent A, Ebeli M, Weijer K, Hanke T . Transient accumulation of human mature thymocytes and regulatory T cells with CD28 superagonist in "human immune system" Rag2(-/-)gammac(-/-) mice. Blood. 2006; 108(1):238-45. DOI: 10.1182/blood-2006-01-0190. View

15.

Watanabe S, Terashima K, Ohta S, Horibata S, Yajima M, Shiozawa Y . Hematopoietic stem cell-engrafted NOD/SCID/IL2Rgamma null mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses. Blood. 2006; 109(1):212-8. DOI: 10.1182/blood-2006-04-017681. View

16.

Poluektova L, Munn D, Persidsky Y, Gendelman H . Generation of cytotoxic T cells against virus-infected human brain macrophages in a murine model of HIV-1 encephalitis. J Immunol. 2002; 168(8):3941-9. DOI: 10.4049/jimmunol.168.8.3941. View

17.

Yahata T, Ando K, Nakamura Y, Ueyama Y, Shimamura K, Tamaoki N . Functional human T lymphocyte development from cord blood CD34+ cells in nonobese diabetic/Shi-scid, IL-2 receptor gamma null mice. J Immunol. 2002; 169(1):204-9. DOI: 10.4049/jimmunol.169.1.204. View

18.

Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K . NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002; 100(9):3175-82. DOI: 10.1182/blood-2001-12-0207. View

19.

Schauer U, Stemberg F, Rieger C, Buttner W, Borte M, Schubert S . Levels of antibodies specific to tetanus toxoid, Haemophilus influenzae type b, and pneumococcal capsular polysaccharide in healthy children and adults. Clin Diagn Lab Immunol. 2003; 10(2):202-7. PMC: 150524. DOI: 10.1128/cdli.10.2.202-207.2003. View

20.

Hiramatsu H, Nishikomori R, Heike T, Ito M, Kobayashi K, Katamura K . Complete reconstitution of human lymphocytes from cord blood CD34+ cells using the NOD/SCID/gammacnull mice model. Blood. 2003; 102(3):873-80. DOI: 10.1182/blood-2002-09-2755. View