Varicella-Zoster Virus (VZV) is an alphaherpesvirus belonging to the Herpesviridae family. It is responsible for two distinct clinical illnesses in humans. The primary infection is varicella, or chickenpox. Following this initial widespread infection, the virus establishes dormancy within the nervous system. Years or even decades later, the dormant virus can reawaken to cause herpes zoster, commonly known as shingles, a painful, localized rash condition. Understanding VZV’s structure, replication, and immune evasion mechanisms reveals its intricate relationship with the human body.
The Physical Structure of VZV
The VZV virion, the complete infectious particle, is a large, spherical structure 150 to 200 nanometers in diameter. Its outermost layer is the envelope, a lipid-rich membrane derived from the host cell. The envelope is studded with numerous viral glycoproteins (gB, gH, gL) responsible for recognizing and interacting with host cells.
Beneath the envelope lies the tegument, an amorphous layer composed of various viral proteins. This layer contains regulatory elements, including immediate-early (IE) viral transactivating factors like IE62. These pre-packaged tegument proteins play a significant role in initiating the infection cycle once the virus enters a new cell.
Encased within the tegument is the nucleocapsid, a symmetrical, icosahedral protein shell. This shell protects the viral genome, which is a linear, double-stranded DNA molecule approximately 125 kilobase pairs in length.
Initial Infection: Cellular Entry and Trafficking
The life cycle begins when VZV glycoproteins attach to specific receptors on the host cell surface. Glycoproteins gB, gH, and gL form a core fusion complex necessary for the next step of the process.
The viral envelope then fuses with the host cell membrane, either directly at the cell surface or within an endocytic vesicle. This fusion event releases the nucleocapsid and the tegument proteins into the cell’s cytoplasm. The tegument proteins are released into the cytoplasm to begin their regulatory functions.
The nucleocapsid travels toward the cell nucleus, utilizing the host cell’s transport machinery along the cytoskeleton. Upon reaching the nucleus, the nucleocapsid docks onto a nuclear pore complex, a channel that controls molecular traffic.
At the nuclear pore, the viral DNA genome is injected into the nucleus. This delivery of the double-stranded DNA makes the viral genome available for transcription and replication by the host cell’s machinery. The nucleocapsid remains outside the nucleus, having completed its function as a protective transport vessel.
Viral Multiplication: Replication and Assembly
Once the VZV genome is inside the nucleus, the lytic cycle begins with the sequential expression of viral genes. This cascade starts with immediate-early (IE) genes, such as IE62, which are expressed rapidly using host transcription factors. The IE protein products act as transactivators, turning on the next set of viral genes.
Next, early (E) genes are expressed, encoding proteins primarily involved in viral DNA replication. This includes VZV DNA polymerase and other factors necessary for synthesizing new viral genomes. DNA replication begins within specialized nuclear compartments, often visible within four to six hours of infection.
Following DNA synthesis, late (L) genes are expressed; these encode the structural proteins needed to build new virions. These late proteins include the major capsid protein (ORF23) and the various glycoproteins for the final envelope. New capsids self-assemble within the nucleus, packaging the replicated DNA genomes inside.
The nucleocapsids acquire a transient envelope layer by budding through the inner nuclear membrane. They then fuse with the outer nuclear membrane (de-envelopment) to be released into the cytoplasm. The nucleocapsid travels to the trans-Golgi network (TGN).
At the TGN, the virion undergoes secondary envelopment, acquiring its final lipid envelope populated with viral glycoproteins. The tegument proteins assemble around the nucleocapsid. The fully mature, infectious virions are then transported in vesicles to the cell surface and spread, often through cell-to-cell fusion.
Immune Evasion and Latency
VZV uses sophisticated strategies to avoid detection by the host’s immune system, enabling long-term persistence. A primary defense mechanism is interfering with antigen presentation by downregulating Major Histocompatibility Complex class I (MHC I) molecules on the surface of infected cells. MHC I molecules normally display viral protein fragments to cytotoxic T cells, signaling the cell for destruction.
VZV proteins, such as IE4 and ORF66, actively sequester MHC I molecules in the Golgi complex, preventing them from reaching the cell surface. This reduction in surface MHC I helps the infected cell evade recognition and killing by CD8+ T lymphocytes. Other viral proteins, including ORF63 and ORF66, interfere with the host’s innate immune response by blocking interferon signaling pathways.
The ultimate evasion strategy is the establishment of latency, a state of dormancy established after the primary infection. VZV travels along peripheral nerves and establishes a lifelong, quiescent infection in the sensory neurons of the dorsal root ganglia (DRG) and trigeminal ganglia. In this latent state, the viral DNA persists as a circular episome, and most viral gene expression is shut down to prevent immune detection.
Latency can be broken by various triggers, including age-related decline in VZV-specific T-cell immunity, stress, or immunosuppression. The loss of immune control allows the viral genome to reactivate, initiating the lytic cycle once more. The reactivated virus travels down the sensory nerve to the skin, causing the localized, painful rash of herpes zoster (shingles).