Combined treatments with interferon (α,β) plus PGA 1 to control early infection with HTLV-I in primary cord blood-derived mononuclear cells

Abstract

Interferon (IFN) α and β can activate and antiviral and immunomodulating response in primary cord blood-derived mononuclear cells (CBMC) exposed to infection with Human T-cell Leukemia Virus type I (HTLV-I), resulting in partial inhibition of early infection in vitro. On the other hand, PGA 1, a PGE 1-derived cyclopentenone prostaglandin, can inhibit in vitro the proliferation of virus-infected CBMC, preventing the emergence of the potentially transformed clone. In order to achieve a complete control of HTLV-I infection in this experimental model, we evaluated whether the antiviral activity of IFNs and the antiproliferative activity of PGA 1 could be preserved in a combination therapy scheme. Recipient CBMC were treated with IFN α or β (1000 IU/ml) at the onset of the co-culture with lethally irradiated virus-donor MT-2 cells, followed by multiple treatments with PGA 1 (4 μg/ml every 4 days, starting on day 0) for 6 weeks post infection (p.i.). In PGA 1-treated co-cultures the percentage of virus-positive CBMC was constantly doubled during culture time as well as the amount of viral transcripts and p19 virus core protein production were increased. The antiviral effects of IFNs, resulting in about a 50% reduction of the percentage of virus-positive CBMC and consequently in a partial inhibition of virus expression (HTLV-I transcription and p19 production) until 4 weeks p.i., were suppressed by multiple PGA 1 treatments. However, the antiproliferative effect of PGA 1 was enforced in IFN-treated co-cultures, leading to earlier control of proliferation of virus-infected cells. Interestingly, infection of CBMC with HTLV-I was associated with persistent expression of 70 kDa heat shock protein (HSP70), for at least 4 weeks p.i. IFNs and PGA 1 showed antagonistic effects on HSP70 production in infected CBMC. In fact, production of HSP70 was suppressed (or prevented) in IFN-treated co-cultures, tested 2 and 4 weeks p.i. The fact that the expression of HSP70 is apparently suppressed (or prevented) by IFN treatment is surprising, since expression of this protein family has been associated with antiviral immunity. PGA 1 could totally reverse the IFN-mediated suppression of HSP70 expression in these co-cultures. It is presently unclear whether HSP70 expression is directly involved in the control of proliferation exerted by PGA 1 against virus-infected CBMC or is an epiphenomenon associated with inhibition of cell growth.