Biology of Circoviruses

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BACKGROUND.***Circoviruses are small, non-enveloped icosahedral viruses that are important pathogens of several animal species. Infectious chicken anemia, is caused by a circovirus called chicken anemia virus (CAV). Controlling outbreaks of CAV during intensive poultry farming is costly and disruptive. Circovirus genomes are small, ranging between 1.7-2.3 kb and circular, which gives the family its name. CAV encodes only 3 open reading frames (ORFs). Pathogenicity of the virus in chickens is due to a single ORF, designated viral protein 3 (VP3), which causes extensive apoptosis in infected cells and is required for efficient viral replication. In order to understand how CAV-VP3 induces cell death, our group purified the cellular protein complexes associated with this protein and found that CAV-VP3 binds to the anaphase promoting complex/cyclosome (APC/C). Several diverse types of virus including Papillomavirus, Adenovirus, Herpesvirus, Poxvirus and Circovirus have all been shown to have proteins that bind and inactivate the APC/C. Although this wide range of viruses have convergently evolved strategies to inhibit the APC/C, the functional importance of this interaction during viral replication is unknown. Continued study of the biology of CAV can therefore provide fundamental insights into general mechanisms of molecular virology and cell biology.***RESEARCH PROGRAM.***Our previous studies focused on the mechanism of cytotoxicity of the VP3 protein of CAV. We found that CAV-VP3 interacts with critical components of the cell cycle and DNA damage response pathway. We now plan to continue our research program by examining how these properties of CAV-VP3 enhance viral replication and spread. ***SPECIFIC AIMS.***Aim 1. Functions of the CAV-VP3 protein required for efficient viral replication.***Our studies have shown that nuclocytoplasmic shuttling and multimerization activity of CAV-VP3 is required for the cytotoxic properties of the protein. We will utilize an in vitro replication system of CAV to assess the impact of each of these activities of CAV-VP3 on replication.***Aim 2. The role the CAV-VP3 interaction with the APC/C in viral replication.***CAV-VP3 interacts and inhibits the anaphase-promoting complex (APC), a critical component of the cell cycle regulatory machinery. In this aim we will study how inhibition of the APC promotes viral replication.***Aim 3. The CAV-VP3 protein as a DNA damage sensor and modulator of DNA damage responses.***We have observed that CAV-VP3 is able to attenuate cellular DNA damage responses. In the final aim we will study how CAV-VP3 is targeted by the DNA damage signaling pathway and the importance of these interactions for efficient viral replication.********