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Herpes simplex virus type 1 (HSV-1) and some of its immediate-early genes stimulate expression of the human immunodeficiency virus (HIV) long terminal repeat (LTR) sequences and the replication of HIV itself. To demonstrate this, the HIV LTR was linked to the indicator gene chloramphenicol acetyltransferase (CAT) and transfected into Vero cells with or without the trans-activating gene (tat) of HIV. Infection of these cells with HSV-1 strain KOS or temperature-sensitive mutant tsB2l or tsE6 resulted in a large increase in CAT activity in the absence of tat and further augmentation in the presence of tat. This stimulation was seen at both their permissive (34°C) and nonpermissive (39OC) temperatures, implying either that HSV-1 infection or immediateearly gene expression is all that is required. In cotransfection assays in Vero cells, cloned HSV-1 immediateearly genes ICPO and ICP4 stimulated CAT activity in the presence of tat, while ICP27 had no effect. On the other hand, in SW480 cells, ICP4 and, to a lesser extent, ICPO genes caused stimulation of CAT activity in the absence of tat. Deletion mutants within the HIV LTR showed that the target for HSV stimulation is distinct from the tat-responsive area and maps near the SPl binding sites. In HeLa cells, ICPO or ICP4 stimulated the replication of a cotransfected clone of HIV, as shown by an increase in reverse transcriptase activity in the culture supernatant.