Host Intrinsic and Innate Intracellular Immunity During Herpes Simplex Virus Type 1 (HSV-1) Infection

Abstract

When host cells are invaded by viruses, they deploy multifaceted intracellular defense mechanisms to control infections and limit the damage they may cause. Host intracellular antiviral immunity can be classified into two main branches: (i) intrinsic immunity, an interferon (IFN)-independent antiviral response mediated by constitutively expressed cellular proteins (so-called intrinsic host restriction factors); and (ii) innate immunity, an IFN-dependent antiviral response conferred by IFN-stimulated gene (ISG) products, which are (as indicated by their name) upregulated in response to IFN secretion following the recognition of pathogen-associated molecular patterns (PAMPs) by host pattern recognition receptors (PRRs). Recent evidence has demonstrated temporal regulation and specific viral requirements for the induction of these two arms of immunity during herpes simplex virus type 1 (HSV-1) infection. Moreover, they exert differential antiviral effects to control viral replication. Although they are distinct from one another, the words "intrinsic" and "innate" have been interchangeably and/or simultaneously used in the field of virology. Hence, the aims of this review are to (1) elucidate the current knowledge about host intrinsic and innate immunity during HSV-1 infection, (2) clarify the recent advances in the understanding of their regulation and address the distinctions between them with respect to their induction requirements and effects on viral infection, and (3) highlight the key roles of the viral E3 ubiquitin ligase ICP0 in counteracting both aspects of immunity. This review emphasizes that intrinsic and innate immunity are temporally and functionally distinct arms of host intracellular immunity during HSV-1 infection; the findings are likely pertinent to other clinically important viral infections.

Keywords: HSV-1; ICP0; PML-NBs; antiviral; innate; interferons; intracellular immunity; intrinsic.

FIGURE 1

HSV-1 virion structure. The virion is composed of the viral genome, capsid, tegument, and envelope. The viral genome is a linear double-stranded DNA (dsDNA) enclosed in the capsid. The tegument is the protein matrix between the capsid and the envelope. The envelope is a lipid bilayer membrane with glycoprotein projections embedded in it. Adapted with permission from Alandijany (2018).

FIGURE 2

HSV-1 replication cycle. The virus attaches via glycoproteins to cellular receptors. It enters the cells via the fusion of the viral envelope with the plasma membrane or endocytosis. The de-enveloped nucleocapsid is transported to the nuclear pores, and the viral DNA (vDNA) is ejected into the nucleus. The viral genes are transcribed in a temporal cascade: immediate early (IE), early (E), and late (L) proteins. IE protein expression is turned on by the virion-associated protein VP16. E proteins require IE protein synthesis for their expression and play critical roles in triggering vDNA replication. The hypothesized mechanisms underlying vDNA replication involve theta replication followed by rolling circle replication. L protein expression is dependent on vDNA replication. The capsid is assembled at sites adjacent to vDNA replication compartments, permitting the insertion of vDNA into the capsid. The nucleocapsid buds through the nuclear membrane, is transported through the cytoplasm, and fuses with the plasma membrane. During this journey, the nucleocapsid acquires tegument and envelope proteins. The release of mature progeny virions promotes attachment to new cells, and the cycle continues. Adapted with permission from Alandijany (2018).

FIGURE 3

Examples of intrinsic restriction factors that combat HSV-1 infection. As soon as the viral genomes are delivered to the nucleus, intrinsic restriction factors are rapidly recruited to the incoming viral genomes. In the absence of viral countermeasures and under low multiplicity of infection (MOI) conditions, these restriction factor recruitment events induce viral genome silencing. Promyelocytic leukemia protein-nuclear body (PML-NB) constituent proteins (e.g., promyelocytic leukemia, PML; speckled 100 kDa, Sp100; death domain associated protein, Daxx; alpha thalassemia/mental retardation syndrome X-linked, ATRX; and MORC family CW-type zinc finger 3, MORC3), E3 SUMO ligases (e.g., protein inhibitor of activated STAT 1 and 4; PIAS1 and PIAS4, respectively), DNA repair proteins (e.g., ring finger protein-8 and -168; RNF8 and RNF168, respectively), and repressive histones are examples of host intrinsic restriction factors.

FIGURE 4

Recognition of HSV-1 infection by pattern recognition receptors (PRRs). Host cells are equipped with several PRRs that can recognize virion components (e.g., glycoprotein and vDNA) and structures accumulated during vDNA replication (e.g., dsRNA). Examples of PRRs include cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS), DExD/H-box helicases (DHX), melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene I (RIG-I), and toll-like receptors (TLRs). It remains highly controversial whether interferon-gamma-inducible protein 16 (IFI16) can sense incoming vDNA in the nucleus (the dashed line represents uncertainty). PRRs signal through the stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1)-IFN regulatory factor 3 and 7 (IRF3/7) pathway to induce interferon (IFN) production. Adapted with permission from Alandijany (2018).

FIGURE 5

IFN signaling cascades. The IFN type I (IFN-I) and III (IFN-III) bind to their cognate receptors, IFNα receptors (IFNAR) and IFNλ receptors (IFNLR), respectively, on the cell surface, leading to the activation of Janus kinase 1 (JAK-1) and tyrosine kinase 2 (TYK-2). As a result, activated signal transducers and activators of transcription 1 and 2 (STAT1 and STAT2, respectively) are phosphorylated and bind to IFN regulatory factor 9 (IRF9) to form ISGF3, which translocates to the nucleus to induce the expression of ISGs. The IFN type II (IFN-II) signaling cascade is triggered when IFNγ binds to IFNγ receptor (IFNGR) and activates JAK1 and Janus kinase 2 (JAK2). Consequently, STAT1 molecules are phosphorylated and localized to the nucleus to transactivate ISG expression. Adapted with permission from Alandijany (2018).

FIGURE 6

Temporal regulation of intrinsic and innate immunity during HSV-1 infection. Schematic diagrams demonstrate the sequential recruitment of intrinsic restriction factors and pattern recognition receptors (PRRs) to viral DNA (vDNA), and the associated antiviral effects. (A) Under low multiplicity of infection (MOI) conditions, intrinsic restriction factors are recruited to vDNA upon nuclear entry to induce viral genome silencing. (B) Under high MOI conditions, escape from the intrinsic immune response and initiation of vDNA replication enables PRR recruitment and induction of interferon (IFN) production. Innate immunity constricts viral propagation and limits the spread of infection.

FIGURE 7

ICP0 structure and functional domains. ICP0 comprises 775 amino acids and is encoded by the IE-0 gene located within the inverted repeats sequences ab and b′a′. ICP0 is composed of three exons (1–19, 20–241, and 242–775 nucleotides; yellow), and two introns (765 and 136 nucleotides; gray). Several functional domains and interacting motifs have been identified in ICP0. A zinc-binding really interesting new gene (RING) finger domain is located within the N-terminal region of ICP0 (residues 116–156). The C-terminal region contains a nuclear localization signal (NLS; residues 500–506), a ubiquitin-specific protease 7 (USP7)-binding motif (residues 618–634), and sequences required for localization at promyelocytic leukemia protein-nuclear bodies (PML-NBs; residues 634–719). Three major phosphorylation sites (P; 224–234, 365–371, and 508–518) of ICP0 have been identified. ICP0 contains several SUMO interaction motif (SIM)-like sequences (SLS-1 to SLS-7). Reproduced with permission from Alandijany (2018).

FIGURE 8

ICP0 counteracts host intrinsic and innate immunity. ICP0 employs multiple strategies to antagonize host intracellular immunity. It targets promyelocytic leukemia protein (PML), speckled 100 kDa (SP100), MORC family CW-type zinc finger 3 (MORC3), protein inhibitor of activated STAT 1 (PIAS1), and interferon-gamma-inducible protein 16 (IFI16) for degradation. It interferes with the recruitment of death domain associated protein (Daxx), alpha thalassemia/mental retardation syndrome X-linked (ATRX), protein inhibitor of activated STAT 4 (PIAS4), and epigenetic repressors to viral DNA (vDNA). It prevents IFN-regulatory factor 3 (IRF3) activity and impairs its function.