Cytomegalovirus (CMV), like other herpes viruses, has evolved mechanisms to evade immune recognition that allow it to prolong acute infection and to establish latency. The coordinated expression of four viral proteins encoded in the US region of the viral genome functions to downregulate class I MHC in infected cells, effectively blocking the presentation of newly synthesized CMV antigens to CD8 + cytotoxic T cells (CTL) in vitro. However, CD8 + CTL are critical effector cells for controlling persistent CMV infection in vivo and this was thought to reflect the contributions of CD8 + CTL specific for a few immunodominant viral antigens that were presented by infected cells prior to the downregulation of Class I MHC. Recent studies by the applicant using a strain of CMV that is deleted of the US genes and can display all potentially immunogenic epitopes from the viral proteome have demonstrated that the CMV-specific CTL repertoire in vivo is much larger and more diverse than previously appreciated. The findings suggest that additional CMV antigens may be important to include in the development of immunotherapy or vaccination for CMV. The proposed experiments are designed to identify novel CMV antigens recognized by CD8 + CTL, to provide insights into their role in controlling CMV replication in normal individuals, and to determine the effects of individual US proteins and cellular counterevasion strategies on the inhibition of antigen presentation to CTL. ? ? The specific aims are: 1. To identify cytomegalovirus genes encoding novel antigens recognized by CD8 + CMV-specific cytotoxic T cells. 2. To determine the frequency and function of CD8 + T cells specific for individual CMV antigens in healthy CMV + individuals with protective immunity. 3. To determine the effects of individual viral immune evasion proteins and cellular counter evasion strategies on the presentation of CMV antigens to CD8 + CTL by CMV-infected cells. ? ?
| Woolfrey, Ann E; Malhotra, Uma; Harrington, Robert D et al. (2008) Generation of HIV-1-specific CD8+ cell responses following allogeneic hematopoietic cell transplantation. Blood 112:3484-7 |
