[Academic Presentation] Recent Advances in the Study of the Pathogenesis of Herpes Zoster

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

 Authors: Chen Wei, Liu Junlian 

Varicella-zoster virus (VZV) exhibits tropism for both the nervous system and the skin. Primary infection manifests as varicella, followed by a latent phase; under various triggering conditions, latent VZV can reactivate and undergo extensive replication, eliciting an immune response in peripheral sensory nerves and the ipsilateral dermatomes they innervate, resulting in erythema, grouped vesicles, and neuralgia. Herpes zoster (HZ), as a reactivation of varicella infection, occurs in approximately 20% of healthy adults and 50% of immunocompromised individuals. In children and adults with intact immune systems, HZ typically resolves without complications; however, patients with impaired cellular immunity are prone to systemic involvement, commonly including pneumonia, hepatitis, encephalomyelitis, and vascular lesions. Postherpetic neuralgia (PHN), which may develop after HZ, significantly impairs patients’ physical and mental well-being and quality of life. Following neuronal infection, VZV initiates replication; when neuronal apoptosis ceases, latent infection is established. When the host experiences external triggers that compromise immune function, VZV resumes vigorous replication and activation, spreading to the skin or other organs and tissues, thereby precipitating HZ. Current research indicates that VZV replication is regulated by several signaling molecules, including open reading frames (ORFs), microRNAs (miRNAs), and pattern‑recognition receptors, which also play roles in VZV latency and reactivation. Cellular immunity assumes a central role in the pathogenesis following VZV reactivation, with the type and prognosis of HZ determined by the extent of viral dissemination and the strength of the antiviral immune response. A thorough elucidation of VZV latency, reactivation, and the VZV‑specific cellular immune responses that ensue is essential for a comprehensive understanding of the mechanisms underlying HZ.

I. Molecular Biological Characteristics of VZV

VZV consists of a double-stranded DNA genome, a capsid, a tegument, and an envelope. The innermost layer is the nucleocapsid, which encloses the DNA genome; the outermost layer is the envelope, derived from the host cell membrane and bearing viral glycoproteins; and the intermediate layer is the tegument, composed primarily of three immediate‑early proteins (IEs) encoded by ORFs 4, 62, and 63. The VZV genome is divided into four regions: the long unique sequence (UL), the short unique sequence (US), the internal repeat sequences (IR), and the terminal repeat sequences (TR), encompassing 71 open reading frames (ORFs) along with promoter‑related elements. Two thirds of these ORFs, together with eight viral glycoproteins, are involved in DNA replication, splicing, packaging, metabolism, and nucleocapsid assembly. Most VZV genes contribute to viral replication, with their gene products expressed sequentially as immediate‑early proteins, early proteins, and late proteins. During latent infection, only the IE62 and IE63 genes—encoding immediate‑early proteins—are transcribed; late‑protein genes, which predominantly encode capsid and glycoprotein components, remain unexpressed. Viral glycoproteins mediate viral attachment and entry into human host cells, are displayed on the plasma membrane of infected cells, and facilitate intercellular spread of the virus.

II. Pathogenic Process of VZV

During primary VZV infection, the virus initially establishes itself in the mucosa of the upper respiratory tract, then replicates within local lymph nodes before entering the bloodstream, resulting in the first viremia. As the virus is transported to organs of the reticuloendothelial system, such as the liver and spleen, a second round of replication occurs, leading to a second viremia and widespread dissemination throughout the body. Approximately 14–16 days after infection, the virus can invade capillary endothelial cells and reach the epidermis; it subsequently travels centripetally along the nerve fibers of the dorsal roots of the spinal cord or the trigeminal ganglia, persisting in latency within the neurons of these dorsal root ganglia.

HZ typically progresses through three stages: The first stage is the latent phase, during which latent VZV reactivates within neurons and immune surveillance is impaired. The second stage is the clinical rash phase, in which the virus is released from the ganglia along neural pathways to the skin; at this point, the host’s memory‑mediated immune response is heightened, and VZV infection remains confined to the dermatome of the initial outbreak. Once this memory‑mediated immune response wanes, the disease advances to the third stage. The third stage is the clinical dissemination phase, in which the virus not only affects the skin but also spreads to the central nervous system and other visceral organs.

III. Latency Mechanism of VZV

All herpesviruses possess the capacity for latency, which is typically lifelong. For most herpesviruses, latency represents a key mechanism for evading immune surveillance. Studies have shown that during latent infection, VZV DNA persists in cells as episomal genomes, accompanied by viral transcripts and synthesized proteins. VZV ORFs and miRNAs play critical roles in maintaining VZV latent infection.

3. The role of 1 IE in VZV latency

Within the VZV genome, most immediate‑early (IE) genes play crucial roles in viral replication, primarily by maintaining latency through the silencing of transcription and expression of related genes. ORF61 can induce the disassembly of ND‑10 structures in the host cell, which otherwise promote viral replication. Studies on the mechanisms underlying VZV latency and reactivation in the nervous system have shown that IE4, IE62, and IE63 are expressed in neurons during latent infection and are predominantly localized in the cytoplasm; it is hypothesized that, for reasons yet unclear, these IE proteins may be sequestered from the nucleus during latency, thereby limiting their trans‑activating functions and impairing VZV replication. Research has further demonstrated that ORF66 inhibits the nuclear import of IE62 via phosphorylation, thus preventing its trans‑activating activity, while also downregulating the expression of major histocompatibility complex class I (MHC‑I) at the cell surface, thereby contributing to viral immune evasion. IE4 and IE63 are indispensable for establishing latent VZV infection. Using a SCID human–mouse chimeric infection model, some investigators have found that during latency, the expression of IE62 and IE63 is reduced; this suppression is attributed to the ability of these IE proteins to counteract neuronal apoptosis, enabling the virus to survive initial entry into neuronal cells and to replicate extensively within the host.

3. The role of miRNAs in VZV latency

miRNA is a non-coding single-stranded RNA consisting of 22 nucleotides that, by complementary binding to target messenger RNAs, induces mRNA degradation or inhibits protein translation. Studies have shown that VZV miRNAs lack target sites for binding to latency-associated region genes, thereby preventing the degradation of latency‑associated ORF‑encoded mRNAs and maintaining viral latency. There are hundreds of distinct miRNAs, each exerting unique regulatory functions; among them, alterations in the levels of seven miRNAs—miR‑190b, miR‑571, miR‑1276, miR‑1303, miR‑943, and miR‑661—have been identified as potential biomarkers for the onset of herpes zoster (HZ). Some researchers suggest that circulating miRNAs in HZ patients can modulate multiple signaling pathways, promoting viral replication and contributing to both inflammatory responses and neuronal damage. For instance, upregulation of miR‑21 activates the signal transducer and activator of transcription 3 (STAT3) pathway, thereby enhancing VZV replication. Further investigations have revealed that VZV‑encoded miRNAs can suppress the expression of antiviral cytokines such as IL‑6 and IL‑10 by regulating the nuclear factor‑κB pathway, thus evading host immune surveillance.

IV. Mechanisms of VZV Activation

Neuronal cells and keratinocytes not only serve as target cells for VZV infection but also function as antigen-presenting cells that mediate immune responses. Through immunomodulatory mechanisms, VZV downregulates the expression of immune molecules such as MHC class I, MHC class II, and intercellular adhesion molecule‑1 (ICAM‑1) on the surface of target cells, and reduces the expression of signaling molecules involved in T‑cell activation. This results in diminished T‑lymphocyte activation and proliferation, enabling VZV‑infected target cells to evade T‑cell–mediated immune recognition and facilitating viral reactivation. VZV activation is a critical step in the pathogenesis of herpes zoster; this is followed by sequential events, including recognition of the virus by pattern‑recognition receptors, infiltration of immune cells, release of cytokines, and interactions among T‑lymphocyte subsets, ultimately leading to damage to neural and cutaneous tissues.

4.1 Pattern Recognition Receptors

Upon VZV activation, the innate immune system—acting as the first line of defense against pathogens—recognizes and binds pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), thereby activating downstream signaling pathways and secreting cytokines to mount an immune response. PRRs include Toll-like receptors (TLRs), C-type lectin‑like receptors, NOD‑like receptors, and retinoic acid‑inducible gene‑I‑like receptors; among these, TLRs are the most extensively studied, recognizing a wide array of pathogens to trigger host immune responses and serving as a bridge between innate and adaptive immunity. Studies have shown that TLR9 functions as a cellular “sensor” for VZV, mediating an innate immune response through type I interferon induction. Furthermore, TLR9, via the MYD88‑dependent signaling pathway, promotes IFN‑α release and supports the development of a specific immune response by Th1 cells.

4.2 CD4+ T cells and CD8+ T cells

Immunosuppression is the primary factor underlying the reactivation of VZV and its progression to HZ. Histologically, HZ is characterized by inflammatory cell infiltration—predominantly lymphocytes surrounding skin lesions and neurons—with T lymphocytes as the major component. Among these, CD4+ T cells and CD8+ T cells are considered the key cellular subsets that determine VZV reactivation and dissemination; their numbers and functional status play distinct roles during the latent infection phase, the rash‑onset phase, and the viral dissemination phase of HZ. Following VZV reactivation, the proportion of CD4+ T cells increases; however, when CD4+ T cells are severely depleted, the extent of cutaneous lesions expands, systemic viral load rises, and viremia persists longer, leading to widespread, generalized skin involvement. The CD8+ T‑cell–mediated immune response plays a critical role in host defense in HZ patients. Steain et al. reported abundant infiltration of memory CD8+ T cells around the dorsal root ganglia in HZ patients; yet, due to reduced expression of surface signaling molecules on antigen‑presenting cells, these CD8+ T cells lose their cytotoxic capacity.

An imbalance in the CD4+/CD8+ T-cell ratio places the host’s immune status in an abnormal state, thereby promoting the onset of herpes zoster (HZ). Studies have shown that, following VZV reactivation and prior to the appearance of the characteristic rash, the ratio of CD4+ T cells to CD8+ T cells declines significantly; as the rash emerges, this ratio begins to rise gradually, eventually returning to the normal range once the skin lesions have resolved. Furthermore, researchers have found that during the acute phase of HZ, the CD4+/CD8+ T-cell ratio is inversely correlated with the development of postherpetic neuralgia (PHN). Consequently, some investigators suggest that an inverted CD4+/CD8+ T-cell ratio could serve as an immunological surveillance marker for patients with HZ and other high-risk populations.

4.3 CD4 Helper T Lymphocyte Subsets

CD4 helper T cells include Th1, Th2, Th17, and regulatory T cells (Tregs). Currently, one of the underlying causes of herpes zoster (HZ) is a disruption of immune homeostasis, leading to a shift in Th cell subsets. Some researchers have reported elevated levels of Th1‑ and Th2‑type cytokines in the serum of HZ patients; however, Zhang et al., who analyzed vesicular fluid from HZ patients, obtained contrasting findings: they observed low expression of Th1 cytokines IL‑2 and TNF‑α, while Th2 cytokines IL‑4 and IL‑10 were highly expressed, resulting in an altered Th1/Th2 ratio. These results suggest that, although Th1 and Th2 cells mediate similar immune responses at different sites in HZ patients, the magnitude of their respective immune effector functions differs—Th1 cells exert stronger protective immunity, whereas Th2 cells contribute more significantly to localized pathological damage in skin and neural tissues.

Th17 cells constitute a distinct CD4+ T-cell subset, separate from Th1 and Th2 cells. Cytokines secreted by Th2 cells, such as IL‑4, IL‑10, and IL‑13, can inhibit the differentiation and development of Th17 cells. However, Agata et al. found that in patients with herpes zoster (HZ), the serum levels of Th17‑type cytokines—including IL‑17, IL‑23, and IL‑21—and Th2‑type cytokines—such as IL‑4 and IL‑12—are all elevated. These findings suggest that, during HZ pathogenesis, the suppressive effect of the dominant Th2 response on Th17 cells is diminished, leading to the concurrent high expression of both Th2‑ and Th17‑type cytokines and placing the host in a state of immune tolerance.

Recently, Treg cells have attracted considerable attention due to their critical roles in autoimmune diseases, inflammatory disorders, organ transplantation, cancer, and various infectious conditions. Together with Th17 cells, they engage in reciprocal regulation during viral infections, jointly maintaining immune homeostasis. By modulating the functions of CD4+ T cells, Treg cells indirectly contribute to the onset and progression of herpes zoster (HZ). Xing et al. enrolled 76 patients in the acute phase of HZ, stratifying them into mild, moderate, and severe groups according to disease severity, and assessed the distribution of T‑lymphocyte subsets in each group. The results showed that, compared with healthy controls, HZ patients exhibited a reduction in CD4+ T cells and a marked increase in Treg cells, with a negative correlation between CD4+ T cells and Treg cells. Furthermore, in the severe group, Foxp3 expression within CD4+CD25+ T cells was significantly enhanced relative to the other two groups. These findings indicate that, in HZ patients, Treg cells are extensively activated, thereby suppressing the proliferation and activation of CD4+ T cells, and that the degree of disease severity correlates positively with the strength of Treg‑mediated suppression.

V. Conclusion

The prevention and treatment of herpes zoster (HZ) have continuously evolved based on in-depth research into its pathogenesis. Recent studies on the immunological mechanisms underlying HZ have identified new avenues for its prevention and therapy. Investigating the structure and function of VZV genes and proteins is instrumental in developing small-molecule inhibitors that exert antiviral activity and prevent postherpetic neuralgia. Moreover, a deeper understanding of HZ pathogenesis at the cellular and molecular levels can inform the development of more effective therapeutic strategies and pharmacological agents.

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