title: Combined treatments with interferon (alpha,beta) plus PGA1 to control early infection with HTLV-I in primary cord blood-derived mononuclear cells.
abstract: Interferon (IFN) alpha and beta can activate an 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, PGA1, a PGE1-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 PGA1 could be preserved in a combination therapy scheme. Recipient CBMC were treated with IFN alpha or beta (1000 IU/ml) at the onset of the co-culture with lethally irradiated virus-donor MT-2 cells, followed by multiple treatments with PGA1 (4 micrograms/ml every 4 days, starting on day 0) for 6 weeks post infection (p.i.). In PGA1-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 PGA1 treatments. However, the antiproliferative effect of PGA1 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 PGA1 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. PGA1 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 PGA1 against virus-infected CBMC or is an epiphenomenon associated with inhibition of cell growth.
authors: Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy.
authors: C
authors: C
authors: D'Onofrio
authors: O
authors: O
authors: Franzese
authors: F
authors: F
authors: Ricci
authors: E
authors: E
authors: Bonmassar
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D015490:HTLV-I Infections / Q000209:etiology / Q000382:microbiology / Q000517:prevention & control*; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage*; D016899:Interferon-beta / Q000008:administration & dosage*; D011454:Prostaglandins A / Q000008:administration & dosage*; D011994:Recombinant Proteins; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects
chemical_list: D006360:Heat-Shock Proteins; D007370:Interferon Type I; D011454:Prostaglandins A; D011994:Recombinant Proteins; D016899:Interferon-beta; C100573:prostaglandin A1