Human cytomegalovirus (HCMV) is a widely prevalent human herpesvirus, which, after primary infection, persists in the host for life. In healthy individuals, the virus is well controlled by the HCMV-specific T cell response. A key feature of this persistence, in the face of a normally robust host immune response, is the establishment of viral latency. In contrast to lytic infection, which is characterised by extensive viral gene expression and virus production, long-term latency in cells of the myeloid lineage is characterised by highly restricted expression of viral genes, including UL138 and LUNA. Here we report that both UL138 and LUNA-specific T cells were detectable directly ex vivo in healthy HCMV seropositive subjects and that this response is principally CD4+ T cell mediated. These UL138-specific CD4+ T cells are able to mediate MHC class II restricted cytotoxicity and, importantly, show IFNγ effector function in the context of both lytic and latent infection. Furthermore, in contrast to CD4+ T cells specific to antigens expressed solely during lytic infection, both the UL138 and LUNA-specific CD4+ T cell responses included CD4+ T cells that secreted the immunosuppressive cytokine cIL-10. We also show that cIL-10 expressing CD4+ T-cells are directed against latently expressed US28 and UL111A. Taken together, our data show that latency-associated gene products of HCMV generate CD4+ T cell responses in vivo, which are able to elicit effector function in response to both lytic and latently infected cells. Importantly and in contrast to CD4+ T cell populations, which recognise antigens solely expressed during lytic infection, include a subset of cells that secrete the immunosuppressive cytokine cIL-10. This suggests that HCMV skews the T cell responses to latency-associated antigens to one that is overall suppressive in order to sustain latent carriage in vivo.
Human cytomegalovirus (HCMV) is a widely prevalent virus, which is normally carried without clinical symptoms, but often causes severe clinical disease in individuals with compromised immune responses. In healthy HCMV carriers, the immune response to HCMV is robust and includes large numbers of virus-specific T-cells that control viral replication during active infection. Despite this prodigious immune response, HCMV is never cleared after primary infection but persists in the host for life: a key feature of persistence is the ability of the virus to establish a type of viral quiescence, termed latency. Although much is known about T-cell responses to viral proteins expressed solely during lytic infection, the interplay between the T-cell response and latent HCMV is not well understood. Here we report the first comprehensive characterisation of the T-cell response to latent HCMV and show that it is composed principally of CD4+ T-cells, which are specific for viral proteins expressed during latency, and are able to detect latent virus in vitro. We further show that these CD4+ T-cell responses to latency-associated viral gene products include T-cells that secrete cIL-10, an immunosuppressive cytokine, which may function to suppress antiviral immune responses and thereby maintain lifelong carriage of the latent virus.