The human HIV/peripheral blood lymphocyte (PBL)-SCID mouse. A modified human PBL-SCID model for the study of HIV pathogenesis and therapy.
PBL from HIV-infected patients were engrafted into CB-17 SCID mice to develop a novel small animal model for the study of HIV pathogenesis and therapy. Engraftment was achieved in 84% of mice, with human Ig (hu-Ig) levels and total human mononuclear cell recovery by peritoneal wash similar to those in control hu-PBL-SCID mice engrafted with uninfected donor cells. The hu-Ig produced by hu-HIV/PBL-SCID mice had broad reactivity against HIV. Virus could be detected in 98% of mice by polymerase chain reaction and/or viral coculture. Viremia was first detected by quantitative polymerase chain reaction on day 7 (approximately 10,000 copies of viral RNA/ml of plasma) and persisted through day 17. Quasispecies analysis of amplified, cloned, proviral DNA of the V3 region of the env gene showed that nucleotide sequences from hu-HIV/PBL-SCID mouse peritoneal wash cells on day 17 were not significantly changed from those derived from donor PBL at the time of injection. Relative to human CD4+ T cell recovery by peritoneal wash in control hu-PBL-SCID mice (CD4 = 19 +/- 2%; n = 40), severe CD4+ lymphocyte depletion (CD4 = 5 +/- 0.5%; n = 59; p < 0.001) was observed in untreated hu-HIV/PBL-SCID mice 18 to 25 days after engraftment. Treatment with 2'-beta-fluoro-2',3'-dideoxyadenosine, a nucleoside analogue, significantly reduced CD4+ T cell depletion (CD4 = 13 +/- 1; n = 59; p < 0.001) and the frequency of virus isolation (70%; p = 0.015) in the hu-HIV/PBL-SCID model. Boosting hu-Ig levels in the mice by injection of purified donor Ig with neutralizing activity did not affect the frequency of CD4+ lymphocyte recovery or virus isolation. The administration of a mAb to TNF had minimal effects. These studies demonstrate that PBL from HIV-infected donors can engraft SCID mice; that HIV can be detected in the spleen, peritoneal wash cells, and blood of these mice; that HIV infection within the model results in rapid CD4+ T cell depletion; and that anti-retroviral therapy is effective in improving CD4+ T cell recovery and reducing the frequency of virus isolation. The hu-HIV/PBL-SCID mouse model thus represents a potentially useful model in which to study HIV pathogenesis and therapy.
Boyle
M J
MJ
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Connors
M
M
Flanigan
M E
ME
Geiger
S P
SP
Ford
H
H
Baseler
M
M
Adelsberger
J
J
Davey
R T
RT
Lane
H C
HC
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes; D017931:DNA Primers / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D016048:Dideoxyadenosine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004195:Disease Models, Animal; D015752:Genes, env; D015658:HIV Infections / Q000209:etiology* / Q000628:therapy* / Q000821:virology; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive; D018655:Lymphocyte Count; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D011533:Proviruses / Q000235:genetics; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014766:Viremia / Q000209:etiology
D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D017931:DNA Primers; D004279:DNA, Viral; D014409:Tumor Necrosis Factor-alpha; C073072:lodenosine; D016048:Dideoxyadenosine