The human HIV/peripheral blood lymphocyte (PBL)-SCID mouse. A modified human PBL-SCID model for the study of HIV pathogenesis and therapy

Abstract

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.