Influenza A virus populations exhibit an enormous amount of genomic diversity, or diversity in the gene coding capacity of individual virions. We are exploring how variation in the number and identity of genome segments delivered to a cell by one or more virions influences the cellular response to infection. We are also examining how genomic diversity influences the replication dynamics of viral populations through a combination of experimental and modeling approaches.
Influenza virus defective interfering particles (DIPs) carry large internal deletions in one or more viral gene segments. DIP genome segments can outcompete wild-type segments for replication and packaging, and thus suppress the replication of wild-type virus. While DIPs are generally considered to act as cheaters or parasites, their effects on viral populations remain poorly understood, especially in vivo. We are currently working to define how DIPs are generated and evolve, and to understand how different DIP sequences affect both the behavior of IAV populations and the host response to infection.
Influenza virus populations primarily consist of semi-infectious particles (SIPs) which fail to express one or more essential viral proteins and require complementation to undergo productive replication. The numbers and gene expression patterns of SIPs produced during replication vary significantly between influenza virus strains, with unknown consequences for population-level phenotypes such as transmissibility or pathogenicity. We are currently defining the viral genetic determinants and molecular mechanisms that regulate SIP production, and using this information to determine how changes in SIP production affect emergent population-level phenotypes.
The genome of influenza virus is divided into eight distinct RNA segments. Functional interactions between these segments play critical, yet poorly understood roles in influencing viral transmission and adaptation. We are mechanistically dissecting the network of intersegment interactions that govern viral replication and evolution, and defining how these interactions influence the process of immune escape.