HERPES-SIMPLEX-VIRUS-MEDIATED ACTIVATION OF HUMAN-IMMUNODEFICIENCY-VIRUS IS INHIBITED BY OLIGONUCLEOSIDE METHYLPHOSPHONATES THAT TARGET IMMEDIATE-EARLY MESSENGER-RNA-1 AND MESSENGER-RNA-3

IE1 and IE3 mRNAs and their protein products (IE110 and IE175, respect ively) were detected in HSV-l-infected U937 cells at 4-15 hours postin fection. In transient expression assays with infectious HIV or an HIV- LTR-directed chloramphenicol acetyltransferase construction (HIV-LTRca t), HSV-1 caused HIV activation (86.7% +/- 6.4% conversion). Electroph oretic mobility shift assays with DNA sequences that encompass the LBP -1 binding site revealed increased levels of DNA-protein complex forma tion with nuclear extracts from HSV-1 infected as compared with uninfe cted U937 cells, Novel bands were not seen. HSV-1 mutants respectively deleted in IE110 (dl1403) or IE175 (d120) activated HIV as well as wi ld-type virus, However, HSV-l-mediated activation was inhibited (26% c onversion) by simultaneous treatment with oligonucleoside methylphosph onates (ONMP) that specifically inhibit expression of IE110 (IE1TI) or IE175 (IE3TI). ONMP did not inhibit activation when used individually (83.8% and 67.8% conversion with IETI1 and IE3TI, respectively). Comb inations of mutant ONMP that do not inhibit IE110 or IE175 expression did not reduce the levels of HSV-1-mediated activation, These findings suggest that HSV genes IE1 and IE3 can independently activate HIV in monocytic cells and ONMP that target HSV IE genes can be used to inhib it HIV activation.