DEFECTIVE RESPONSE TO T-CELL MITOGENS IN MICE INJECTED WITH HUMAN-IMMUNODEFICIENCY-VIRUS TYPE 1-INFECTED U937 CELLS

Swiss mice were injected intraperitoneally with uninfected or human im munodeficiency virus type 1 (HIV-1) infected human U937 cells. At 6 da ys, no residual human cells were detected in mouse tissues as determin ed by PCR analysis of DNAs from injected mice using primers and probes for the human HLA-DQ alpha gene. At 6 to 12 months, approximately 60% of the HIV-1-injected mice had antibodies to HIV-1 gp 120 and gp41 pr oteins. Fifteen percent of the animals showed evidence of HIV-1 infect ion as determined by PCR analyses of DNA from peripheral blood leukocy tes and by in situ hybridization for detection of HIV-1 mRNA in perito neal cells. In this set of experiments, spleen cells from mice sacrifi ced at different times after injection were cultured for 48 h in the p resence or absence of mitogens [i.e.: concanavalin (Con A) or anti-CD3 antibody] and then tested for lymphocyte proliferation. At 10 to 12 m onths, splenocytes from approximately 80% of Swiss mice injected with HIV-1-infected U937 cells exhibited a marked defect in their prolifera tive response to Con A or anti-CD3 antibody as compared with spleen ce lls from both uninjected or U937 cell-injected mice. Similar results w ere obtained at 12 months in C3H/HeJ mice. Non-responding spleen cells from HIV-1-injected Swiss mice did not proliferate in response to ant i-CD3 antibody even in the presence of co-stimulatory molecules such a s phorbol myristate acetate or anti-CD28 antibody. Splenocytes from th ese mice also exhibited an impaired capacity to produce interferon-gam ma and interleukin-4 after mitogen stimulation. No T cell defects were observed in control-injected mice. Immunofluorescence analyses reveal ed a significant decrease in the percentage of both CD4(+) and CD8(+) spleen cells in HIV-1-injected mice. These data indicate that immunoco mpetent mice can be used to investigate some HIV-1-related immune dysf unctions in vivo.