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Review
. 2020 Jan;30(1):e2081.
doi: 10.1002/rmv.2081. Epub 2019 Aug 20.

Immunomodulatory roles of human herpesvirus-encoded microRNA in host-virus interaction

Afsar R Naqvi  1
Affiliations
Review

Immunomodulatory roles of human herpesvirus-encoded microRNA in host-virus interaction

Afsar R Naqvi. Rev Med Virol. 2020 Jan.

Abstract

Human herpesviruses (HHV) are large, double stranded, DNA viruses with high seroprevalence across the globe. Clinical manifestation of primary HHV infection resolve shortly, however, this period is prolonged in immunocompromised patients or individuals with suppressed immunity. Examining molecular mechanisms of HHV-encoded virulence factors can provide finer details of HHV-host interaction. A unique genetic feature of most members of HHV is that they encode multiple microRNAs (miR). In this review, I will provide mechanistic insights into the immunomodulatory functions of herpesvirus-encoded viral miR (v-miR) that favor viral persistence and spread by ingenious immune evasion schemes. Similar to host miR, v-miR can simultaneously regulate expression of multiple transcripts including host- and virus-derived. V-miRs, by virtue of their direct interaction with various transcripts, can regulate expression of critical components of host innate and adaptive immune system. V-miRs are also exported through exosomal route and gain entry into various cells even at distant sites, thereby allowing HHV to manipulate cellular and tissue immunity. Targeting v-miR may serve as a novel and promising therapeutic candidate to mitigate HHV-mediated clinical manifestations.

Keywords: human herpesvirus; immune responses; viral microRNA.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors have stated explicitly that there are no conflicts of interest in connection with this article.

Figures

FIGURE 1
FIGURE 1
Schematic depiction of viral miR biogenesis and their impact on infected and bystander host cells. A series of events leading to the production of viral miR and modulation of host functions is summarized. Virus bind to cell surface receptors via glycoproteins leading to fusion at the plasma membrane or fusion with an endocytic membrane after endocytosis. Internalized virion sheds envelop and is directed towards nucleus, facilitated by host cytoskeleton proteins. In nucleus, viral transcripts (including v-miR precursors), are generated. Host miR biogenesis machinery (eg, DGCR8 and Dicer) recognize viral miR stem-loop structure and generate mature v-miRs. These molecules acts as autocrine and paracrine modulators. In the infected cells, v-miRs can regulate both host and viral transcripts thereby shifting host transcriptome more favorable towards virus. Additionally, v-miRs can be packaged into exosomes and gain entry into bystander cells. Steady influx of v-miRs in non-infected bystander cells can also modulate their cellular functions, including immune responses and thus contribute to viral persistence and immune evasion
FIGURE 2
FIGURE 2
Overview of viral miR-mediated suppression of host innate immune pathways. The illustration summarizes known mechanisms by which individual viral miR interact with host genes involved in virus recognition and activation of innate immune responses. Viral miR promote immune evasion by directly targeting host genes involved in the recognition of virion, virus-derived nucleic acids (DNA/RNA) or proteins to suppress antiviral pathways. Viral miR have evolved to target, essentially, all of the known viral defense mechanisms by targeting one or more critical components of the innate immune pathway. Functions of selected validated herpesvirus-encoded miR and host innate immunity genes are highlighted in the schematic. Viral miR inhibit production of proinflammatory cytokines and interferons that are required for recruitment and activation of adaptive arm of immunity, which can elicit robust antiviral response to contain herpesvirus infection by clearing infected cells
FIGURE 3
FIGURE 3
Viral miR-mediated evasion of adaptive immune responses. Antigens are presented by two major pathways, MHC class I and MHC class II. In MHC class I pathway, endogenous viral antigens are degraded via proteasome machinery, translocated to endoplasmic reticulum through TAP proteins and are processed by proteases like ERAP. Processed peptides are assembled with MHC-I complex to be presented predominantly to CD8+ T cells. MHC class II pathway involves exogenous antigen internalization by several pathways, including phagocytosis, macropinocytosis, and endocytosis. Antigens are trafficked to a mature or late endosomal compartment where they are processed and loaded onto MHC-II molecules that present antigens to CD4+ T cells. Numerous viral miR are known to impair both MHC class I and II pathways by targeting one or more components of the same pathways. In addition, some critical genes (eg, MICB) are targeted by multiple herpesvirus miR indicating selective evolution of miR sequences that can interfere with antigen processing and presentation pathway. Inhibition by viral miR is shown as blocked line highlighted in red. By virtue of their direct interaction with host and viral transcripts, v-miRs can impair components of MHC class I (antigenic peptide transporter TAP, and protease ERAP1) and class II (cathepsin B); inhibit release of proinflammatory and antiviral cytokines; protect infected cell from CD4+/CD8+ T cell response and NK cell-mediated cytolysis; reduce highly antigenic viral antigens (LMP1/ LMP2A)
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