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

3. 1. The role of IE in VZV latency

Within the VZV genome, most immediate‑early (IE) proteins play crucial roles in viral replication, primarily by silencing the transcription and expression of related genes to maintain latency. ORF61 can induce the disassembly of ND‑10 structures within the host cell, which otherwise promote viral replication. Studies on the mechanisms of VZV latency and reactivation in the nervous system have shown that IE4, IE62, and IE63 are expressed in neurons harboring latent VZV infection and are predominantly localized in the cytoplasm. It is hypothesized that, during latency, these IE proteins may, for some reason, be restricted from entering the nucleus, thereby limiting their trans‑activating functions and impairing VZV replication. Research has further demonstrated that ORF66, through phosphorylation, prevents IE62 from entering the nucleus to exert its trans‑activating activity, while simultaneously downregulating the expression of major histocompatibility complex class I (MHC‑I) on the cell surface, thus contributing to viral immune evasion. IE4 and IE63 are indispensable for establishing latent VZV infection. Using a SCID human–mouse chimeric infection model, researchers have investigated IE proteins and found that, during latency, the expression of IE62 and IE63 is reduced. This reduction is attributed to the ability of these IE proteins to counteract neuronal apoptosis, enabling the virus to survive within neurons upon initial entry and facilitating its extensive replication within host cells.

3. 2. The role of miRNAs in VZV latency

miRNA is a non-coding single-stranded RNA consisting of 22 nucleotides that, by binding complementarily 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 ORF 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; research has identified seven miRNAs—miR‑190b, miR‑571, miR‑1276, miR‑1303, miR‑943, and miR‑661—whose expression changes at the molecular level may serve as potential biomarkers for HZ pathogenesis. Some researchers suggest that circulating miRNAs in HZ patients can modulate multiple signaling pathways to promote viral replication and contribute to the disease’s inflammatory response and neuronal damage. For example, upregulation of miR‑21 activates the signal transducer and activator of transcription 3 (STAT3) pathway, thereby enhancing VZV replication. Further studies 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.

4 VZV Activation Mechanism

Neuronal cells and keratinocytes not only serve as VZV‑infected target cells also serve as antigen‑presenting cells, mediating the immune response. 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 impairs T‑lymphocyte activation and proliferation, enabling VZV‑infected target cells to evade T‑cell–mediated immune recognition and leading to viral reactivation. VZV reactivation is a critical step in the development of herpes zoster; this is followed by sequential processes, including recognition of the virus by pattern‑recognition receptors, infiltration of immune cells, release of cytokines, and interactions among T‑lymphocyte subsets, ultimately resulting in 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 eliciting an immune response through cytokine secretion. 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; they recognize a wide array of pathogens to trigger host immune responses and serve as a bridge between innate and adaptive immunity. Studies have shown that TLR9 functions as a cellular “sensor” for VZV, mediating a type I interferon–dependent innate immune response. Furthermore, TLR9, via the MYD88‑dependent signaling pathway, promotes IFN‑α release and facilitates the development of a Th1‑mediated adaptive immune response.

4. 2 CD4+ T cells and CD8

+T cell–mediated cellular immunity is the primary cause of VZV reactivation leading 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 most critical subsets determining 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 activation, the proportion of CD4+ T cells increases; however, when CD4+ T cells become severely depleted, the extent of cutaneous lesions expands, viral load rises, and viremia persists longer, resulting in widespread systemic skin involvement. CD8+ T cell–mediated immune responses also contribute significantly to host defense in HZ patients. Steain et al. reported abundant memory CD8+ T cell infiltration around dorsal root ganglia in HZ patients; reduced expression of surface signaling molecules on antigen‑presenting cells impairs the cytotoxic capacity of these CD8+ T cells. An imbalance in the CD4+/CD8+ T cell ratio—tilting toward a relative deficiency of CD8+ T cells—renders the host immune system dysregulated, thereby promoting HZ pathogenesis. Studies have shown that, from VZV activation until the appearance of typical rash, the CD4+/CD8+ T cell ratio declines markedly; upon rash onset, this ratio begins to rise gradually, eventually returning to baseline levels after lesion resolution. Furthermore, researchers have observed an inverse correlation between the CD4+/CD8+ T cell ratio during the acute phase of HZ and the incidence of postherpetic neuralgia (PHN). Consequently, some investigators propose that an inverted CD4+/CD8+ T cell ratio could serve as an immunological surveillance marker for HZ patients and high‑risk populations.

4.3 CD4+ T helper lymphocyte subsets

CD4 helper T cells include Th1, Th2, Th17, and regulatory T cells (Treg). 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 different 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 a skewed Th1/Th2 ratio. These results suggest that, although Th1 and Th2 cells mediate similar immune responses at different sites in HZ patients, their relative strengths differ—Th1 cells exert stronger protective immunity, whereas Th2 cells contribute more to local skin and neural tissue pathology. Th17 cells represent a distinct CD4+ T‑cell subset, separate from Th1 and Th2. Cytokines secreted by Th2 cells, such as IL‑4, IL‑10, and IL‑13, can inhibit the differentiation and development of Th17 cells. Nevertheless, Agata et al. found that in HZ patients, serum levels of Th17 cytokines IL‑17, IL‑23, and IL‑21, as well as Th2 cytokines IL‑4 and IL‑12, were all elevated. This indicates that the suppressive effect of Th2 cells—previously dominant in HZ pathogenesis—has diminished, with both Th2 and Th17 cytokines being highly expressed, thereby 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 conditions, organ transplantation, cancer, and various infectious disorders. Together with Th17 cells, they also engage in reciprocal regulation during viral infections, jointly maintaining immune homeostasis. Treg cells indirectly influence the onset and progression of HZ by modulating the functions of CD4+ T cells. Xing et al. enrolled 76 patients in the acute phase of HZ, stratifying them into mild, moderate, and severe groups based on disease severity, and assessed the distribution of T‑lymphocyte subsets in each group. Compared with healthy controls, the HZ cohort exhibited reduced CD4+ T cells and markedly increased Treg cells, with a negative correlation between CD4+ T cells and Treg cells. Furthermore, among the three groups, the severe group showed significantly enhanced Foxp3 expression within CD4+CD25+ T cells. These findings suggest that, in HZ patients, Treg cells are extensively activated, 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.