My laboratory studies the human DNA tumor virus, adenovirus (Ad). Ad has proven to be an excellent model system to study the regulation of cellular proliferation, gene expression, and host antiviral responses to infection. Recombinant Ad vectors also are promising agents for therapeutic gene delivery for both short term and long term treatment of a variety of inherited and acquired diseases. Our research is focused in two general areas. First, we study how viral early proteins regulate cellular antiviral responses during infection. Second, we study how infectious virus is assembled and use this information to generate novel vectors for human gene therapy.
Adenovirus regulation of cellular antiviral responses.
Viruses with linear, dsDNA genomes, such as Ad, encounter a number of host cell responses that may severely inhibit virus replication. Cellular sensors recognize viral DNA to activate an interferon (IFN) response that can block virus replication. The ends of the linear Ad genome is sensed as damaged DNA which triggers a DNA damage response (DDR). The DDR severely inhibits Ad DNA replication if unabated. Ad has evolved multiple mechanisms to inhibit a DDR. The Ad5 E4-ORF3 protein relocalizes and sequesters nuclear proteins involved in a DDR into nuclear inclusions termed tracks. Our research focuses on how the E4-ORF3 protein functions in this process. Ad also counteracts innate and IFN-induced antiviral activities during the early stages of infection. We have found that Ad early gene expression and viral DNA replication is blocked during an IFN response. The Ad E4-ORF3 protein counteracts this effect and our research focuses on how the IFN response represses Ad gene expression and how this effect is inhibited by E4-ORF3.
Adenovirus assembly and viral vectors for gene therapy.
We study the fundamental mechanism that directs virus assembly during the late stages of Ad infection. Ad empty capsids are first assembled in the nucleus and subsequently the viral genome is encapsidated. We have defined viral DNA sequences that direct the packaging of Ad DNA into capsids as well as viral proteins that mediate this process. Our studies focus on understanding the underlying mechanism by which the Ad genome is recognized by the packaging machinery and selectively encapsidated into the virus particle. We also are developing new Ad vectors for gene therapy. These studies utilize Ad and adeno-associated virus (AAV) to generate novel Ad-AAV hybrid viruses with unique properties that facilitate vector production as well as provide a new means to efficiently produce recombinant AAV vectors.