ANTIPROLIFERATIVE ACTIVITY OF CYCLOPENTENONE PROSTAGLANDINS IN EARLY HTLV-1 INFECTION IS INDEPENDENT OF IL-2 AND IS ASSOCIATED WITH HSP70 INDUCTION

Cyclopentenone prostaglandins PGA(1) and PGJ(2) can inhibit the growth of HTLV-1 infected cord blood-derived human mono nuclear cells (CBMC) , both after acute infection and in chronically infected, immortalized cells. When CBMC were exposed to HTLV-1 infection by coculturing with lethally irradiated, virus-donor allogeneic MT-2 cells, they underwen t a proliferative response, that peaked within the first week and then declined. PG treatment did not inhibit the initial proliferation (day 4) of cocultured CBMC, while multiple treatments with PGA(1) and more efficiently with PGJ(2) suppressed the late cell proliferation (from day 8 onward). The pharmacological effects of PGA(1) and PGJ(2) were r eversible and therefore multiple treatments were required to maintain their antiproliferative activity. Increasing concentrations (20, 40, 8 0 IU/ml) of recombinant IL-2 did not affect the virus-associated proli ferative response of CBMC, and exogenous IL-2 did not revert the antip roliferative effect of both PGs. Arrest of proliferation in cocultured CBMC occurred concomitantly with expression of high levels of HSP70 i n the cells. In fact, though HSP70 expression was induced early (day 5 ) after exposure to HTLV-1, its expression was further increased after multiple PG treatments and high levels were found when the antiprolif erative effect of PGs became manifest. Since HSP70 protein family is i nvolved in the control of cell cycle as well as in antigen processing and presentation during the immune response against tumor cells and pa thogens, the persistent expression of this protein in PG-treated cocul tures suggested that, beside inhibiting the growth of virus-infected c ells, HSP70 expression might play a role in modulating the immune func tion of CBMC. However, unlike in most virus infection models, in which cyclopentenone PGs exert clear antiviral effects by inhibiting the sy nthesis and maturation of virus proteins, no antiviral activity was fo und in this model of infection. This strongly suggests that the main e ffect of these PGs against HTLV-1 infected cells consists in inhibitin g proliferation in vitro without affecting viral expression.