T-CELL DYSFUNCTIONS IN HU-PBL-SCID MICE INFECTED WITH HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) SHORTLY AFTER RECONSTITUTION - IN-VIVO EFFECTS OF HIV ON HIGHLY ACTIVATED HUMAN IMMUNE CELLS

The state of activation of the immune system may be an important facto r which renders a host more receptive to human immunodeficiency virus (HIV) and more vulnerable to its effects. To explore this issue with a practical in vivo model, we developed a modified protocol of HIV infe ction in hu-PBL SCID mice. First, we assessed the time course of activ ation of human peripheral blood lymphocytes (hu-PBL) in the peritoneal cavity of SCID mice. At 2 to 24 h after the intraperitoneal injection into SCID mice, there was a clear-cut increase in the percentage of h u-PBL expressing early activation markers (CD69), concomitant with the release of soluble intercellular adhesion molecule-1 (sICAM) and the soluble interleukin-2 receptor (sIL-2R) and with the accumulation of m RNAs for a number of human cytokines. At 2 weeks, virtually all of the hu-PBL expressed the memory phenotype (CD45RO) and HLA-DR antigens as well. Cells collected from the SCID mouse peritoneum at 2 and 24 h af ter transplantation were fully susceptible to in vitro infection with HIV type I (HIV-1) in the absence of either IL-2 or mitogens. The inje ction of HIV into hu-PBL-SCID mice at 2 h after reconstitution resulte d in a generalized and productive HIV infection of the xenochimeras. T his early HIV-1 infection resulted in a dramatic depletion of human CD 4(+) cells and in decreased levels of sICAM-1 (in the peritoneal lavag e fluid) as well as of sIL-1R and immunoglobulins M and A (in the seru m). Enzyme-linked immunosorbent assay and/or reverse transcriptase PCR analysis showed higher levels of IL-4, IL-5, and IL-10 in the HIV-inf ected animals than in control hu-PBL-SCID mice, while gamma interferon levels in the two groups were comparable. When we compared the curren t model of HIV-1 infection at 2 weeks after the intraperitoneal inject ion of the hu-PBL in the SCID mice with the model described here, we f ound that the majority of immune dysfunctions induced in the 2-h infec tion of the xenochimeras are not inducible in the 2-week infection. Th is supports the concept that the state of activation of human cells at the moment of the in vivo infection with HIV-1 is a crucial factor in determining the immune derangement observed in AIDS patients. These r esults show that some immunological dysfunctions induced by HIV infect ion in AIDS patients can be mimicked in this xenochimeric model. Thus, the hu-PBL-SCID mouse model may be useful in exploring, in vivo, the relevance of hu-PBL activation and differentiation in HIV-1 infection and for testing therapeutic intervention directed towards either the v irus or the immune system.