CD4 promoter transactivation by human herpesvirus 6

Area of Science:

• Molecular Virology
• Immunology
• Gene Regulation

Background:

• Human herpesvirus 6 (HHV-6) is known to induce CD4 gene transcription and expression in CD4(-) cells.
• The precise molecular mechanisms underlying this phenomenon have remained largely unidentified.

Purpose of the Study:

• To elucidate the mechanisms by which HHV-6 transactivates the CD4 promoter.
• To identify specific viral factors and cellular binding sites involved in HHV-6-mediated CD4 gene expression.

Main Methods:

• Utilized reporter gene constructs driven by the CD4 promoter to assess HHV-6 transactivation.
• Employed deletion mutants and specific CD4 promoter mutants to map functional elements.
• Performed electrophoretic mobility shift assays (EMSAs) with specific antibodies to identify protein-DNA interactions.

Main Results:

• HHV-6 efficiently transactivates the CD4 promoter, even in the presence of viral DNA polymerase inhibitors.
• An ATF/CRE binding site (-67 to -60) upstream of the CD4 gene is crucial for HHV-6 transactivation and forskolin activation.
• CREB-1 binds to the -79 to -52 region of the CD4 promoter, and HHV-6 ORFs U86 and U89 show transactivation potential, though independent of the CRE element.

Conclusions:

• HHV-6 utilizes specific elements within the CD4 promoter, notably the ATF/CRE site, for transactivation.
• CREB-1 is a key cellular factor involved in the interaction between HHV-6 and the CD4 promoter.
• Additional HHV-6 open reading frames likely contribute to the complex regulation of CD4 gene expression by the virus.