Human Cytomegalovirus Latency: Approaching the Gordian Knot

Abstract

Herpesviruses have evolved exquisite virus-host interactions that co-opt or evade a number of host pathways to persist. Persistence of human cytomegalovirus (CMV or HCMV), the prototypical β-herpesvirus, is particularly complex in the host organism. Depending on host physiology and the cell types infected, CMV persistence is comprised of latent, chronic, and productive states that may occur concurrently. Viral latency is a central strategy by which herpesviruses ensure their life-long persistence. While much remains to be defined about the virus-host interactions important to CMV latency, it is clear that checkpoints comprised of viral and cellular factors exist to either maintain a latent state or initiate productive replication in response to host cues. CMV offers a rich platform for defining the virus-host interactions and understanding the host biology important to viral latency. This review describes current understanding of the virus-host interactions that contribute to viral latency and reactivation.

Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34 + Human Progenitor Cells

“…Because signaling and entry ultimately set the stage for the successful infection of a target cell, we next determined how EGFR signaling during the entry process might contribute to the initial steps in the establishment of latency in CD34 ϩ HPCs. Although HCMV latency is characterized by a limited viral transcription program (17,28,29), there is abundant evidence that the virus is able to manipulate a variety of host cellular processes during the establishment of latency to optimize the latency program or to prime cells for lytic reactivation (2,53). For example, a limited number of latency-associated viral gene products, in association with a panel of cellular microRNAs (miRNAs), have been shown to alter viral replication and to activate cellular signaling pathways to control cell survival, immune surveillance, and transcription of cellular gene products (50,(54)(55)(56)(57)(58)(59)(60)(61)(62)(63).…”

“…KEYWORDS CD34 ϩ HPC, EGFR, HCMV, latency, virus entry H uman cytomegalovirus (HCMV) establishes a persistent infection that remains for the lifetime of its human host and is marked by periods of latency and reactivation (1,2). HCMV infection causes severe disease in immunocompromised patients, including allogeneic hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) patients, and in congenitally infected neonates (1,(3)(4)(5).…”

Alternative promoters drive human cytomegalovirus reactivation from latency

“…The IE proteins, in particular IE1-72 kilodalton (kDa) and IE2-86 kDa proteins, referred to as IE1 and IE2, play critical roles in initiating the HCMV lytic cycle by transactivating the expression of cellular and viral genes and suppressing the innate immune response (3). During latency, IE gene expression is repressed, resulting in diminished viral gene expression and the absence of productive replication (4). Signals that stimulate reactivation induce IE gene expression to allow reentry into the viral replicative cycle (5), and this de-repression of IE genes is considered a pivotal event controlling the switch between latent and reactivated states.…”

Recent advances in CMV tropism, latency, and diagnosis during aging

“…We propose a model whereby UL135 and UL138 together with EGFR comprise a molecular switch that regulates states of latency and replication in HCMV infection by regulating EGFR trafficking to fine tune EGFR signaling (Buehler et al 2016). Understanding the mechanisms by which HCMV modulates its latent cycle is critical to ultimately control latency and reactivation (Goodrum 2016). For example, if HCMV is a driver of aging, then suppressing or limiting viral reactivation may assuage age-related risks or pathology associated with HCMV seropositivity.…”

“…Investigators at the workshop have also concluded that a number of areas deserve further and more in-depth investigation. For example, pertinent topics related to latency and reactivation were discussed (Goodrum 2016;Dupont and Reeves 2016). How do we define latency in an infected human?…”