Evasion of CD8 ⁺ T Cells Is Critical for Superinfection by Cytomegalovirus

Abstract

Cytomegalovirus (CMV) can super-infect persistently infected hosts despite CMV-specific humoral and cellular immunity; however, how it does so remains undefined. Here, we demonstrate that super-infection of rhesus CMV-infected rhesus macaques (RM) requires evasion of CD8+ T cell immunity by virally-encoded inhibitors of MHC-I antigen presentation, particularly the homologues of human CMV US2, 3, 6 and 11. In contrast, MHC-I interference was dispensable for primary infection of RM, or for the establishment of a persistent secondary infection in CMV-infected RM transiently depleted of CD8+ lymphocytes. These findings demonstrate that US2-11 glycoproteins promote evasion of CD8+ T cells in vivo thus supporting viral replication and dissemination during super-infection, a process that complicates the development of preventative CMV vaccines, but that can be exploited for CMV-based vector development.

The Cell Biology of Cytomegalovirus: Implications for Transplantation

“…US2-11 glycoproteins promote evasion of CD8+ T cells in vivo, contributing to viral replication and dissemination during superinfection, a process that complicates the development of CMV vaccines but is useful for CMV-based vector development (66). A trial of simian immunodeficiency virus (SIV) vaccines that include rhesus CMV (RhCMV) vectors showed establishment of indefinitely persistent, high-frequency, SIVspecific effector memory T cell responses at potential sites of SIV replication in rhesus macaques.…”

Stimulation of Human EBV- and CMV-Specific Cytolytic Effector Function Using Allogeneic HLA Molecules

“…HIV is highly efficient at evading immune responses through mechanisms such as modulation of MHC class II presentation (33) and downregulation of MHC class I molecules (3,(33)(34)(35). Many other viral immune evasion strategies are also described (36)(37)(38)(39)(40).…”

Socioeconomic Impact of HIV/AIDS on Households under Free Antiretroviral Therapy in Preah Sihanouk Province, Cambodia

“…While CMV is subdivided into several genotypes, extensive genetic diversity might not entirely explain the lack of protection by CMV-specific CD8+ T cells from the superinfecting strain, as the large size of the viral genome might allow for the generation of a significant degree of cross-reactive responses. Accordingly, based on observations made in CMV-infected Rhesus macaques, it has been proposed that productive superinfection by CMV relies on the US2, US3, US6 and US11 viral proteins that all dampen HLA class-I presentation and allow the virus to evade CMVspecific CD8+ T cell responses, while these factors are not required to establish the primary infection [93]. Thus, it cannot be ruled out that, in addition to the considerable genetic variability of HIV-1, accessory proteins such as Nef and Vpu, which have been shown to affect HLA class-I antigen presentation, contribute to counteracting existing HIV-1-specific immune responses to facilitate HIV-1 superinfection.…”