Influenza A virus is a major public health problem and a potentially lethal bioterrorism agent. The most cost- effective intervention for a wide spread infection, such as influenza, is through prevention by vaccination. However, the value of current influenza vaccines is limited because they have to be reformulated every year due to waning of the elicited antibody responses to viral coat proteins hemagglutanin (HA) and neuraminidase (NA) in about six months and rapid changes of viral HA and NA genes. CD8 T cells play a critical role in clearance of influenza virus. Compared to antibody responses that are predominantly targeted to HA and NA, CD8 T cells can respond to epitopes derived from not only HA and NA but also other viral proteins, which do not change as rapidly as HA and NA. Vaccines that induce CD8 T cell responses to the more conserved viral components will provide an alternative to current vaccines and might eliminate the need for the yearly reformulation. However, development of vaccines that induce memory CD8 T cells have been challenging, partly due to a lack of understanding of memory CD8 T cell development and maintenance. We have developed an adoptive transfer model of influenza virus infection in which antigen-specific CD8 T cells can be followed at any time and in any anatomical location. Using this system, we propose to investigate key questions that are pertinent to memory CD8 T cell development and maintenance to influenza virus. Specifically, the cellular and molecular mechanisms by which IFN-gamma regulates contraction of effector CD8 T cells will be investigated. The causes underlying the rapid disappearance of memory CD8 T cells in the lung following influenza infection will be determined. An efficient lentivirus- mediated gene transfer will be developed to investigate gene function in memory CD8 T cell development and maintenance. It is anticipated that findings from the proposed studies will help to advance the basic understanding of immunological memory as well as provide strategies for the development of vaccines that can induce CD8 T cell responses to influenza virus in humans.
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