Human cytomegalovirus (hCMV) is a herpesvirus that persists indefinitely by way of a latent infection. Up to 99% of the world's population is latently infected with the virus. Reactivation from latency causes significant morbidity and mortality in immune compromised individuals. Coexistence of latent hCMV in the host poses increased risk of age-related pathologies, including heart disease. There is no vaccine for hCMV and existing antivirals do not clear the virus because they fail to target the latent virus. The mechanisms underlying hCMV latency are poorly understood. Defining these mechanisms is critical to ultimately controlling or eradicating hCMV. During the previous funding period, the UL138 protein, pUL138, was define as the first virus-coded determinant of hCMV latency. pUL138 is encoded by a polycistronic locus, termed the UL133/8 locus, which coordinates the expression of three additional, previously unstudied proteins. Surprisingly, one of these proteins, pUL135, antagonizes the action of pUL138. Thus, while pUL138 suppresses virus replication for latency, pUL135 overcomes pUL138-enforced latency to promote reactivation. Based on our discoveries, we propose a new model whereby pUL135 and pUL138 form a switch that actively drives infection towards latency or reactivation. The goal for this renewal application is to defin the mechanisms by which the UL135/UL138 switch functions. To this end, we have identified cellular interacting partners for pUL138 and pUL135. Importantly, pUL135 and pUL138 each interact with cellular regulators of ubiquitination and protein trafficking that result in opposing effects on receptor tyrosine kinase (RTK) expression at the cell surface. Our findings allow us to test the hypothesis that pUL135 and pUL138 antagonize one another to balance latency and reactivation by exerting opposite effects on cellular ubiquitination and protein trafficking pathways. In the next funding period, we will define the molecular interplay between pUL135 and pUL138 that tips the balance between replicative or latent states of infection. Further, we will determine the mechanisms by which pUL135 and pUL138 regulate protein trafficking during infection and how this virus modulation of cellular trafficking pathways impacts RTK function and viral latency and reactivation. This work will establish a framework within which to identify novel targets for antivirals targeting latent reservoirs-the key to controlling or eradicating hCMV.

Public Health Relevance

Persistent viruses are a major health threat and a source of emerging infectious disease. Mechanisms governing persistence are poorly understood and this is a major impediment to developing therapeutic strategies to cure persistent viruses. We have identified viral factors that function balance quiescent and active states of human cytomegalovirus (CMV) persistence. Our work to define the mechanisms by which these viral factors and the cellular pathways they target will contribute substantially to our understanding of virus-host interactions that contribute to CMV disease in the context of congenital infection, transplantation, immune suppression, and aging and will ultimately identify new targets for novel antivirals aimed at the ability of the virus to persist.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Beisel, Christopher E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arizona
Organized Research Units
United States
Zip Code
Zeltzer, Sebastian; Zeltzer, Carol A; Igarashi, Suzu et al. (2018) Virus Control of Trafficking from Sorting Endosomes. MBio 9:
Rak, Michael A; Buehler, Jason; Zeltzer, Sebastian et al. (2018) Human Cytomegalovirus UL135 Interacts with Host Adaptor Proteins To Regulate Epidermal Growth Factor Receptor and Reactivation from Latency. J Virol 92:
Leng, Sean X; Kamil, Jeremy; Purdy, John G et al. (2017) Recent advances in CMV tropism, latency, and diagnosis during aging. Geroscience 39:251-259
Gordon, Claire L; Miron, Michelle; Thome, Joseph J C et al. (2017) Tissue reservoirs of antiviral T cell immunity in persistent human CMV infection. J Exp Med 214:651-667
Kim, Jung Heon; Collins-McMillen, Donna; Buehler, Jason C et al. (2017) 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. J Virol 91:
Cheng, Shu; Caviness, Katie; Buehler, Jason et al. (2017) Transcriptome-wide characterization of human cytomegalovirus in natural infection and experimental latency. Proc Natl Acad Sci U S A 114:E10586-E10595
Collins-McMillen, Donna; Goodrum, Felicia D (2017) The loss of binary: Pushing the herpesvirus latency paradigm. Curr Clin Microbiol Rep 4:124-131
Nikolich-Zugich, Janko; Goodrum, Felicia; Knox, Kenneth et al. (2017) Known unknowns: how might the persistent herpesvirome shape immunity and aging? Curr Opin Immunol 48:23-30
Buehler, Jason; Zeltzer, Sebastian; Reitsma, Justin et al. (2016) Opposing Regulation of the EGF Receptor: A Molecular Switch Controlling Cytomegalovirus Latency and Replication. PLoS Pathog 12:e1005655
Caviness, Katie; Bughio, Farah; Crawford, Lindsey B et al. (2016) Complex Interplay of the UL136 Isoforms Balances Cytomegalovirus Replication and Latency. MBio 7:e01986

Showing the most recent 10 out of 25 publications