Molecular studies were performed to identify and characterize the human herpesvirus-6 (HHV-6) genes that can activate the Human immunodeficiency virus (HIV) promoter. Members of the herpesvirus family are frequently associated with acquired immunodeficiency syndrome (AIDS). HHV-6 was initially isolated from patients with AIDS and form patients with lymphoproliferative disorders. HHV-6 productively infects many of the same cell types as HIV-1, particularly CD4 T cells and nearly every individual carries HHV-6. Co- infection of T cells with HIV-1 and HHV-6 leads to increased cytopathic effects. It is postulated that HHV-6 plays a cofactor role in hastening th development of AIDS. HHV-6 can activate the HIV-1 promoter in T-cell lines. By introducing DNA into cells in culture, we have shown that a HHV-6 gene segment, which can cause tumorigenic transformation of mouse cells and human keratinocytes, ca increase the expression of the indicator chloramphenicol acetyltransferase (CAT) gene linked to the HIV-1 promoter. This activation was mediated through a Sp1 (cellular factor) binding site present in the HIV-1 promoter and activation was dramatically reduced by oligomers designed to block the Sp1 binding sites. For efficient activation, more than one Sp1 site were required. NF-kB sites of the HIV-1 promoter were not essential for HHV-6 gene mediated activation. Our initial studies with deletion clones identified a small protein (115 amino acids) coding sequence in the HHV-6 gene segment involved in this function. Further studies are necessary to confirm the role of this protein in the activation of the HIV-1 promoter. This study is important to understand how HHV-6 could play a role in HIV pathogenesis. The project will also provide knowledge and tools for development of novel antiviral therapies and safe viral vectors for gene therapy of AIDS.
