Herpes Simplex Virus Type 1 and Host Antiviral Immune Responses: An Update

Abstract

Herpes simplex virus type 1 (HSV-1) infection activates a rapid stimulation of host innate immune responses and a delicate interplay between virus and host immune elements regulates the whole events. Although host immune elements play well in limiting the HSV-1 infection by interfering viral replication, they are still unable to remove the virus completely, because HSV-1 proteins are efficient enough to bypass the host antiviral immune responses and virus succeed to reactivate again from latency at opportune time. Type 1 interferon signaling pathway is the central point of innate immunity along with some of the activated neutrophils, monocytes, macrophages, and dendritic cells, and some natural killer cells play role, while the CD8⁺ T cells are crucial in adaptive immunity. In this review, the current knowledge of host and HSV-1 interaction has been described that how the host antiviral immune responses occur and what are the mechanisms of viral evasion adapted by virus to counteract with both arms of immunity.

Introduction

Herpes simplex virus type 1 (HSV-1), is a popular human pathogen found worldwide, but highly prevalent in developing countries. It belongs to the family Herpesviridae, which causes oral herpes and at initial stages, cold sores and blisters appear. HSV-1 is well known for its lifelong latency in neurons and can replicate whenever reactivated throughout the life of host. Bodily secretions are shed, which ultimately pass on to the naive patient and increase the success rate of infection in human (49,53).

A complex interaction between the host and viral proteins is determined by the type of host cells and the viral genes activated. These genes encode proteins and perform functions in assisting viral replication, as well as in the activation of immune response to virus. Likewise, the severity and duration of infection is dependent upon the host factors like immune health and genetic susceptibility (11).

Immune elements play a pivotal role in providing protection against HSV-1 infection by interfering with viral replication and maintaining virus in a latent state for long period without production of infectious viral particles and appearance of infection symptoms. Both innate and adaptive immune responses occur in case of HSV-1 infection. Type 1 interferon (IFN) signaling pathway, which is first innate immune response against virus, is activated by the virion. This IFN pathway is dependent upon a number of pattern recognition receptors (PRRs), which have specific nucleic acid and DNA and RNA sensors, and after recognition of virus, the interferon-stimulated genes (ISGs) are activated to inhibit the viral replication and limit the rate of HSV-1 infection (13). Similarly, the adaptive immune responses are also important to play role in disease succession, latency, and control of viral multiplication. CD8⁺ T cells are important in this regard; mainly, by the production of IFN-γ and CD4⁺ T cells, they also have a minor role by providing protection to some extent, when other immune effectors are absent (10).

The main focus of this article is the HSV-1 interaction with the host as to how the host antiviral defense machinery is engaged to overcome infection and the HSV-1 develops mechanisms to find escape from these immune elements to establish infection.

Innate Immune Response

Innate immune system provides first line of defense against HSV-1 infection by limiting viral replication, and the type 1 IFN signaling pathway is the important component of innate immunity. Type 1 IFN comprised production of IFN-α and IFN-β and mediates a broad range of immune responses toward viral infection. Nucleic acid sensing is a very crucial strategy used by innate immune system to detect the virus in HSV-1 infection. Different types of nucleic acid-sensing receptors are present, which can activate signaling pathways known as PRRs and play their role by expression of ISGs (10). These cytosolic PRRs include many receptors, including Toll-like receptors (TLRs), cytosolic DNA and RIG-I (retinoic acid-inducible gene-I)-like receptors (RLRs), and some other DNA and RNA sensors that can detect cytoplasmic DNA and RNA structures (57) (Table 1), and then some of the specific components of HSV-1 diminish the production of Type-1 IFN by the downregulation of signaling pathway.

Table 1.

Some of the Pattern Recognition Receptors and Their Functions in Innate Immunity

		Ref.
TLRs
TLR3	Specific role in host antiviral immunity, after detection of dsRNA, induce expression of type 1 IFNs and inflammatory cytokines. TLR3 deficiency increases viral replication in fibroblasts.	(1,63,64)
TLR9	Double-stranded DNA of HSV-1 containing unmethylated CpG motifs is detected by TLR9	(31)
MyD88	An adaptor protein, which receives the signal transduction from TIR domain of TLR and IL-1R and recruits other protein kinases, resulting in activation of JNK and NF-κB pathways, activating IFN-1 and other proinflammatory cytokines, and also involves in the formation of discrete protein complexes to activate IRF3 and IRF7 for expression of IFN-β.	(37)
TRAF6	Act as an adaptor molecule for the transmission of intracellular signals.	(56)
RLR
RIG-I	Recognizes RNA bearing 5′-triphosphate group, transmits signals to adaptor proteins for expression of type 1 IFNs and inflammatory cytokines.	(14,26)
MDA5	Mainly recognizes dsRNA, transmits signals to adaptor proteins for expression of type 1 IFNs and inflammatory cytokines.	(14,26)
TRAF3	Links upstream type 1 IFN signaling responses of MAVS to TBK1 for type 1 IFN production.	(42)
Cytosolic DNA receptors
STING	Play role in host restriction against HSV-1 and can induce robust production of IFN-β in HEK293T cells.	(34)
cGAS	Novel cytosolic DNA sensor, activates STING for signal transduction as host defense mechanism against HSV-1.	(32)
IFI16	Upon HSV-1 recognition, IFI16 get acetylated and interacts with STING for IFN production to neutralize viral replication.	(3)

cGAS, cyclic GMP-AMP synthase; dsRNA, double-stranded RNA; HSV-1, herpes simplex virus type 1; IFI16, IFN-γ inducible protein 16; IFN, interferon; IL, interleukin; IRF, interferon regulatory factor; MAVS, mitochondrial antiviral-signaling protein; MDA5, melanoma differentiation-associated gene 5; NF-κB, nuclear factor-κB; RIG-I, retinoic acid-inducible gene-I; RLR, RIG-I-like receptor; STING, stimulator of interferon genes; TBK1, TANK binding kinase 1; TIR, Toll/interleukin-1 receptor; TLRs, Toll-like receptors; TRAF, TNF receptor-associated factor.

TLR-mediated IFN-1 response

Membrane-bound TLRs like TLR2, TLR3, TLR4, and TLR9 (35,48) are important components of host defense against HSV-1, which play their role after recognition of pathogen-associated molecular patterns (PAMPs), and can detect nucleic acid inside the endosomal compartment. These TLRs then engage some of the downstream adaptor proteins like myeloid differentiation primary response protein (MyD88) and TNF receptor-associated factor 6 (TRAF6), which is the member of TRAF protein and can detect nucleic acids inside the endosomal compartments for the initiation of signaling cascades for IFN-β expression. Components of HSV-1 like US3, ICP4, and ICP34.5 have effects in antiviral signaling like downregulation of messenger RNA and their surface expression in TLR-mediated IFN-1 response (29,44), and ICP0 will do the proteosomal degradation of MyD88 (65), and similarly, US3 will degrade the TRAF6.

RLR-mediated IFN-1 response

RLRs, including RIG-I and melanoma differentiation-associated gene 5, (MDA5) and other RNA receptors can detect distinct RNA structures. RIG-I and MDA5 recognize short double-stranded RNA (dsRNA) (51) and longer dsRNA (45). Activation of interferon regulatory factor 3 (IRF3) and nuclear factor-κB by RLR signaling leads to production of type 1 IFN and proinflammatory cytokines, and US11 is the HSV-1 protein that targets the antiviral signaling by preventing interaction of RIG-1 with IPS-1 by deubiquitination and by prevention of dimerization and interaction of IPS-1 with MDA5 (59). Similarly, TRAF3 is one of the important components of RLRs, which leads to the type 1 IFN production and UL36, which is the largest tegumented protein of HSV-1 that blocks the IFN-β production by deubiquitination (54).

DNA sensors mediated IFN-1 response

The responsibility of cytosolic DNA detection is carried out by cyclic GMP-AMP synthase (cGAS) by DNA sensor signaling pathway. This pathway also includes stimulator of interferon genes (STING), which is an ISG and is an important adaptor for the induction of type 1 IFN by cytosolic DNA and play major role in innate immune signaling (2,4). cGAS, which is the most important sensor of cytosolic DNA, belongs to nucleotidyl transferase family. cGAS upon binding to the double-stranded DNA undergoes some conformational changes, which then catalyze ATP and GTP for the production of cyclic GMP-AMP (cGAMP), and this cGAMP then binds to STING and cause some conformational changes in it to activate it. This STING-mediated immune response is affected by ICP0 and US3-PK by disrupting the functional stability of STING (23). In the absence of TLRs, endosomal membrane also contains IFN-γ inducible protein 16 (IFI16), which has been proved to maintain normal levels of IFN in epithelial cells of cornea (12), and ICP0 is HSV-1 protein that degrades the IFI16 and is also responsible to enhance the expression of the HSV-1α proteins (8).

In DNA sensing signaling pathway, VP24 protein, a serine protease of HSV-1, also plays a crucial role to inhibit the IFN-β production by activation of interferon stimulatory DNA, cGAS, and STING, and the IFN-β promoter activation triggered by STING is also inhibited by it. VP24 also has the ability to inhibit the activation of IRF3 by breaking the interaction between TANK-binding kinase 1 and IRF3, which in turn block IFN-β production (62).

Some of the proteins may also act as cytosolic DNA sensors and play role in viral restriction known as DNA-dependent activator of IRF, DDX41, and DNA-dependant protein kinase, which have cell type-specific role (21,41).

Type 1 IFN signaling induces expression of several different types of ISGs, including dsRNA-dependent protein kinase (PKR), Ribonuclease L, 2′-5′ oligoadenylate synthetase, zinc finger antiviral protein, and tetherin. Different sets of ISGs work together to enhance type 1 IFN signaling and antiviral activity to inhibit viral replication (Table 2).

Table 2.

The Roles of Interferon-Stimulating Genes in Immunity

ISGs	Role in immunity	Ref.
PKR	PKR phosphorylates eukaryotic translation initiation factor eIF2, thus inhibiting its activity and preventing viral gene expression	(13)
Ribonuclease L	Acts upon the mRNA transcripts that get accumulated as a result of PKR action, and degrades them actively	(13)
2′-5′ oligoadenylate synthetase	Activates ribonuclease L	(13)
Zinc finger antiviral protein	A restriction factor that prevents accumulation of viral mRNA in cytoplasm	(17)
Tetherin	Restrict HSV-1 replication by suppressing virus release	(6)

elF2, E74 Like ETS Transcription Factor 2; ISGs, interferon-stimulated genes; mRNA, messenger RNA; PKR, dsRNA-dependent protein kinase.

Activated neutrophils, monocytes, and macrophages

Attracted neutrophils secrete tumor necrosis factor α (TNF-α) that activates caspase 8-dependent pathway, which plays a role in cell lysis and apoptosis of viral-infected epithelial cells. In addition, neutrophils also help in phagocytosis of apoptotic and necrotic epithelial cells. Monocytes recruited to site of infection phagocytose infective viral particles and apoptotic cells, and also differentiate into tissue macrophages. Macrophages play an important role in limiting the infection in peripheral tissues and trigeminal ganglia until the activation of cellular immune system (9,38). Macrophages secrete cytokines and act as antigen-presenting cells that present and process viral particle for the action of cells of adaptive immunity. Important proinflammatory cytokines secreted by macrophages include TNF-α, RANTES, interleukin-6, type 1 IFN, and nitric oxide (NO). NO released from macrophages has been shown to significantly lower HSV-1 level in experiments performed on mouse models.

Dendritic cells

Dendritic cells (DCs) are an adaptable and heterogenic group of antigenic cells that play a significant role in pathogen recognition at infection sites and PAMPs. These are also most important for defensive HSV-specific T cells. HSV recognition by DCs promotes the secretion of different types of antiviral cytokines as well as release of IFN-α/β, which put forth effective antiviral activities like early blocking of HSV gene expression, causing hindrance in the discharge of virions from infected cells. Along with these, DCs also limit the infection expansion from peripheral tissues to the nervous system. Similarly, pre-dendritic cells usually represent a major source of release of IFN-α/β and also activate the TLR9 by bringing out IFN-α/β secretion of HSV (5).

Viral-infected DCs are unable to mature, but they still release cytokines, which help in the maturation of uninfected DCs (9). Viral-infected DCs either undergo apoptosis by downregulating cellular FLICE like inhibitory protein (25) or engulfed by mature DCs, where they are processed and presented to the cells of adaptive immunity (7).

Natural killer cells

Natural killer cells (NKc) as a part of the innate immune system play an important role in recognition and ultimately rapid removal of cells infected with virus. The activation of NKc is not only dependent on DCs by cytokine secretion or direct cytolytic function on target cells (24) but also on integrated signals distributed by the activation of germ line-encoded cells and inhibitory receptors for ligands. By the stochastic expression of NKc, activation and inhibitory receptors are responsible for interaction with a target infected cells (50). Similarly, NKc are important component in protection of naive C57BL/6 mice against HSV-1 infection and play an important role in endurance and corneal scarring compared to T cells or macrophages (18).

NKc induce apoptosis in HSV-1-infected peripheral epithelial cells and control virus levels by cell death (19). NKc contain granules of perforins and granzymes A and B. ICP47 is a viral early gene product that interferes with transporter associated with antigen presentation, leading to reduction in viral peptide expression through major histocompatibility class 1 (MHC) class I (60). This reduction in antigen presentation of MHC-I is an indication for NKc to target virus-infected cells (47). Moreover, TLR2 receptors present on surface of NKc can bind with HSV-1 gD protein leading to activation of NKc (27).

Adaptive Immune Response

The most common and overwhelming cause of HSV-1 spread is the reactivation of virus from neuronal latent state, which is the key to its success to establish lifelong infection. Adaptive immune elements play a role in disease progression and latency, and evidences support the role of CD8⁺ T cells in HSV-1 inhibition in sensory neurons of human (28).

Cytotoxic (CD8⁺) T cells

HSV-1 reactivation from latency is a frequent and overwhelming cause of disease progression worldwide. This reactivation of virus promotes the active transport of virus toward periphery and ultimately to skin, which results in more severity of disease, that is, from cold sore to blinding of corneal lesions and sometimes to lethal encephalitis. By the production of IFN-γ of HSV-specific CD8⁺ T cells, HSV-1 reactivation can be blocked in ex vivo and in vivo trigeminal ganglia cultures. Studies suggest that constant in vivo regulation of latent HSV-1 by CD8⁺ T cells and especially stress-induced reactivation of HSV-1 from latent state, in compromising CD8⁺ T cell, caused an observation of latently infected neurons (15).

Another study describes the role of CD8⁺ T cell lytic granule component, granzyme B, which is necessary for neuronal latency in both ex vivo and in vivo trigeminal ganglia cultures. Viral inactivation occurs by a nonlethal mechanism of degradation of HSV-1 protein, ICP4 by CD8⁺ T cell lytic granules. ICP4, which is an immediate early protein, is required for further gene expression (28).

CD8⁺ T cells respond to viral infection by producing IFN-γ, TNF-α, perforin, and granzymes. By release of performed granules or through death, receptor signaling CD8⁺ T cells induce apoptosis in infected cells. Granzymes, granulysin, and perforins are present in performed granules, they together induce apoptosis of infected cells. Perforins polymerize on surface of target cell membrane, allowing granzymes and granulysin to enter into cell (33). It has also been reported that mannose six phosphate receptor helps in internalization of granzyme B thorough endocytosis in the absence of perforins (39). Perforins play an important role in inducing apoptosis (16). Granulysin is a small cationic protein present on the surface of NKc, T helper cells, and cytotoxic T lymphocytes (CTLs) (30). Granulysin induces cell lysis by interacting with negatively charged cell membrane proteins and by releasing cytochrome C (30). Granzymes A and B are serine proteases and induce apoptosis either in caspase-independent or caspase-dependent pathways (55). Granzyme A works in caspase-independent pathway and hydrolyzes histone proteins of single-stranded DNA, resulting in its cleavage leading to cell death (40). Granzymes B work in caspase-dependent pathway and induce apoptosis directly by procaspase3 directly or increase permeability of mitochondria and cleave Bcl2-interacting domain (Bid) protein (46).

CD8⁺ T cells also release IFN-γ, which promotes immune response by enhancing inhibition of viral replication, and interfering with cell cycle. Antigen presentation by MHC-I, by processing viral peptides, can be increased by immune proteosomal subunits, which are induced by IFN-γ (52). IFN-γ induces expression of antiviral genes like PKR, and reduces viral replication, as these antiviral genes inhibit translation of viral proteins within the cell expression of p21 (36) and p27 (58), which play a role in arresting the cell cycle and in activation of naive T cells into T helper cells (20).

CD8⁺ T cells induce apoptosis as they have CD95 receptors, binding of specific ligands to these receptors initiate caspase 8 signaling process. CD95 receptor contains a binding site known as death effecter domain for procaspase 8. Binding of procaspase 8 to this domain results in cleavage of procaspase 8 and formation of active caspase 8, which is primary downstream regulator for apoptosis. Activated caspase 8 and granzyme B cleave Bid to truncated Bid, which induces release of cytochrome c leading to apoptosis through the intrinsic pathway (61). This mechanism allows viral-specific CTLs to induce apoptosis in viral infected cells, and removing these cells from body and limiting their ability to replicate. This mechanism seemed to be an effective way against viruses in peripheral tissues where mitogenic cells can replace apoptotic cells. However, neurons of nervous system are nonmitogenic and represent a problem as clearance of virus-infected neurons cannot be replaced (43). It seems that CD8⁺ T cells induce granule-mediated apoptosis to overcome latent infection; however, neurons infected with virus in latent phase rarely undergo apoptosis.

Cytotoxic (CD4⁺) T cells

In addition to CD8⁺ T cells, there is also evidence showing importance of CD4⁺ T cells playing role in immunity against HSV-1 infection. Experiments on CD8-depleted and CD8-deficient mice have shown a compensatory role of CD4⁺ T cells, where in the absence of CD8⁺ T cells, CD4⁺ T cells are sufficient to clear the virus both from the mucosal as well as from the neural locations. CD4⁺ T cell immunity does not involve Fas or perforin activity, showing a nonlytic mechanism for control of virus. Moreover CD4⁺ T cells also release high levels of IFN-γ, proving the importance of cytokines against HSV-1 infection (22).

Conclusion

Although host innate and adaptive immune elements play an important role in limiting HSV-1 infection like type 1 IFN signaling pathway, activated neutrophils, macrophages, DCs, and CD8⁺ T cells help in limiting the viral infection by interfering viral replication, but are still unable to remove the virus completely from the host immune system.

In this study, our current knowledge of HSV-1 interaction with host and host immune responses against infection has enhanced our understanding of HSV-1 infection. This review can be beneficial for the development of antiviral drugs and therapies against HSV-1, particularly in immunocompromised patients, and will open future perspective to study the different immune pathways individually adopted by the HSV-1 to find ways to escape from host immune system.

Footnotes

Author Disclosure Statement

The authors declare that they have no competing interests.

Authors' Contributions

I.A., S.Y., and M.S. contributed to main text and S.A. edited the article. All authors read and approved the final article.

Funding Information

The authors are partially supported by Higher Education Commission (HEC)-Pakistan and University of the Punjab, Lahore, Pakistan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

References

Abe

, and Barber

. Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-κB activation through TBK1. J Virol, 2014; 88:5328–5341.

Abe

, Harashima

, Xia

, et al. STING recognition of cytoplasmic DNA instigates cellular defense. Mol Cell, 2013; 50:5–15.

Ansari

, Dutta

, Veettil

, et al. Herpesvirus genome recognition induced acetylation of nuclear IFI16 is essential for its cytoplasmic translocation, inflammasome and IFN-β responses. PLoS Pathog, 2015; 11:e1005019.

Barber

. STING-dependent cytosolic DNA sensing pathways. Trends Immunol, 2014; 35:88–93.

Bedoui

, and Greyer

. The role of dendritic cells in immunity against primary herpes simplex virus infections. Front Microbiol, 2014; 5:533.

Blondeau

, Pelchen-Matthews

, Mlcochova

, et al. Tetherin restricts herpes simplex virus 1 and is antagonized by glycoprotein M. J Virol, 2013; 87:13124–13133.

Bosnjak

, Miranda-Saksena

, Koelle

, et al. Herpes simplex virus infection of human dendritic cells induces apoptosis and allows cross-presentation via uninfected dendritic cells. J Immunol, 2005; 174:2220–2227.

Boutell

, Sadis

, and Everett

. Herpes simplex virus type 1 immediate-early protein ICP0 and its isolated RING finger domain act as ubiquitin E3 ligases in vitro. J Virol, 2002; 76:841–850.

Cheng

, Tumpey

, Staats

, et al. Role of macrophages in restricting herpes simplex virus type 1 growth after ocular infection. Invest Ophthalmol Vis Sci, 2000; 41:1402–1409.

10.

Chew

, Taylor

, and Mossman

. Innate and adaptive immune responses to herpes simplex virus. Viruses, 2009; 1:979–1002.

11.

Conrady

, Drevets

, and Carr

. Herpes simplex type I (HSV-1) infection of the nervous system: is an immune response a good thing?. J Neuroimmunol, 2010; 220:1–9.

12.

Conrady

, Zheng

, Fitzgerald

, et al. Resistance to HSV-1 infection in the epithelium resides with the novel innate sensor, IFI-16. Mucosal Immunol, 2012; 5:173–183.

13.

Egan

, Wu

, Wigdahl

, et al. Immunological control of herpes simplex virus infections. J Neurovirol, 2013; 19:328–345.

14.

Fitzgerald

, McWhirter

, Faia

, et al. IKK&epsi; and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol, 2003; 4:491–496.

15.

Freeman

, Sheridan

, Bonneau

, et al. Psychological stress compromises CD8+ T cell control of latent herpes simplex virus type 1 infections. J Immunol, 2007; 179:322–328.

16.

Froelich

, Orth

, Turbov

, et al. New paradigm for lymphocyte granule-mediated cytotoxicity target cells bind and internalize granzyme B, but an endosomolytic agent is necessary for cytosolic delivery and subsequent apoptosis. J Biol Chem, 1996; 271:29073–29079.

17.

Gao

, Guo

, and Goff

. Inhibition of retroviral RNA production by ZAP, a CCCH-type zinc finger protein. Science, 2002; 297:1703–1706.

18.

Ghiasi

, Cai

, Perng

G-C

, et al. The role of natural killer cells in protection of mice against death and corneal scarring following ocular HSV-1 infection. Antiviral Res, 2000; 45:33–45.

19.

Grubor-Bauk

, Arthur

, and Mayrhofer

. Importance of NKT cells in resistance to herpes simplex virus, fate of virus-infected neurons, and level of latency in mice. J Virol, 2008; 82:11073–11083.

20.

Harvat

, Seth

, and Jetten

. The role of p27Kip1 in gamma interferon-mediated growth arrest of mammary epithelial cells and related defects in mammary carcinoma cells. Oncogene, 1997; 14:2111–2122.

21.

Hornung

. SnapShot: nucleic acid immune sensors, part 1. Immunity, 2014; 41:868, 868.e861.

22.

Johnson

, Chu

C-F

, and Milligan

. Effector CD4+ T-cell involvement in clearance of infectious herpes simplex virus type 1 from sensory ganglia and spinal cords. J Virol, 2008; 82:9678–9688.

23.

Kalamvoki

, and Roizman

. HSV-1 degrades, stabilizes, requires, or is stung by STING depending on ICP0, the US3 protein kinase, and cell derivation. Proc Natl Acad Sci USA, 2014; 111:E611–E617.

24.

Kassim

, Rajasagi

, Ritz

, et al. Dendritic cells are required for optimal activation of natural killer functions following primary infection with herpes simplex virus type 1. J Virol, 2009; 83:3175–3186.

25.

Kather

, Raftery

, Devi-Rao

, et al. Herpes simplex virus type 1 (HSV-1)-induced apoptosis in human dendritic cells as a result of downregulation of cellular FLICE-inhibitory protein and reduced expression of HSV-1 antiapoptotic latency-associated transcript sequences. J Virol, 2010; 84:1034–1046.

26.

Kawai

, Takahashi

, Sato

, et al. IPS-1, an adaptor triggering RIG-I-and MDA5-mediated type I interferon induction. Nat Immunol, 2005; 6:981–988.

27.

Kim

, Osborne

, Zeng

, et al. Herpes simplex virus antigens directly activate NK cells via TLR2, thus facilitating their presentation to CD4 T lymphocytes. J Immunol, 2012; 188:4158–4170.

28.

Knickelbein

, Khanna

, Yee

, et al. Noncytotoxic lytic granule–mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science, 2008; 322:268–271.

29.

Lagos

, Vart

, Gratrix

, et al. Toll-like receptor 4 mediates innate immunity to Kaposi sarcoma herpesvirus. Cell Host Microbe, 2008; 4:470–483.

30.

Latinovic-Golic

, Walch

, Sundstrom

, et al. Expression, processing and transcriptional regulation of granulysin in short-term activated human lymphocytes. BMC Immunol, 2007; 8:1.

31.

Latz

, Verma

, Visintin

, et al. Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nat Immunol, 2007; 8:772–779.

32.

X-D

, Wu

, Gao

, et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science, 2013; 341:1390–1394.

33.

Liu

, Khanna

, Chen

, et al. CD8+ T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons. J Exp Med, 2000; 191:1459–1466.

34.

, Li

, Yu

, et al. Positive feedback regulation of type I interferon by the interferon-stimulated gene STING. EMBO Rep, 2015; 16:202–212.

35.

, and He

. Recognition of herpes simplex viruses: Toll-like receptors and beyond. J Mol Biol, 2014; 426:1133–1147.

36.

Meurs

, Chong

, Galabru

, et al. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell, 1990; 62:379–390.

37.

Mogensen

. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev, 2009; 22:240–273.

38.

Mott

, Brick

, van Rooijen

, et al. Macrophages are important determinants of acute ocular HSV-1 infection in immunized mice. Invest Ophthalmol Visual Sci, 2007; 48:5605–5615.

39.

Motyka

, Korbutt

, Pinkoski

, et al. Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell–induced apoptosis. Cell, 2000; 103:491–500.

40.

Mueller

, Jones

, Chen

, et al. The early expression of glycoprotein B from herpes simplex virus can be detected by antigen-specific CD8+ T cells. J Virol, 2003; 77:2445–2451.

41.

O'Neill

, and Bowie

. Sensing and signaling in antiviral innate immunity. Curr Biol, 2010; 20:R328–R333.

42.

Oganesyan

, Saha

, Guo

, et al. Critical role of TRAF3 in the Toll-like receptor-dependent and-independent antiviral response. Nature, 2006; 439:208–211.

43.

Okouchi

, Ekshyyan

, Maracine

, et al. Neuronal apoptosis in neurodegeneration. Antioxid Redox Signal, 2007; 9:1059–1096.

44.

Peri

, Mattila

, Kantola

, et al. Herpes simplex virus type 1 Us3 gene deletion influences Toll-like receptor responses in cultured monocytic cells. Virol J, 2008; 5:1.

45.

Pichlmair

, Schulz

, Tan

C-P

, et al. Activation of MDA5 requires higher-order RNA structures generated during virus infection. J Virol, 2009; 83:10761–10769.

46.

Pinkoski

, Waterhouse

, Heibein

, et al. Granzyme B-mediated apoptosis proceeds predominantly through a Bcl-2-inhibitable mitochondrial pathway. J Biol Chem, 2001; 276:12060–12067.

47.

Ravetch

, and Lanier

. Immune inhibitory receptors. Science, 2000; 290:84–89.

48.

Reuven

, Fink

, and Shai

. Regulation of innate immune responses by transmembrane interactions: lessons from the TLR family. Biochim Biophys Acta, 2014; 1838:1586–1593.

49.

Roizman

, and Whitley

. An inquiry into the molecular basis of HSV latency and reactivation. Annu Rev Microbiol, 2013; 67:355–374.

50.

Rowe

, Leger

, Jeon

, et al. Herpes keratitis. Prog Retin Eye Res, 2013; 32:88–101.

51.

Schlee

, Roth

, Hornung

, et al. Recognition of 5′ triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity, 2009; 31:25–34.

52.

Sijts

, and Kloetzel

P-M

. The role of the proteasome in the generation of MHC class I ligands and immune responses. Cell Mol Life Sci, 2011; 68:1491–1502.

53.

Steiner

, and Benninger

. Update on herpes virus infections of the nervous system. Curr Neurol Neurosci Rep, 2013; 13:1–7.

54.

Wang

, Wang

, Li

, et al. Herpes simplex virus 1 ubiquitin-specific protease UL36 inhibits beta interferon production by deubiquitinating TRAF3. J Virol, 2013; 87:11851–11860.

55.

Waterhouse

, Sedelies

, Sutton

, et al. Functional dissociation of ΔΨm and cytochrome c release defines the contribution of mitochondria upstream of caspase activation during granzyme B-induced apoptosis. Cell Death Differ, 2006; 13:607–618.

56.

, and Arron

. TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Bioessays, 2003; 25:1096–1105.

57.

, and Chen

. Innate immune sensing and signaling of cytosolic nucleic acids. Annu Rev Immunol, 2014; 32:461–488.

58.

Xaus

, Cardó

, Valledor

, et al. Interferon γ induces the expression of p21 waf-1 and arrests macrophage cell cycle, preventing induction of apoptosis. Immunity, 1999; 11:103–113.

59.

Xing

, Wang

, Lin

, et al. Herpes simplex virus 1 tegument protein US11 downmodulates the RLR signaling pathway via direct interaction with RIG-I and MDA-5. J Virol, 2012; 86:3528–3540.

60.

York

, Roop

, Andrews

, et al. A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Cell, 1994; 77:525–535.

61.

Yoshida

, Koide

, Uchijima

, et al. IFN-γ induces IL-12 mRNA expression by a murine macrophage cell line, J774. Biochem Biophys Res Commun, 1994; 198:857–861.

62.

Zhang

, Su

, and Zheng

. Herpes simplex virus 1 serine protease VP24 blocks the DNA-sensing signal pathway by abrogating activation of interferon regulatory factor 3. J Virol, 2016; 90:5824–5829.

63.

Zhang

S-Y

, Jouanguy

, Ugolini

, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science, 2007; 317:1522–1527.

64.

Zhang

, Jouanguy

, Sancho-Shimizu

, et al. Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses. Immunol Rev, 2007; 220:225–236.

65.

Zhao

, Liang

, Sun

, et al. Kaposi's sarcoma-associated herpesvirus-encoded RTA impairs innate immunity via ubiquitin-mediated degradation of MyD88. J Virol, 2015; 89:415–427.

Herpes Simplex Virus Type 1 and Host Antiviral Immune Responses: An Update

Abstract

Introduction

Innate Immune Response

TLR-mediated IFN-1 response

RLR-mediated IFN-1 response

DNA sensors mediated IFN-1 response

Activated neutrophils, monocytes, and macrophages

Dendritic cells

Natural killer cells

Adaptive Immune Response

Cytotoxic (CD8+) T cells

Cytotoxic (CD4+) T cells

Conclusion

Footnotes

Author Disclosure Statement

Authors' Contributions

Funding Information

References

Cytotoxic (CD8⁺) T cells

Cytotoxic (CD4⁺) T cells