Human Cytomegalovirus Latency and Reactivation in and Beyond the Myeloid Lineage

Abstract

AbstrAct:After primary infection with human cytomegalovirus (HCMV), which rarely causes any serious clinical problems in the immune competent, the virus persists subclinically for the lifetime of the host due, at least in part, to its ability to undergo latent infection. By contrast, HCMV can be a serious cause of morbidity, and in some cases mortality, upon primary infection of, or reactivation in, immune suppressed individuals. While current antivirals that target its lytic lifecycle have helped enormously in managing HCMV disease, to date, there are no available antivirals that target latent infection. In this review, we discuss research using natural and experimental models of latency that has led to some understanding of how HCMV latency is maintained, and reactivation controlled, in the myeloid lineage. Such analyses are now beginning to inform us of novel rationales that could allow the development of novel antivirals to target latency, itself.

Latency-Associated Viral Interleukin-10 (IL-10) Encoded by Human Cytomegalovirus Modulates Cellular IL-10 and CCL8 Secretion during Latent Infection through Changes in the Cellular MicroRNA hsa-miR-92a

“…In healthy individuals, a robust T cell response to primary infection is believed to ensure that clinical symptoms rarely occur. However, like all herpesviruses, HCMV persists for life, and this is mediated, at least in part, by its ability to enter a latent life cycle ( 2 , 3 ).…”

“…In general, latent infection of otherwise healthy carriers is also asymptomatic, as is the sporadic reactivation of the virus, which is believed to occur routinely in latently infected individuals in vivo . However, in immunocompromised individuals (including AIDS patients and transplant recipients), primary infection, as well as reactivation from latency, carries a risk of severe morbidity and mortality ( 2 , 3 ).…”

“…During latency, the lytic transcription program is heavily suppressed. This results in a lack of production of infectious virions, and viral gene expression is restricted to a substantially reduced number of latency-associated transcripts ( 2 , 3 , 5 – 11 ). However, these latently infected cells can reactivate virus as a result of their differentiation into macrophages and dendritic cells (DCs) ( 2 , 3 ).…”

There's Always Another Way! Cytomegalovirus’ Multifaceted Dissemination Schemes

“…Another role that PMNs might play during HCMV's life cycle is aiding dissemination after reactivation from latency. As reviewed in [21] bone marrow is a major reservoir for latent HCMV [84]. Upon CXCR2 stimulation, neutrophils egress from the bone marrow [85].…”

“…Overview of HCMV dissemination. [21] Dr. Frank Fenner, studying mouse pox, postulated that during a viral infection the virus would replicate at the infection site, then disseminate to the regional lymph nodes, followed by replication in blood filtering organs. These organs would then produce large quantities of virus that results in disease [22,23].…”