Modulation by the Polyoxotungstate HPA-23 of Epstein--Barr Virus Early Antigen Expression in Raji Cells Treated with Iododeoxyuridine

Abstract

SUMMARYThe polyoxotungstate HPA-23 was found to exert a differential effect on the induction of Epstein-Barr virus early antigen in Raji cells induced with 5-iodo-2'-deoxyuridine (IUdR). Thus, treatment of Raji cells concomitantly with IUdR and HPA-23 inhibited early antigen expression, and the extent of inhibition was proportional to the duration of treatment with HPA-23. In contrast, pretreatment of Raji cells with HPA-23 prior to induction with IUdR stimulated early antigen expression in exponentially multiplying but not in stationary-phase ceils. HPA-23 alone had no effect on early antigen expression in Raji cells. Activation of the latent Epstein-Barr virus genome by IUdR is dependent upon incorporation of the thymidine analogue into cellular DNA during the S-phase of the cell cycle. Synthesis of EpsteinBarr virus DNA also takes place during S-phase, suggesting a possible participation in this process of cellular DNA polymerase ct which is thought to be responsible for cellular DNA replication and the activity of which increases several-fold during Sphase. Treatment of Raji cells with HPA-23 caused a marked decrease in DNA polymerase ct activity, which could result in an inhibition of IUdR incorporation leading to the observed reduction of early antigen expression in ceils treated concomitantly with IUdR and HPA-23.

Differential inhibition of various mammalian DNA polymerase activities by ammonium 21‐tungsto‐9‐antimoniate (HPA23)

“…Treatment of Raji cells with HPA23 caused a marked decrease in DNA polymerase CI activity which could presumably result in an inhibition of IdUrd incorporation leading to the reduction of early antigen expression in the cells treated simultaneously with IdUrd and HPA23 [13]. These results also suggested possible inhibition of eukaryotic DNA polymerase activities by HPA23.…”

“…associated reverse transcriptase, since the enzyme activity was strongly inhibited in the presence of the drug [12]. In spite of these findings, specificity of the inhibition by HPA23 of various eukaryotic DNA polymerases has remained to be elucidated.Our recent works on the modulation of Epstein-Barr virus gene expression in a human lymphoblastoid cell line (Raji) have revealed that HPA23 inhibited early antigen expression induced by 5-iodo-2'-deoxyuridine (IdUrd) [13]. Treatment of Raji cells with HPA23 caused a marked decrease in DNA polymerase CI activity which could presumably result in an inhibition of IdUrd incorporation leading to the reduction of early antigen expression in the cells treated simultaneously with IdUrd and HPA23 [13].…”

“…Our recent works on the modulation of Epstein-Barr virus gene expression in a human lymphoblastoid cell line (Raji) have revealed that HPA23 inhibited early antigen expression induced by 5-iodo-2'-deoxyuridine (IdUrd) [13]. Treatment of Raji cells with HPA23 caused a marked decrease in DNA polymerase CI activity which could presumably result in an inhibition of IdUrd incorporation leading to the reduction of early antigen expression in the cells treated simultaneously with IdUrd and HPA23 [13].…”

Clinical trial of tolerance of HPA-23 in patients with acquired immune deficiency syndrome

“…HPA-23 (ammonium-21-tungsto-9-antimoniate) inhibits retrovirus replication by inhibiting RNA-dependent DNA polymerases and thus could be effective in the treatment of HIV-1 infections and AIDS. HPA-23 inhibits nucleic acid polymerases in vitro (1,4,7,10) and has antiviral activity both in vitro (14) and in vivo (8,9). Furthermore, HPA-23 inhibits HIV-1 reverse transcriptase in vitro (5).…”

Reverse Transcriptase Activity (Rta) in Lymphocyte Cultures of Aids Patients Treated With Hpa-23

“…In vitro, HPA-23 inhibits the DNA poly¬ merase of E. coli (5). In conjunction with iododeoxyuridine, HPA-23 diminishes expression of Epstein-Barr virus early antigen production by Raji cells (9).…”