The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

Abstract

While the host immune response following primary human cytomegalovirus (HCMV) infection is generally effective at stopping virus replication and dissemination, virus is never cleared by the host and like all herpesviruses, persists for life. At least in part, this persistence is known to be facilitated by the ability of HCMV to establish latency in myeloid cells in which infection is essentially silent with, importantly, a total lack of new virus production. However, although the viral transcription programme during latency is much suppressed, a number of viral genes are expressed during latent infection at the protein level and many of these have been shown to have profound effects on the latent cell and its environment. Intriguingly, many of these latency-associated genes are also expressed during lytic infection. Therefore, why the same potent host immune responses generated during lytic infection to these viral gene products are not recognized during latency, thereby allowing clearance of latently infected cells, is far from clear. Reactivation from latency is also a major cause of HCMV-mediated disease, particularly in the immune compromised and immune naive, and is also likely to be a major source of virus in chronic subclinical HCMV infection which has been suggested to be associated with long-term diseases such as atherosclerosis and some neoplasias. Consequently, understanding latency and why latently infected cells appear to be immunoprivileged is crucial for an understanding of the pathogenesis of HCMV and may help to design strategies to eliminate latent virus reservoirs, at least in certain clinical settings.

Human Cytomegalovirus (HCMV)-Specific CD4 + T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

“…The paradox with the association of CMV seropositivity with the loss of immune function in older people is that overt CMV disease as a result of reactivation or new infections is not observed; however, there is an increase in detectable virus in urine in older people (44). This strongly suggests that the immune response to HCMV itself retains sufficient functionality within the older immunocompetent population but that immunomodulation as a consequence of lifelong carriage of HCMV may alter the immune response (57). Secretion of the immunomodulatory cytokine IL-10 (58) by CMV-specific CD4 ϩ T cells is a candidate for mediating the immunomodulation of the CMV-specific T cell response during ageing.…”

“…The use of in vitro stimulation of CD4 ϩ T cells with HCMV peptide pools or viral lysate allows the determination of T cell effector functions, but this is in the absence of immune evasion molecules expressed by CMV during its lytic life cycle. Examination of CMV-specific T cell responses in the absence of viral immunomodulation is not representative of the situation during CMV infection or reactivation in the host (57). CMV genome-encoded proteins target many aspects of the immune response, including the evasion of natural killer cell responses, the interferon response, and perturbation of immunomodulatory pathways (reviewed in reference 53).…”

Low Expression of Estrogen Receptor-α and Progesterone Receptor in Human Breast Cancer Tissues Is Associated With High-Grade Human Cytomegalovirus Protein Expression

“…In humans, the virus can escape immune elimination and establish latency in myeloid lineage cells 26 . During inflammation, latent infections may be re-activated 27 , leading to production of new viral particles and release of factors that can enhance inflammation and damage surrounding tissues.…”

CMV immunology

“…5 In this special issue, Wills et al have summarized strategies for immune evasion during latent HCMV infection and have discussed how the understanding of these mechanisms could help in designing new approaches for targeting latent HCMV. 6 The ultimate aim of these approaches is to prevent reactivation and life-threatening disease in some patient groups. CD8 1 T cells play an essential role in the control of CMV infection.…”