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Review
. 2022 Feb:52:135-147.
doi: 10.1016/j.coviro.2021.11.016. Epub 2021 Dec 16.

Virus-host protein interactions as footprints of human cytomegalovirus replication

Matthew D Tyl  1 , Cora N Betsinger  1 , Ileana M Cristea  2
Affiliations
Review

Virus-host protein interactions as footprints of human cytomegalovirus replication

Matthew D Tyl et al. Curr Opin Virol. 2022 Feb.

Abstract

Human cytomegalovirus (HCMV) is a pervasive β-herpesvirus that causes lifelong infection. The lytic replication cycle of HCMV is characterized by global organelle remodeling and dynamic virus-host interactions, both of which are necessary for productive HCMV replication. With the advent of new technologies for investigating protein-protein and protein-nucleic acid interactions, numerous critical interfaces between HCMV and host cells have been identified. Here, we review temporal and spatial virus-host interactions that support different stages of the HCMV replication cycle. Understanding how HCMV interacts with host cells during entry, replication, and assembly, as well as how it interfaces with host cell metabolism and immune responses promises to illuminate processes that underlie the biology of infection and the resulting pathologies.

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Conflict of interest statement

Declaration of Interest:

The authors declare that there is no conflict of interest.

Declarations of interest: none

Figures

Figure 1.
Figure 1.. Overview of the HCMV replication cycle.
[1] The virion binds to host transmembrane proteins to promote internalization into the cell. The virion delivers the capsid and accompanying tegument proteins into the cytoplasm by either [a] direct fusion at the plasma membrane or [b] receptor-mediated endocytosis. [2] The capsid traffics along microtubules towards the nucleus. [3] The capsid docks on the nuclear pore and injects its stored genome. [4] The genome becomes histone-associated in a replication-independent manner. [5] Histone post-translational modifications (PTMs) are modified to remodel viral nucleosomes and promote immediate-early (IE) gene expression—the first group of genes expressed in the characteristic herpesvirus temporal cascade of gene expression. [6] IE proteins activate expression of delayed-early (DE) genes important for genome replication. [7] DE proteins replicate the HCMV genome. [8] Late (L) genes, which produce viral capsid proteins and glycoproteins, begin high-level gene expression. [9] Newly synthesized genomes are packaged into viral capsids. [10] The capsid acquires its first layer of tegument proteins and egresses from the nucleus by budding through both nuclear membranes. [11] The capsid acquires its second layer of tegument proteins and becomes enveloped at a new proviral organelle composed of secretory system components, the virion assembly complex. [12] Newly formed virions traffic to the plasma membrane. [13] Virions egress from the cytoplasm and spread to other cells. Example host-virus interactions: (I) DNA sensors bind the incoming viral genome, both inducing cytokine expression from the host genome and repressing viral gene expression. These DNA sensors are targeted and inhibited by viral proteins. (II) The HCMV genome encounters nuclear domain 10 (ND10) bodies, which intrinsically repress expression from viral genomes. HCMV proteins deconstruct ND10 during the early stages of infection to relieve this repression. (III) Viral proteins stall the cell cycle at the G1/S boundary to prevent the competition over nucleotides. (IV) HCMV induces a global upregulation of cellular metabolic pathways to support different facets of its replication cycle (OXPHOS = oxidative phosphorylation).
Figure 2.
Figure 2.. Methods used for investigating protein-protein and protein-nucleic acid interactions during HCMV infection.
Immunoaffinity purification coupled with mass spectrometry or western blotting, proximity labeling, and yeast or bacterial two-hybrid screening are powerful techniques for investigating interactions of single viral or host proteins of interest. Conversely, microarrays and thermal proximity coaggregation profiling provide global insight into virus-host interactions.
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