[Academic Presentation] Latency, Recurrent Infection, and Prevention & Treatment of Herpes Simplex Virus

 Article reprinted from: Chinese Medical Abstracts – Dermatology, February 2017, Vol. 34, No. 1. 

 Authors: Fan Jianyong, Zhao Yang, Yang Huilan 

The herpesvirus family comprises enveloped, double-stranded DNA viruses with genome lengths of approximately 120–240 kb. Based on their biological characteristics and genomic architecture, herpesviruses are classified into three subfamilies: α-, β-, and γ-herpesviruses. Herpes simplex virus (HSV), belonging to the α‑subfamily, is widely distributed in nature and can infect humans as well as numerous animal species, exhibiting a strong tropism for human skin tissues. Herpesviruses primarily establish infection through the skin, mucosal surfaces, and nervous tissue, causing corresponding pathological manifestations, and are common etiological agents of viral diseases in humans. HSV is divided into two serotypes: HSV‑1 and HSV‑2. Following infection, HSV‑1 predominantly causes labial herpes, pharyngitis, and keratitis, and may also lead to severe conditions such as sporadic encephalitis; HSV‑2, on the other hand, typically results in genital herpes (GH) via entry through broken skin or mucosal barriers. Recent epidemiological studies have shown that, among the pathogens responsible for genital herpes, both HSV‑1 and HSV‑2 play equally significant roles and can persist in a latent state within the host for extended periods. During latent infection, the structure and function of the viral genome remain intact, while transcriptional regulation and associated gene expression processes are essentially quiescent. This phase does not involve full‑scale genome replication; instead, limited local transcription occurs, and under specific conditions, the virus may transition into a proliferative replication cycle. The proliferative replication of HSV involves a cascade of transcriptional events driven by interactions between viral regulatory proteins and host cellular molecules; however, our understanding of the transcriptional regulatory mechanisms underlying latent infection and the transition to replicative proliferation remains limited. Currently, the incidence of genital herpes is rising rapidly and recurrence is frequent, posing substantial challenges to its diagnosis, treatment, and prevention. Elucidating the molecular mechanisms governing latent infection and viral reactivation is crucial for uncovering the fundamental principles behind HSV‑mediated recurrent disease and for identifying therapeutic targets, thereby enabling effective strategies to prevent and manage HSV infection and latent relapse. This review summarizes the biological characteristics of HSV, potential mechanisms underlying latent reactivation, clinical approaches to the prevention and management of HSV infection, and recent advances in the development of HSV vaccines.

I. Biological Characteristics of Herpes Simplex Virus

HSV‑1 is a spherical virus composed of an envelope, a capsid, a core, and a viral membrane. The viral core contains double-stranded linear DNA, organized in a helical filamentary structure, with a genome size of approximately 125–240 kb. The HSV‑2 genome is about 154 kb in length. In the HSV‑2 HG52 strain, the G+C content is roughly 70%, and the genome consists of an 18% short segment (S) and an 82% long segment (L), covalently linked at the L–S junction. Each segment harbors terminal inverted repeat sequences (TRL, IRL, IRS, and TRS) as well as internal unique sequences (ML and US). Due to their distinct linkage patterns, the HSV‑2 genome exists as four distinct isomeric forms. HSV exhibits diverse transcriptional regulatory mechanisms, a complex genomic architecture, and a large number of genes that often overlap.

HSV‑2 genes are transcribed and expressed through a tightly regulated cascade, which, in chronological order, is divided into three categories: immediate‑early genes (IE or α), early genes (E or β), and late genes (L or γ). Immediate‑early genes are the first to be expressed following infection and can be transactivated by the viral late protein VP16. The activation of latent viral infection and its lytic replication are closely associated with immediate‑early proteins or infected cell polypeptides (ICPs); these include ICP47, ICP4, ICP27, ICP22, and ICP0. ICP0 and ICP4 play pivotal roles in viral replication. Early gene expression is mediated by the transactivation of proteins encoded by immediate‑early genes, while a cascade‑like regulatory mechanism governs the transcription and expression of both early and late genes. The early genes comprise β1 and β2; β1 consists of ICP6 and ICP8, whereas β2 encodes key viral proteins involved in nucleic acid metabolism, including thymidine kinase and DNA polymerase. The products of late genes are primarily structural proteins, such as glycoproteins, capsid proteins, and envelope proteins, which are implicated in viral adsorption, entry, fusion, and antigenicity.

II. Mechanisms of Latent Infection by Herpes Simplex Virus

HSV is highly contagious, capable of causing a wide range of common diseases, and readily establishes latent infections. HSV‑1 and HSV‑2 can remain latently infected for life in the trigeminal ganglion and the sacral dorsal root ganglia, respectively. Kesan et al. once defined the latency of HSV‑1 as follows:

① The virus can persist in the host organism without the host exhibiting any associated clinical symptoms.

② Latent HSV infection can be reactivated from its latent state, accompanied by the production of infectious viral particles;

③ When the virus is in a latent infection state, it does not express any replication‑related genes; however, latency‑associated transcripts (LATs) accumulate extensively within the host cell nucleus.

④ The virus does not express relevant antigens, but the viral genome can be detected in the host.

This definition characterizes the phenotype of HSV‑1 latent infection across four distinct levels and is consistent with the situation in HSV‑2 latency. Although, with the gradual advancement of detection technologies, viral genes associated with productive infection—such as ICPO and TK kinase—are found to be expressed at low levels during latent infection, researchers attribute this to the dynamic equilibrium between latency and reactivation.

The main reasons why HSV‑2 establishes latent infection in the body are as follows:

① Immune evasion following viral infection;

② The inhibition of immediate-early viral protein expression by the LAT gene and its regulatory mechanisms;

③ Interactions between the viral genome and the host cell, including viral gene–mediated inhibition of cellular proteins and RNA synthesis, selective translation of HSV‑encoded viral mRNAs, and the regulatory roles of herpesviruses in the cell cycle and apoptosis;

④ Regulatory effects mediated by microRNAs encoded by the viral genome;

⑤ CTCF regulates the latent reactivation of the HSV genome by binding to CTCF‑specific sequences within the viral genome.

2.1 Mechanisms by which HSV evades immune surveillance

DNA and RNA viruses from diverse taxonomic groups can evade immune surveillance and persist long-term within the host. Successful immune evasion is one of the primary factors underlying chronic herpesvirus infections. The underlying mechanisms encompass the following six major aspects.

2.1.1 Restrictive Expression of Viral Genes

Almost all viruses exploit this mechanism to varying degrees to evade surveillance by the host immune system, with herpesviruses and certain retroviruses being particularly prominent. Once herpes simplex virus establishes latency within neurons, transcription of virtually all viral genes—except for a single one—is shut down, leaving the infected neuron virtually devoid of any detectable viral components. Extensive research has demonstrated that LAT functions to suppress the expression of viral genes.

2.1.2 Exploitation of the host’s immune-privileged sites

A small subset of human tissues and organs is protected from immune cell infiltration, enjoying an “immune privilege.” Consequently, viruses that enter these immune‑privileged sites can temporarily evade immune surveillance without triggering local inflammatory responses. The blood–brain–spinal fluid barrier of the central nervous system (CNS) restricts lymphocyte entry, making CNS‑resident pathogens less readily recognized by T lymphocytes. As a result, the CNS serves as a reservoir for chronic infection and latency of several viruses, including HSV.

2.1.3 Mutation of Viral Antigens

HSV can also evade host immune surveillance through genetic mutations. When the virus undergoes mutation, the antigens it encodes likewise change. Variations in surface antigens may enable mutant viral strains to temporarily escape neutralization or opsonization by pre-existing antibodies, thereby gaining a selective advantage. Cytotoxic T lymphocytes (CTLs) and helper T cells (Th cells) play crucial roles in eradicating and controlling chronic viral infections, as they recognize T‑cell epitopes presented by MHC molecules on viral proteins. If genetic mutations during viral replication happen to alter the original T‑cell epitope—such that the resulting peptide either fails to bind to the host’s MHC molecule or, even when bound, is no longer recognized by T cells—the mutant strain can temporarily circumvent CTL and Th cell responses, acquiring a replicative advantage absent in the parental strain. This phenomenon has been demonstrated in HSV, hepatitis B virus, and Epstein–Barr virus.

2. 1.4 Interference with antigen presentation by host cells

Lipid antigens presented by CD1d molecules on the surface of antigen-presenting cells can elicit an immune response from NK cells, which is crucial for the host’s defense against viral antigens. Liu et al. found that HSV‑1 infection suppresses the expression of CD1d on antigen‑presenting cells. This suppression does not result from HSV‑mediated inhibition of CD1d synthesis; rather, it arises from the redistribution of endocytosed CD1d molecules to the lysosomal membrane, thereby preventing their re‑emergence on the cell surface. It may also be due to HSV‑induced blockade of the trafficking of newly synthesized CD1d to the cell surface. Furthermore, studies have shown that the HSV‑encoded ICP47 can bind to the antigen‑presentation‑related transporters TAP‑1/2, thereby inhibiting the translocation of viral peptides into the endoplasmic reticulum and their subsequent loading onto nascent MHC class I molecules, ultimately impeding their presentation to CD8⁺ T cells.

2. 1. 5 Inhibition of TCR Signal Transduction

T lymphocytes are a critical component of the immune response against HSV infection. Yang et al. demonstrated that HSV inactivates T cells by inhibiting TCR signal transduction. This inhibition of TCR signaling occurs both at the T cell activation‑inducing complex—the initial step in the TCR signaling cascade—and at downstream steps, including suppression of calcium influx and multiple MAPK (mitogen‑activated protein kinase) pathways. HSV‑induced T cell inactivation results in reduced phosphorylation of tyrosine residues within the T cell activation‑inducing complex, whereas such tyrosine phosphorylation is essential for TCR signal transduction.

2.1.6 Interference with the Function of Immune Effectors

Interferons constitute the host’s first line of defense against viral infection. Extensive research has demonstrated that interferons comprise a family of soluble proteins that mediate antiviral effects, regulate cell growth, and modulate the activation of immune responses. The intrinsic antiviral activity of interferons is both highly effective and rapid. Consequently, many viruses evade host immune surveillance by inhibiting interferon synthesis or downstream antiviral pathways. Davis et al. found that the HSV-encoded ICP34.5 plays a critical role in enabling the virus to escape the host’s innate immune response. ICP34.5 dephosphorylates eIF2α—a translation initiation factor phosphorylated by PKR during the antiviral response—thereby reducing the expression of cytokines such as interferon‑β. Mogensen reported that HSV‑1’s immediate‑early gene product VP16 suppresses the expression of proinflammatory cytokines by destabilizing IL‑6 mRNA. This suppression is not mediated directly by VP16 but depends on the viral immediate‑early genes encoding ICP4 and ICP27. During the early stages of HSV infection, these proteins are expressed in a VP16‑dependent manner. The HSV envelope glycoprotein gC can bind complement component C3b, thereby protecting the virus from neutralization by complement. Experiments have shown that wild-type HSV strains retain full infectivity in the presence of complement, whereas mutant strains lacking gC are neutralized by complement even in the absence of antibodies.

2. The role of the 2 LAT genes in HSV latency and reactivation

The LAT family comprises major LATs (2.0 kb, 1.5 kb, and 1.45 kb) and a minor LAT (8.3 kb). These RNAs are partly linear and partly circular, yet they are all activated through distinct folding patterns. The minor LAT is an 8.3‑kb transcript that, upon splicing, yields a 2.0‑kb LAT; further removal of approximately 500 bp generates either a 1.5‑kb or a 1.45‑kb LAT. LAT is thought to play a critical role in the efficient establishment of latency. Moreover, deletion of small segments within the LAT promoter has been shown to cause a sharp reduction in the number of latently infected cells, underscoring that LAT transcription is essential for establishing latent infection. LAT exhibits multifunctional properties and contributes to both the establishment and maintenance of HSV latency. Currently, the primary approach to investigating LAT’s role in latent infection involves the use of deletion mutants.

2. 2. 1 The role of LAT in establishing latent infection

LAT is thought to play a crucial role in the efficient establishment of latency; even partial deletion of short segments within the LAT promoter can lead to a sharp reduction in the number of latently infected cells, suggesting that LAT transcription is essential for the establishment of latent infection.

2. 2. 2 The role of LAT in maintaining latent infection

The mechanisms that maintain HSV latency remain unclear. Two competing hypotheses have been proposed: one posits that, during latency, the 2.0-kb LAT transcript suppresses ICP0 protein expression via an antisense RNA–mediated mechanism, thereby blocking viral replication; the other suggests that a non‑canonical LAT isoform, also through an antisense RNA–dependent pathway, inhibits ICP4 protein expression to prevent viral replication and delay the transition into the lytic phase. Studies have further revealed that several sets of mRNAs encoding lytic viral genes are transcribed during latency, though their low levels make them difficult to detect. Chen et al. observed that, in LAT‑mutant strains during latency, the transcriptional levels of the immediate‑early gene ICP4 and the early gene TK were several-fold higher than those in wild‑type virus. Further investigations demonstrated that ICP4 downregulates the expression of the RNA‑binding protein GRSF1 by binding to the precursor of miR‑101, hsa‑mir‑101‑2, thereby suppressing HSV‑1 replication.

2. 2. 3 The role of LAT in viral recurrence

During the reactivation phase, early expression of the LAT gene may play a crucial role in transitioning lytic genes from a silent to an active state. In the latent phase, ICP4 mRNA is continuously expressed in the ganglia, albeit at very low levels. Consequently, the emergence of ICP4 mRNA and its upregulation can serve as a hallmark of the virus’s entry into the lytic replication cycle. Experimental data indicate that, in mice harboring the LAT gene, the HSV‑1 viral DNA load is threefold higher than in LAT‑deficient mice, and its activation and expression are associated with CD8, PD‑1, and Tim‑3.

2.2.4 LAT exerts anti-apoptotic functions by encoding microRNAs

MicroRNAs (miRNAs) are a newly discovered class of small, single-stranded, non-coding RNAs that regulate gene expression and serve as critical regulators of RNA stability and translational efficiency in animals, plants, and viruses. Both HSV‑1 and HSV‑2 LATs encode multiple functional miRNAs, with their expression levels during latency markedly higher than during acute infection. For HSV‑1, Cui et al., using computational modeling and sequence alignment with miRNA databases, identified 24 candidate miRNA pairs and 13 miRNA precursors. In 2010, Igor Jura et al. confirmed, via high-throughput sequencing, 17 miRNAs expressed by HSV‑2; to date, the MiRBase database has cataloged 18 such miRNAs. Recent work from our group has demonstrated that miR‑H4‑5p, encoded by HSV‑2 LATs, targets the host cell genes CDKN2A and CDKL2, reducing their mRNA and protein levels, thereby counteracting ActD‑induced apoptosis and promoting entry into the S phase of the cell cycle, thus enhancing cellular proliferation. In contrast, miR‑H3 also suppresses ActD‑induced apoptosis but exerts no significant effect on the cell cycle; its precise molecular mechanisms remain unclear. These findings indicate that HSV‑2 miRNAs modulate both viral and host gene expression through RNA interference, inhibiting neuronal apoptosis and facilitating the maintenance of latent viral infection. By up- or downregulating miRNA expression, it is possible to alter the expression of target genes, achieving therapeutic or interventionist goals. As a novel class of drug‑targetable molecules, miRNAs have increasingly attracted attention across disciplines. New therapeutic strategies for HSV‑2 may emerge by targeting miRNAs to specifically block or disrupt HSV‑2 replication. Although these approaches are currently at the experimental stage, there is reason to believe that small‑molecule miRNA‑based therapeutics could become a promising avenue for treating latent HSV infections.

2.3 The role of CTCF in HSV latency and reactivation

CTCF comprises 727 amino acid residues; its middle domain (M‑domain), consisting of 312 residues, adopts 11 consecutive zinc‑finger motifs. The N‑terminal (N‑domain) and C‑terminal (C‑domain) regions contain 265 and 150 residues, respectively. CTCF is a ubiquitously expressed, highly evolutionarily conserved 11‑zinc‑finger DNA‑binding protein that engages target DNA sequences of approximately 50 base pairs via its zinc fingers, forming diverse CTCF–DNA complexes. By binding to distinct genomic loci, it orchestrates a wide array of functions, including transcriptional repression and activation, hormone‑regulated gene silencing, methylation‑dependent chromatin insulation, as well as roles in eukaryotic histone acetylation, parental imprinting, and heterochromatin formation. Moreover, through self‑assembly into multimers or interactions with other proteins, and by co‑localizing with subnuclear structures, CTCF contributes to the establishment and maintenance of specific chromatin architectures, thereby playing a pivotal role in epigenetic regulation. CTCF serves as a central node in regulatory networks governing cell growth, proliferation, and development; the extent of mRNA and protein downregulation correlates significantly with the degree of inhibition of cellular growth, underscoring the critical importance of proper CTCF expression for cell viability. Many insulator elements harbor numerous CTCF binding sites; DNA methylation at these sites can block CTCF binding and thereby suppress its function. CTCF is also the only transcription factor experimentally shown to mediate the enhancer‑blocking activity of various insulators. As a core component of higher‑order chromatin architecture, CTCF’s functions are remarkably conserved from Drosophila to humans, encompassing even human pathogens such as EBV, KSHV, and HSV, which can induce epigenetic alterations. Model viruses have been employed to investigate how higher‑order chromatin structures respond to external perturbations.

Studies have shown that the HSV‑1 genome contains numerous CTCF‑specific binding sites, particularly within the LAT, ICPO, and ICP4 regions. During latent HSV‑1 infection, CTCF protein is enriched at insulator elements; in wild‑type latently infected HSV‑1, activation triggers the dissociation of CTCF from its binding sites. The CTCF‑binding sequences upstream of ICPO and ICP4 constitute canonical insulators that can attenuate the enhancer activity of LAT. Overall, during both latency and reactivation, the extent of CTCF–DNA binding is dynamically regulated to modulate HSV‑1 gene expression. These findings underscore the critical role of epigenetic regulation in the transition between HSV‑1 latency and reactivation. Within the 2.0‑kb intron of HSV‑1 LAT, a large number of CTCF binding sites are present, and CTCF can regulate the expression of virus‑replication‑related genes by binding to and releasing from these sites, thereby influencing viral latency and recurrence. Our group’s latest research represents the first preliminary investigation into CTCF binding on HSV‑2. We have identified CTCF binding sites at the 3′ end of HSV‑2 LAT and within its introns, which exert an inhibitory effect on promoter activity and may play a pivotal role in HSV‑2 latency. This work opens new avenues for exploring the mechanisms underlying HSV‑2 latency and recurrence, as well as for developing therapeutic strategies.

III. Advances in the Prevention and Treatment of HSV Infection

3.1 Clinical Treatment of HSV Infection

At present, the primary therapeutic goals for HSV infection include alleviating symptoms, reducing recurrence, minimizing viral shedding, and easing the patient’s psychological burden. Treatment strategies mainly comprise systemic antiviral therapy, topical treatment, immunotherapy, and health education.

Based on the recommendations of the 2009 Chinese Clinical Guidelines for Genital Herpes, systemic antiviral therapy remains the primary treatment approach. Commonly used agents include acyclovir, valacyclovir, and famciclovir, which are administered either as intermittent therapy or long-term suppressive therapy. Intermittent therapy involves treating outbreaks by initiating antiviral medication within 24 hours of the onset of prodromal symptoms or skin lesions: oral acyclovir 200 mg five times daily for 5 days; or acyclovir 400 mg three times daily for 5 days; or valacyclovir 500 mg twice daily for 5 days; or valacyclovir 300 mg twice daily for 7 days; or famciclovir 250 mg three times daily for 5 days. For first‑episode herpes simplex infections, the treatment course should be extended to 10 days. For patients with frequent recurrences (more than six episodes per year), long-term suppressive therapy may be recommended: oral acyclovir 400 mg twice daily; or valacyclovir 500 mg once daily, typically for a duration of 6 months or longer. Although long-term suppressive therapy can reduce the frequency of herpes simplex recurrences, there is currently no evidence that it prevents relapse after discontinuation of medication. In addition, topical treatments play a supportive role in managing herpes simplex lesions, such as cleansing or wet‑compressing the affected area with saline or a 3% boric acid solution; when there is no significant exudation, topical application of 3% acyclovir cream or 1% penciclovir cream may be considered. Combined immunomodulatory therapy is also an important clinical strategy for treating herpes simplex. Commonly used immunomodulators include thymosin, interferon, transfer factor, IL‑2, levamisole, and imiquimod. Furthermore, providing patients with appropriate health education and psychological support—encouraging regular lifestyle habits, moderate physical activity, and good mental well‑being—is equally essential as pharmacologic treatment.

3.2 Prevention of HSV Infection and Advances in Vaccine Development

3. 2. 1 Prevention of HSV Infection

Antiviral therapy, or its combination with immunotherapy, is often insufficient to completely eradicate HSV from the body and achieve a cure; therefore, prevention of HSV infection is of paramount importance. Counseling, sexual health education, and vaccination are the most critical preventive measures. The sources of herpes simplex virus transmission include symptomatic patients as well as subclinical or asymptomatic shedders; given the latter’s more insidious nature, they pose an even greater clinical concern. Avoiding unprotected sexual intercourse, using condoms consistently throughout sexual activity, and promptly treating sexual partners are among the most fundamental preventive strategies. Developing an effective and safe vaccine is essential for both preventing and treating HSV infections.

3. 2. 2 HSV Vaccine Research

HSV vaccine research has been ongoing for many years and has made some progress; however, current efforts remain confined to in vitro studies, animal experiments, and pre‑marketing clinical trials, with no HSV vaccine yet approved for market release worldwide. Depending on their composition and mechanisms of action, HSV‑2 vaccines can be classified into inactivated vaccines, attenuated live vaccines, replication‑deficient viral vaccines, subunit vaccines, peptide vaccines, live vector vaccines, and DNA vaccines. Early inactivated HSV vaccines have largely been discontinued due to poor efficacy, low immunogenicity, and potential carcinogenic risks.

3.2.2.1 Attenuated live vaccine

Attenuated live vaccines are generated by deleting genes responsible for HSV virulence, latency, or reactivation—often through genetic knockout techniques—resulting in vaccine strains that retain replicative capacity and immunogenicity but lack pathogenicity or exhibit reduced virulence. In the early 2000s, several clinical trials of attenuated live HSV‑2 vaccines demonstrated that they prevented recurrence in 37.5% of patients. More recently, progress has been made in developing an ICPO‑mutant HSV‑2 vaccine strain; the HSV‑20△NLS strain has been shown in animal studies to be both safe and highly immunogenic. Reports indicate that among 115 mice inoculated with HSV‑20△NLS, 114 survived a subsequent HSV challenge, whereas only 3 of 45 control mice vaccinated with a gD subunit vaccine remained alive after viral exposure, demonstrating an efficacy 10–100 times greater than that of the gD subunit vaccine and suggesting its potential as a robust candidate for HSV‑2 vaccination. Another promising candidate for an attenuated live HSV‑2 vaccine is HSV‑2‑gD27, which, as confirmed by in vitro and animal experiments, loses infectivity toward neuronal cell lines and murine sensory ganglia while eliciting an immune response without causing disease. A major limitation of using attenuated live vaccines is the potential for reversion to wild-type HSV.

3.2.2.2 Replication-Defective Viral Vaccines

Replication-deficient viral vaccines are a special class of live vaccines in which essential genes required for viral replication have been deleted, and they likewise demonstrate favorable safety and immunogenicity. The non‑infectious single‑cycle virus (DISC), developed in 2000, is a unique replication‑deficient HSV mutant that lacks the UL22 gene region, thereby preventing expression of the gH glycoprotein and rendering it incapable of infecting normal cells. However, results from its Phase II clinical trial were less than optimal: despite good safety, it failed to effectively suppress recurrent HSV‑2 infections or improve disease course. Current candidates under development for replication‑deficient viral vaccines include ACAM529, CJ2‑gD2, and the gE2‑del strain, among others.

3.2.2.3 Subunit Vaccines

Subunit vaccines represent the most extensively studied class of HSV vaccines. These vaccines are formulated by combining recombinantly expressed HSV subunit antigens with appropriate adjuvants. Viral surface glycoproteins, such as gD and gB, are typically selected as antigens. The gD2–aluminum hydroxide–MPL vaccine, developed by GSK, was evaluated in two phase III clinical trials; results showed that it conferred protection only in women who were seronegative for HSV‑1, whereas it provided no significant protection in seropositive women or in men. A more recent large, randomized, double-blind trial involving 8,323 women confirmed that this vaccine can effectively prevent HSV‑1 infection but does not prevent genital herpes or other infections caused by HSV‑2. These findings suggest that a single glycoprotein or even a few glycoproteins may be insufficient to elicit an immune response against HSV‑2. Nevertheless, several promising new subunit vaccine candidates—such as gD2△TMR340‑363 (ICP4383‑766), gD‑Fc, and gC2 + gD2—are currently under development, offering renewed hope for the creation of an effective HSV‑2 vaccine.

3.2.2.4 Peptide Vaccine

The synthetic peptides contained in peptide vaccines can elicit protective immune responses against HSV by targeting T‑cell or B‑cell antigenic epitopes in vivo. Recent animal and human studies have demonstrated that peptide vaccines exhibit strong immunogenicity, inducing HSV‑specific CD4+ and CD8+ T‑cell responses. Peptide vaccines thus represent one of the promising vaccine candidates.

3.2.2.5 Live-Vector Vaccines

Live‑vector vaccines use heterologous vectors—such as adenoviruses and vaccinia virus—to express certain subunit components of HSV; vaccination elicits a robust HSV‑specific immune response in the host. Studies have shown that a vaccinia virus Ankara (MVA) vector expressing HSV‑2 glycoprotein D can induce strong cellular and humoral immunity. Furthermore, a recombinant Vibrio cholerae vector (rVCG) co‑expressing Chlamydia major outer membrane protein (MOMP) and HSV‑2 glycoprotein D can elicit high levels of anti‑Chlamydia and anti‑HSV‑2 antibodies in vivo and trigger a potent Th1‑type immune response. A major drawback of such vaccines is that the presence of heterologous vectors may prompt the host to generate diverse antibody responses, potentially compromising vaccine efficacy and posing risks to human health.

3. 2. 2. 6 DNA vaccine

DNA vaccines originated in 1990 as a novel approach to developing an HSV vaccine. Because the gD2 and gB2 genes serve as the primary antigens that elicit immune responses, they have been widely employed in the design of HSV DNA vaccines. A clinical trial of an HSV‑2 DNA vaccine demonstrated that it can induce a specific cellular immune response without eliciting a humoral immune response. These findings suggest that the immunogenic efficacy of DNA vaccines still requires further improvement.

IV. Conclusion

As our understanding of the herpes simplex virus continues to grow, we will gain a renewed appreciation for the mechanisms by which HSV establishes latency and evades both innate and adaptive immune defenses. New therapeutic strategies for HSV will likely emerge from miRNA‑based approaches, aimed at specifically inhibiting or disrupting viral replication. Although these concepts remain largely experimental, there is reason to believe that, with sustained research efforts, it may be possible to develop drugs capable of achieving a complete cure for HSV‑associated diseases. Meanwhile, the development of an HSV vaccine still faces numerous challenges that require resolution, and its eventual clinical availability may take additional time. A more in-depth investigation into the immunological characteristics and infection mechanisms of HSV will provide crucial guidance for vaccine design.

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