Varicella-Zoster Virus (VZV), or Human Herpesvirus 3 (HHV-3), belongs to the herpesvirus family. It causes two distinct clinical diseases: varicella (chickenpox) and herpes zoster (shingles). An initial infection establishes a lifelong residence within the human nervous system. The virus’s ability to transition between active replication and a dormant state dictates its pathogenicity and disease recurrence.
The Genetic Blueprint of VZV
VZV possesses a large, linear, double-stranded DNA genome approximately 125,000 base pairs in length. This genome contains at least 70 unique open reading frames (ORFs), which code for the proteins necessary for viral survival and replication. The genome structure includes unique long and unique short regions, flanked by internal and terminal inverted repeat sequences.
The viral genes are expressed in a carefully regulated cascade categorized into three kinetic classes: immediate-early (IE), early (E), and late (L) genes. Immediate-early genes, such as ORF62, act as transactivators that initiate the entire process of lytic replication by switching on other viral genes. Conversely, specific genes play a role in regulating the switch to dormancy, including ORF63, which is thought to be involved in maintaining the latent state.
Proteins encoded by the early genes, like the viral DNA polymerase, are responsible for replicating the viral genome. These proteins are the primary targets of antiviral medications. Late genes typically encode the structural proteins, such as glycoproteins, that form the outer shell and envelope of the new virus particles.
Establishing Pathogenicity: Primary Infection and Latency
VZV pathogenicity begins when the virus enters the body, typically through the respiratory tract, infecting mucosal epithelial cells. Following local replication, the virus enters the bloodstream, often carried within infected T-cells, leading to viremia. This systemic spread culminates in the primary infection, varicella, characterized by a widespread vesicular rash on the skin.
The virus demonstrates neurotropism. VZV travels from the infected skin lesions or through the bloodstream via retrograde axonal transport up the sensory nerve endings. It eventually reaches the cell bodies of the sensory neurons housed within the dorsal root ganglia (DRG) along the spinal column and the trigeminal ganglia in the head.
Within these ganglia, the virus establishes latency, a state of dormancy that can persist for decades. During latency, the vast majority of viral genes are silenced, effectively hiding the virus from the immune system and preventing active replication. Only a few specific viral transcripts are expressed, including a non-coding RNA known as the VZV Latency-Associated Transcript (VLT).
The restricted expression of VLT and transcripts from ORF63 helps maintain the viral genome as a circular episome within the neuron’s nucleus. This occurs without producing infectious viral particles. This minimal gene activity allows the virus to maintain its presence without destroying the host neuron or alerting the host’s immune surveillance mechanisms.
Reactivation: The Mechanism Behind Shingles
Reactivation of VZV occurs when the latent virus switches back to a lytic, actively replicating cycle. This transition is primarily triggered by a decline in VZV-specific cell-mediated immunity (CMI). CMI naturally wanes with age, making older adults the most susceptible population, though immunosuppression can also cause reactivation.
The genetic switch begins in the sensory neuron within the DRG, reversing the restricted expression pattern of latency-associated genes. Immediate-early genes, particularly ORF62, are turned back on, initiating the full cascade of viral gene expression necessary for replication. This allows the virus to produce new infectious particles and overcome immune control.
Once replication is underway in the ganglia, newly formed virions travel down the sensory nerve axon via anterograde transport towards the skin. This journey causes inflammation and pain before the virus reaches the skin surface. The resulting rash, which appears as a painful band of blisters, is strictly localized to the dermatome innervated by the single reactivating ganglion.
The nerve damage caused by viral movement and replication can persist long after the rash clears, leading to postherpetic neuralgia (PHN). PHN is a chronic pain condition resulting from the destruction or malfunction of sensory nerve fibers damaged during reactivation.
Targeting VZV: Therapeutic and Preventive Strategies
Understanding the VZV life cycle and its genetic traits has aided the development of effective therapeutic and preventive measures. Antiviral medications, such as acyclovir, valacyclovir, and famciclovir, are the primary treatment for active VZV infections. These drugs are nucleoside analogs that rely on the virus’s own genetic machinery to become active.
The viral thymidine kinase (encoded by ORF36) phosphorylates the drug, transforming it into an active compound. This activated drug then interferes with the viral DNA polymerase, an early gene product, effectively terminating the growing DNA chain and halting viral replication. These antivirals are most effective when administered early in the course of infection, as they block the lytic cycle.
Preventive strategies focus on vaccines that prime the immune system to maintain cell-mediated immunity against VZV. The initial live-attenuated varicella vaccine prevents the primary infection (chickenpox) and the establishment of latency. To prevent shingles in adults, a recombinant zoster vaccine is now widely used.
This recombinant vaccine specifically targets VZV glycoprotein E (gE), a structural protein encoded by the late genes, and combines it with an adjuvant system. The goal of this vaccine is not to treat active infection, but to boost the VZV-specific CMI in older individuals. This immunological reinforcement helps maintain surveillance over the latent virus in the ganglia, preventing the age-related decline in immunity that triggers reactivation.