An improved protocol for efficient engraftment in NOD/LTSZ-SCIDIL-2Rγnull mice allows HIV replication and development of anti-HIV immune responses.
Cord blood hematopoietic progenitor cells (CB-HPCs) transplanted immunodeficient NOD/LtsZ-scidIL2Rγ(null) (NSG) and NOD/SCID/IL2Rγ(null) (NOG) mice need efficient human cell engraftment for long-term HIV-1 replication studies. Total body irradiation (TBI) is a classical myeloablation regimen used to improve engraftment levels of human cells in these humanized mice. Some recent reports suggest the use of busulfan as a myeloablation regimen to transplant HPCs in neonatal and adult NSG mice. In the present study, we further ameliorated the busulfan myeloablation regimen with fresh CB-CD34+cell transplantation in 3-4 week old NSG mice. In this CB-CD34+transplanted NSG mice engraftment efficiency of human CD45+cell is over 90% in peripheral blood. Optimal engraftment promoted early and increased CD3+T cell levels, with better lymphoid tissue development and prolonged human cell chimerism over 300 days. These humanized NSG mice have shown long-lasting viremia after HIV-1JRCSF and HIV-1Bal inoculation through intravenous and rectal routes. We also saw a gradual decline of the CD4+T cell count, widespread immune activation, up-regulation of inflammation marker and microbial translocation after HIV-1 infection. Humanized NSG mice reconstituted according to our new protocol produced, moderate cellular and humoral immune responses to HIV-1 postinfection. We believe that NSG mice reconstituted according to our easy to use protocol will provide a better in vivo model for HIV-1 replication and anti-HIV-1 therapy trials.
Immunology and infectious diseases unit GIGA-I3, University of Liege, Liege, Belgium.
Maneesh
M
Singh
Pratibha
P
Singh
Gilles
G
Gaudray
Lucia
L
Musumeci
Caroline
C
Thielen
Dolores
D
Vaira
Claire
C
Vandergeeten
Laurence
L
Delacroix
Ellen
E
Van Gulck
Guido
G
Vanham
Laurence
L
de Leval
Souad
S
Rahmouni
Michel
M
Moutschen
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage; D049109:Cell Proliferation; D036101:Cord Blood Stem Cell Transplantation / Q000379:methods*; D018450:Disease Progression; D006678:HIV / Q000276:immunology* / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007109:Immunity / Q000276:immunology*; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency* / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D014779:Virus Replication / Q000276:immunology*
D018952:Antigens, CD34; D053631:Interleukin Receptor Common gamma Subunit; D011948:Receptors, Antigen, T-Cell; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D017493:Leukocyte Common Antigens