An updated review of HSV-1 infection-associated diseases and treatment, vaccine development, and vector therapy application

Abstract

Herpes simplex virus type 1 (HSV-1) is a globally widespread virus that causes and associates with a wide range of diseases, including herpes simplex encephalitis, herpes simplex keratitis, and herpes labialis. The interaction between HSV-1 and the host involves complex immune response mechanisms, including recognition of viral invasion, maintenance of latent infection, and triggering of reactivation. Antiviral therapy is the core treatment for HSV-1 infections. Meanwhile, vaccine development employs different strategies and methods, and several promising vaccine types have emerged, such as live attenuated, protein subunit, and nucleic acid vaccines, offering new possibilities for the prevention of HSV-1 infection. Moreover, HSV-1 can be modified into a therapeutic vector for gene therapy and tumour immunotherapy. This review provides an in-depth summary of HSV-1 infection-associated innate and adaptive immune responses, disease pathogenesis, current therapeutic approaches, recent advances in vaccine development, and vector therapy applications for cancer treatment. Through a systematic review of multiple aspects of HSV-1, this study aims to provide a comprehensive and detailed reference for the public on the prevention, control, and treatment of HSV-1.

Keywords: HSV-1 vaccine; Herpes simplex virus 1; herpes labialis; herpes simplex keratitis; herpes simplex meningitis; immune response.

Figure 1.

HSV virus structure (above). HSV consists of four main components, including the viral genome, an icosahedral capsid consisting of 162 capsid particles, a tegument composed of 20-23 different viral periplasmic proteins with structural and regulatory roles, and a lipid bilayer envelope containing multiple glycoproteins. Schematic diagram of the HSV genome (below). The herpesvirus genome consists of two unique regions, UL (unique long sequence) indicated as light yellow shading, and US (unique short sequence – dark blue), both of which are flanked by reverse repetitive sequences (TRL/IRL and TRS/IRS).

Figure 2.

Replication process of HSV-1. Steps as follows, (1) viral attachment, (2) entry of HSV-1, (3) entry of HSV-1 capsid into the nucleus, (4) transcription, (5) translation, (6) replication, (7) capsid assembly, (8) modification of envelope proteins, (9) translocation of envelope proteins, (10) endocytosis, (11) envelope, and (12) release of HSV-1.

Figure 3.

HSV-1 mediates innate immune signalling and escape strategies. IFN-I and inflammatory cytokines induce antiviral immunity, whereas HSV-1 proteins can hijack multiple steps downstream of the TLRs, RLRs, and DNA sensor signalling pathways. TLRs are located at the plasma membrane and in the nuclear endosomes, where they sense different ligands such as viral dsRNA, dsDNA, and glycoproteins and switch signals through TRIF and MyD88, which then leads to activation of IRF and NF-κB. Various viral proteins, including ICP0, US3, UL36USP, ICP4, and VP16 are sufficient to abrogate the TLR signalling pathway. rig-I and MDA5 in the RLR receptor detect distinct RNA structures and signals through the junction protein MAVS protein, triggering IRF3 and nf-κB activation. US11, UL36USP, and UL37 block MDA5 and RIG-I-mediated antiviral signalling pathways. Cytoplasmic DNA sensors, such as cGAS, IFI16, DDX41, and DAI, recognize double-stranded DNA in the cytoplasm and trigger the production of IFN-I through STING signalling. VP22, UL37, and UL41 can directly interact with cGAS and inhibit its enzymatic activity, subsequently inhibiting downstream signalling. ICP0, ICP27, ICP34.5, US3, US11, VP16, VP24, and UL46 interrupt signal transduction at the level of the TBK1-IRF3 axis. US3, ICP0, UL24, VP16, ORF61, UL42, and VP24 interrupt signal transduction at the level of the TBK1-nf-κB axis. HSV-1 also affects NLRP3 inflammatory factor assembly, which in turn inhibits IL-1β and IL-1B-mediated apoptosis. Black lines indicate cellular processes. Red lines indicate processes regulated by HSV.

Figure 4.

HSV-1 elicits immune cell responses. (1) B lymphocytes generate a first signal of activation by recognizing HSV-1 antigen-C3d complexes via BCR and its co-receptor CD21. A second signal of activation is induced by surface CD40 binding to surface CD40L on Th2 cells. Differentiation into plasma cells and memory B cells in response to IL-4 and IL-13. Antibodies cause apoptosis of infected cells through the neutralization of antigens, ADCC effect, and the CDC effect. (2) initial T lymphocytes activated by classical DCs produce and receive IL-2 themselves and differentiate into Th0 cells. Th0 cells receive CD40, IL-12, and ifn-γ stimulation produced by classical DCs and differentiate into Th1 cells for CTL activation. (3) apc-activated CTL cells receive IL-2 stimulation from themselves and Th1, and differentiate into effector CTLs and memory CTLs. Effector CTLs release various toxic mediators and secrete ifn-γ to induce the role of macrophages and NK cells through the binding of TCR-CD3 complexes with antigenic peptide-mhc class I molecules complexes on the surface of target cells. (4) after NK cells recognize infected cells, they trigger the caspase-3 cascade reaction through FasL or TNF, leading to apoptosis.

Figure 5.

Treatment of HSK. Drugs for the treatment of HSK can be divided into four categories, including clinical antiviral drugs, potential drugs, inhibitors, and combination therapy.

Figure 6.

Treatment of herpes labialis. Herpes labialis treatment medications can be divided into three categories, including conventional treatments, antiviral drugs, and novel treatments.