Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that persists for life. Although HCMV is generally benign in healthy individuals, the virus can cause disease in immunocompromised populations and HCMV is the leading infectious cause of congenital disease in newborns. The reasons why the immune system is able to control, but unable to eradicate HCMV are unknown. Our main hypothesis is that immunomodulatory CMV genes, particularly modulators of innate and adaptive cellular immunity, enable the establishment and maintenance of persistent infection in immunocompetent individuals. A better understanding of these immune modulatory processes will be essential for the development of vaccines against HCMV as well as for the optimization of CMV-based vaccine vectors that have recently assumed center stage in the development of vaccines against HIV. Our work in non-human primate models of CMV infection revealed a series of unexpected results that indicate a complex relationship between CMV and the innate and adaptive cellular immune response involving viral evasion, viral recruitment and viral manipulation of the host's immune response. Particularly novel is our finding that rhesus CMV-encoded genes enable the virus to control the epitope specificity of the adaptive, CD8+ T cell immune response. We discovered that while wildtype RhCMV or HCMV elicits conventional MHC-I restricted CD8+ responses, deletion of a single gene, Rh189 or US11, respectively, results in the additional induction of T cells that recognize canonical MHC-I epitopes, i.e. immunodominant in a non-CMV context. Since such stringent control of T cell specificity has not been observed before for any infectious agent, we will elucidate why primate CMVs prevent the induction of canonical T cells and by what molecular mechanism.
In Specific Aim 1 we will determine how canonical T cells control secondary infections by RhCMV and in Specific Aim 2 we will determine the role of MHC-I- downregulation in the prevention of canonical T cell priming by Rh189 and US11. Preliminary data further demonstrate that RhCMV interferes with MHC-II cell surface expression by redistribution to cytoplasmic vesicles suggesting that RhCMV inhibits direct antigen presentation by MHC-II. Furthermore, we discovered that upon deletion of subunits of the gH/gL/UL131A/UL130/UL128 pentamer RhCMV elicits MHC-II-restricted CD8+ T cells at a high frequency, another unprecedented finding.
In Specific Aim 3 we will therefore characterize the mechanism of MHC-II downmodulation by RhCMV to test the hypothesis that pentamer-intact RhCMV prevents priming of MHC-II-restricted CD8+ T cells by downregulating MHC-II in antigen presenting cells whereas pentamer-deficient RhCMV is unable to do so since the pentameric complex is essential for viral entry into non-fibroblast cells. The results of this work are expected to provide new insights into the control of unconventional CD8+ T cell targeting by CMV that will ultimately lead to improved vaccines for HCMV and improved vaccine vectors based on HCMV.
Human cytomegalovirus (HCMV) establishes asymptomatic chronic infection in the vast majority of the world's population despite eliciting and maintaining considerable adaptive immune responses. However, HCMV can cause disease in immunocompromised individuals, such as the developing fetus or transplant recipients, indicating that the immune system can control but not eliminate HCMV. Our goal is to obtain a better understanding of this complex interaction between the host's immune response and viral immune evasion mechanisms in order to improve the design of vaccines against HCMV as well as harnessing the unique immunology and biology of CMV for the development of CMV-based vaccines.
| Früh, Klaus; Picker, Louis (2017) CD8+ T cell programming by cytomegalovirus vectors: applications in prophylactic and therapeutic vaccination. Curr Opin Immunol 47:52-56 |
| Malouli, Daniel; Nakayasu, Ernesto S; Viswanathan, Kasinath et al. (2012) Reevaluation of the coding potential and proteomic analysis of the BAC-derived rhesus cytomegalovirus strain 68-1. J Virol 86:8959-73 |
| Viswanathan, Kasinath; Smith, M Shane; Malouli, Daniel et al. (2011) BST2/Tetherin enhances entry of human cytomegalovirus. PLoS Pathog 7:e1002332 |
