Background:  Severe combined immunodeficiency (SCID) mice reconstituted with human peripheral blood mononuclear cells (PBMC), termed hu-PBL-SCID mice, have served as a valuable animal model of infection by pathogenic HIV-1 strains using CCR5 as a co-receptor (R5 HIV-1). In this model, however, HIV-1 strains using CXCR4 as a co-receptor (X4 HIV-1) do not efficiently infect and replicate. To overcome this problem with X4 HIV-1, we have focused on the effect of human IL-4 that enhances CXCR4 expression on T cells and X4 HIV-1 infection, and thus generated hu-PBL-SCID mice using newly constructed human IL-4-transgenic (hIL-4⁺) SCID mice.

Methods:  hIL-4⁺ and hIL-4^– SCID mice generated from the C.B-17 strain or BALB/cA-RAG2^–/^–IL-2Rγ^–/^– mice were depleted of mouse NK cells by injecting anti-IL-2Rβ intraperitoneally on day 2. Human PBMC were transplanted intraperitoneally on day 1. X4 HIV-1 NL4-3 strain was inoculated intraperitoneally on day 0. A prototype of CXCR4 antagonist, KRH-1636, was given intraperitoneally on days 0 and 1 (n = 4 to 6, 2 to 4 groups per experiment). Sera and peritoneal lavage fluids were collected on day 6 to 8. Cells in peritoneal lavage fluids were analyzed for CD4/CXCR4 expression by flow cytometry and cultured in IL-2⁺ media. hIL-4 levels of the sera and HIV-1 p24 levels of the sera, peritoneal lavage fluids, and culture supernatants were assayed by ELISA.

Results:  In hu-PBL-hIL-4⁺ SCID mice, an increase in percentages of CXCR4⁺CD4⁺ cells was observed when compared to those in the hIL-4^– SCID mice. The levels of p24 produced in culture supernatants of cells from X4 HIV-1-infected hu-PBL-hIL-4⁺ SCID mice were much higher (as much as 100-fold) than those from the hIL-4^– SCID mice. The in vivo infection of hu-PBL-hIL-4⁺ SCID mice by NL4-3 strain was significantly blocked with KRH-1636 administration.

Conclusions:  The present study shows that the hu-PBL-hIL-4⁺ SCID mice are more permissive to X4 HIV-1 infection than the controls, and that this model may be useful not only for studying X4 HIV-1 infection in vivo but also developing new therapeutic strategies against X4 HIV-1 strains. Data on the efficacy of new CXCR4 antagonists against the infection with multi-drug resistant clinical isolates will be also presented.