Viral persistence is among the most poorly understood phenomena in virology. Human cytomegalovirus (HCMV) persists indefinitely in the host by way of a latent infection. While the coexistence of latent HCMV is typically asymptomatic in the immune-competent host, it is associated with increased risk of age-related pathologies including atherosclerosis. Reactivation of HCMV from latency often results in devastating disease in individuals with weakened cellular immunity. Further, HCMV is the leading cause of infectious disease-related birth defects. There is no vaccine and current antivirals have limited efficacy because they fail to target latently infected cells. We have a lon-standing focus investigating viral determinants important to HCMV persistence. We have discovered a novel polycistronic locus, UL133/8, encoding four proteins unique to clinical isolates of HCMV. UL133/8 encodes pUL138, the only demonstrated determinant for HCMV latency, in addition to three novel proteins, pUL133, pUL135, and pUL136. The UL133/8 locus governs cell type-dependent outcomes of infection as the locus is dispensable for replication in fibroblasts, augments replication in endothelial cells, and suppresses replication in CD34+ hematopoietic progenitor cells (HPCs). From this locus, pUL135 has emerged as a master regulator of infection. A virus lacking only UL135 exhibits a surprising and severe defect for vira replication in fibroblasts. This defect in replication is complemented by the additional disruption of UL138, suggesting HCMV coordinates the expression of antagonistic activities from a single locus. We hypothesize that pUL135 functions to overcome pUL138-mediated suppression of viral replication through its interaction with cellular proteins, and that this activity contribute to reactivation from latency.
The aims of this proposal will define the requirement of UL135 in infection and determine the mechanisms by which it promotes viral replication and reactivation.
In Aim 1, we will define the role of pUL135 in replication and its differential regulation in three contexts of infection: fibroblasts, endothelial cells, and CD34+ HPCs. We hypothesize that pUL135 functions to oppose pUL138 in infection through its interaction with cellular proteins. We have found that both pUL135 and pUL138 antagonistically regulate cell surface levels of EGFR. We have identified the Abelson interacting protein-1 (ABI-1) as a prominent interacting partner of pUL135. As EGFR is a natural target of ABI-1, we hypothesize that pUL135 opposes pUL138, and its regulation of EGFR, through the interaction with ABI-1.
Aim 2 will investigate the significance of the pUL135: ABI-1 interaction and other key interactions bridged by ABI-1 to the function of pUL135 in viral replication, latency/ reactivation, and the regulation of EGFR.
In Aim 3, we investigate the significance of pUL135 and its interactions to viral latency in vivo using NOD/LtSz-scidIL2?cnull humanized mice, the only animal model for HCMV latency. Our studies will define exciting virus-host interactions that will provide mechanistic insight into the role of the novel UL133/8 locus in infection and its function as the first molecular switch defined for HCMV persistence.

Public Health Relevance

Our proposal addresses issues of central importance to the success of viruses in the human host and their pathogenesis. We will determine how master regulatory networks in the cell affect outcomes of viral infection and how the virus-coded determinants perturb these networks. This work will contribute substantially to our understanding of virus-host interactions that contribute to viral 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)
High Priority, Short Term Project Award (R56)
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Virology - A Study Section (VIRA)
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Beisel, Christopher E
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University of Arizona
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United States
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