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bioRxiv · 10.1101/2023.09.05.556359

Virion-associated US28 rapidly modulates Akt activity to suppress HCMV lytic replication in monocytes

Mahmud, J.·Geiler, B. W.·Biswas, J.·Miller, M. J.·Myers, J. E.·Matthews, S. M.·Wass, A. B.·O'Connor, C. M.·Chan, G. C.
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Abstract

Establishing a non-productive quiescent/silent infection within monocytes is essential for spread of human cytomegalovirus (HCMV). Yet, how HCMV establishes a quiescent infection in monocytes remains unclear. US28 is a viral G protein-coupled receptor (GPCR) essential for silent infections within cells of the myeloid lineage. We found virion-associated US28 was rapidly delivered to monocytes, while de novo synthesized US28 was delayed for several days. A recombinant mutant virus lacking US28 (US28{Delta}) was unable to establish a quiescent infection, resulting in a fully productive lytic replication cycle. Mechanistically, viral entry of US28{Delta} phosphorylated Akt at both serine 473 (S473) and threonine 308 (T308), which contrasted with the site-specific phosphorylation of Akt at S473 following WT infection. Preventing Akt bi-phosphorylation prevented lytic replication of US28{Delta}, and ectopic expression of a constitutively phosphorylated Akt variant triggered lytic replication of WT infection. Our data demonstrate that virion-delivered US28 fine-tunes Akt activity to permit HCMV infection to enter a quiescent state following primary infection of monocytes.

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Mahmud, J., Geiler, B. W., Biswas, J., Miller, M. J., Myers, J. E., Matthews, S. M., Wass, A. B., O'Connor, C. M., Chan, G. C.. 2023-09-05. Virion-associated US28 rapidly modulates Akt activity to suppress HCMV lytic replication in monocytes. https://doi.org/10.1101/2023.09.05.556359

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