Human cytomegalovirus mir-us25-1 targets the gtpase rhoa to inhibit cd34+ hematopoietic progenitor cell proliferation to maintain the latent viral genome

Nicole L. Diggins, Lindsey B. Crawford, Meaghan H. Hancock, Jennifer Mitchell, Jay A. Nelson

Research output: Contribution to journalArticlepeer-review

Abstract

Human cytomegalovirus (HCMV) microRNAs play essential roles in latency and reactivation in CD341 hematopoietic progenitor cells (HPCs) via regulation of viral and cellular gene expression. In the present study, we show that HCMV miR-US25-1 targets RhoA, a small GTPase required for CD341 HPC self-renewal, prolifera-tion, and hematopoiesis. Expression of miR-US25-1 impairs signaling through the nonmuscle myosin II light chain, which leads to a block in cytokinesis and an inhibition of proliferation. Moreover, infection with an HCMV mutant lacking miR-US25-1 resulted in increased proliferation of CD341 HPCs and a decrease in the proportion of genome-containing cells at the end of latency culture. These observations provide a mechanism by which HCMV limits proliferation to maintain latent viral genomes in CD341 HPCs. IMPORTANCE Each herpesvirus family establishes latency in a unique cell type. Since herpesvirus genomes are maintained as episomes, the virus needs to devise mechanisms to retain the latent genome during cell division. Alphaherpesviruses overcome this obstacle by infecting nondividing neurons, while gammaherpesviruses tether their genome to the host chromosome in dividing B cells. The betaherpesvirus human cytomegalovirus (HCMV) establishes latency in CD341 hematopoietic progenitor cells (HPCs), but the mechanism used to maintain the viral genome is unknown. In this report, we demonstrate that HCMV miR-US25-1 downregulates expression of RhoA, a key cell cycle regulator, which results in inhibition of CD341 HPC proliferation by blocking mitosis. Mutation of miR-US25-1 during viral infection results in enhanced cellular proliferation and a decreased frequency of genome-containing CD341 HPCs. These results reveal a novel mechanism through which HCMV is able to regulate cell division to prevent viral genome loss during proliferation.

Original languageEnglish (US)
Article numbere00621-21
JournalmBio
Volume12
Issue number2
DOIs
StatePublished - 2021

Keywords

  • CD34 hematopoietic progenitor cells
  • Human cytomegalovirus
  • Latency
  • MiRNA
  • RhoA

ASJC Scopus subject areas

  • Microbiology
  • Virology

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