In vitro immunomodulatory properties of tucaresol in HIV infection

The immunomodulatory properties of tucaresol (compound 589C80) were tested on in vitro antigen- and mitogen-stimulated proliferation and cytokine prod uction by peripheral blood mononuclear cells (PBMC) of HIV-infected individ uals and healthy controls (HC). Results showed that tucaresol: (1) increase s influenza A virus-, gp 160 peptide-, and HLA alloantigen-stimulated proli feration as well as interleukin (IL)-2 and interferon gamma (IFN gamma) pro duction by PBMC of HN-infected individuals with higher CD4 counts (>500/mul ) but had only a marginal immunomodulatory effect on PBMC of patients with lower CD4 counts (<500/<mu>l); (2) did not modify IL-10 production; (3) aug mented CD25 expression on mitogen-stimulated T cells of HC but not of HIV-i nfected individuals; and (4) marginally increased CTL activity. The immunom odulatory properties of tucaresol were confirmed by PCR analyses; additiona l data showed that tucaresol costimulated CDS-dependent triggering of T cel ls and that this stimulation was independent of CD28 costimulation. The imm unomodulatory effects of tucaresol on T cell functions are characterized by a bell-shaped dose response curve; the action of the compound is optimal i n the 100 to 300 muM range. Analyses of mitogen-stimulated apoptosis demons trated that the lack of effect of tucaresol at higher doses is not the resu lt of increased cell death, suggesting a role of functional impairment. The se data confirm that tucaresol can stimulate T helper cell function and enh ance the production of type 1 cytokines, thus eliciting cell-mediated immun ity, and warrant its potential utility in the therapy of HIV infection. (C) 2000 Academic Press.