Buffered memory: a hypothesis for the maintenance of functional, virus-specific CD8(+) T cells during cytomegalovirus infection.

Chronic infections have been a major topic of investigation in recent years, but the mechanisms that dictate whether or not a pathogen is successfully controlled are incompletely understood. Cytomegalovirus (CMV) is a herpesvirus that establishes a persistent infection in the majority of people in the world. Like other herpesviruses, CMV is well controlled by an effective immune response and induces little, if any, pathology in healthy individuals. However, controlling CMV requires continuous immune surveillance, and thus, CMV is a significant cause of morbidity and death in immune-compromised individuals. T cells in particular play an important role in controlling CMV and both CD4(+) and CD8(+) CMV-specific T cells are essential. These virus-specific T cells persist in exceptionally large numbers during the infection, traffic into peripheral tissues and remain functional, making CMV an attractive vaccine vector for driving CMV-like T cell responses against recombinant antigens of choice. However, the mechanisms by which these T cells persist and differentiate while remaining functional are still poorly understood, and we have no means to promote their development in immune-compromised patients at risk for CMV disease. In this review, I will briefly summarize our current knowledge of CMV-specific CD8(+) T cells and propose a mechanism that may explain their maintenance and preservation of function during chronic infection

The establishment of cytomegalovirus latency in organs is not linked to local virus production during primary infection

Recovery from primary cytomegalovirus (CMV) infection is associated with resolution of the productive infection without clearance of the virus genome from affected organs. The presence of latent CMV genome in multiple organs provides the molecular basis for recurrence of CMV within multiple organs, and explains the diversity in the organ manifestations of recrudescent CMV disease during states of immunodeficiency. As a part of a unifying concept of multifocal CMV latency and recurrence, previous work has demonstrated the importance of primary virus replication for the overall load of latent CMV in organs and the risk of recurrence. In the present report, the establishment of CMV latency was studied in a murine model in which the course of primary infection in the immunocompromised host after syngeneic bone marrow transplantation was modulated by a CD8(+) T cell immunotherapy. The antiviral CD8(+) effector cells limited virus replication in all organs and protected the recipients from lethal CMV disease, but after resolution of the productive infection virus DNA remained. Interestingly, the copy number of latent virus DNA in tissue did not quantitatively reflect the preceding virus production in the respective organ. Specifically, in contrast to the case in the lungs and the salivary glands, virus replication in the spleen was suppressed by CD8(+) T cells to below the limit of detection; yet, virus DNA was also detected in the spleen during latency and accordingly, virus recurrence in the spleen could be induced. These findings demonstrate that the control of virus replication in a particular organ does not prevent the establishment of latency in that organ

Hematopoietic stem-cell deficiency resulting from cytomegalovirus-infection of bone-marrow stroma

Cytomegalovirus (CMV) recurrence from latency is a major risk factor in bone marrow transplantation (BMT). Owing to the immunodepletive treatment, ablation of the immune control of latent CMV is responsible for recurrence and cytopathogenic spread of the virus in vital tissues. There is increasing evidence for reconstituting bone marrow being itself a target tissue of CMV. By inhibiting post-transplantation hematopoiesis, CMV is causal for maintenance of the immunocompromised state, which leads to a prolonged phase of persistent virus replication. Based on results in a murine model of BMT and concurrent CMV infection, we discuss possible mechanisms of CMV-mediated bone marrow graft failure. It is concluded that an irremediable damage of bone marrow stroma by CMV is responsible for a reduced rate of regeneration of the marrow-repopulating, pluripotent stem cell