The role of herpesviruses as s possible cofactor in the progression and pathogenesis of the acquired immune deficiency syndrome (AIDS) is being investigated. AIDS patients develop a wide variety of opportunistic infections and we have been studying the interactions of herpes simplex (HSV) and varicella-zoster (VZV) viruses with the human immunodeficiency virus (HIV) in controlled laboratory experiments. Recombinant clones containing the long terminal repeat (LTR) sequences from the HIV were linked to the indicator gene chloramphenicol acetyltransferase (CAT) and CAT activity was used as a measure of stimulation of the HIV. Infection of cells harboring the HIV-LTR-CAT with herpes simplex virus types 1 or 2 (HSV) or varicella-zoster virus led to stimulation of CAT activity. Two HSV genes, ICP4 and ICP0 and two VZV genes, the products of open reading frames 4 and 62 were shown to be responsible for this effect. The stimulation seen with these HSV and VZV genes differed depending on which cell types was used implying that cellular proteins were playing a major role in the HIV activation seen by herpesviruses. Analysis of deletion mutants within the HIV-LTR revealed that the regions of the LTR required for HSV activation maps to the SP1 and NF-kB binding sequences. The experiments showing HSV activation were extended by the use an infectious clone of HIV whose replication can be stimulated by HSV infection as well as by various cloned HSV genes. We have shown that in HeLa cells, HSV infection stimulates the release of active NF-kB that is required for HIV LTR directed transcription. We are now in the process of determining if this is the mechanism by which HSV activates HIV gene expression.
