Herpes Simplex Virus (HSV) types 1 (HSV-1) and 2 (HSV-2) are highly prevalent human pathogens, infecting billions worldwide. HSV-1, often associated with orolabial lesions, has an estimated global seroprevalence exceeding 67% in people under 50, while HSV-2 is generally linked to genital infections. Both viruses are classified as neurotropic, meaning they possess the ability to infect and travel through the nervous system. While most infections result in mild, recurrent skin or mucosal outbreaks, this neurotropic property allows the virus to establish lifelong dormancy and, in rare instances, invade the central nervous system (CNS). The journey from initial entry to potential neurological disease highlights the virus’s manipulation of human cellular machinery.
Initial Infection and Viral Entry Mechanisms
The infection process typically begins when the virus contacts a susceptible host, often through damaged epithelial cells on mucosal surfaces (oral, genital, or ocular regions). Initial attachment involves two viral envelope glycoproteins, gC and gB, which bind loosely to heparan sulfate proteoglycans on the host cell surface. This initial binding promotes viral adsorption.
The critical step for internalization is membrane fusion, managed by a core fusion machinery involving four viral glycoproteins: gB, gD, and the gH/gL heterodimer. Glycoprotein D (gD) is the major receptor-binding protein, which must engage specific host cell receptors, such as Nectin-1 or Herpesvirus Entry Mediator (HVEM). This binding causes a conformational change in gD, triggering the fusion proteins (gH/gL and gB) to merge the viral envelope with the host cell membrane. This fusion creates a pore through which the viral nucleocapsid and associated proteins are released into the host cell cytoplasm, where the viral genetic material is transported toward the nucleus for replication.
The Journey: Axonal Transport and Establishing Latency
Following local replication, the virus must navigate the peripheral nervous system (PNS) to ensure its long-term survival. The nucleocapsid, containing the viral double-stranded DNA, is internalized at the nerve endings and transported along axons toward the neuronal cell body. This movement is accomplished through retrograde axonal transport, a process that hijacks the cell’s internal transport system utilizing microtubules and the motor protein dynein.
For HSV-1, this journey typically ends in the trigeminal ganglion, which innervates the face and oral cavity. HSV-2 most commonly establishes residence in the sacral ganglia, which serve the genital region. Upon reaching the ganglion, the virus establishes a latent infection, a state of lifelong dormancy where the viral genome circularizes and persists as an episome within the neuron’s nucleus.
During latency, the expression of most viral genes required for active replication is silenced. A small region remains transcriptionally active, producing the Latency-Associated Transcripts (LATs). LATs are non-coding RNAs that are the most abundant viral transcripts during latency, and they are believed to play a role in maintaining the dormant state and blocking programmed cell death. The presence of LATs signifies a quiescent infection that can be reactivated by various stressors, such as fever, stress, or immune suppression.
Breaching the Barrier: Mechanisms of CNS Invasion
The transition from a latent infection in the peripheral ganglia to an active infection within the Central Nervous System (CNS) is a rare event. This invasion typically occurs during viral reactivation, where the dormant virus begins to replicate. The primary hypothesis for how HSV-1 breaches the CNS involves a direct neuronal route: anterograde spread from the trigeminal ganglion.
The virus travels along nerve tracts connecting the trigeminal ganglion to the brain, leading directly into the medial temporal and inferior frontal lobes. This specific pathway explains the characteristic focal nature of the resulting disease, Herpes Simplex Encephalitis (HSE). Once inside the brain parenchyma, the virus replicates, causing direct cytolytic destruction of neurons and triggering an intense inflammatory response.
The pathological mechanism involves a rapid, lytic, and hemorrhagic process that is asymmetrically distributed. The host’s immune response, while intended to clear the infection, contributes significantly to tissue damage through the activation of microglial cells and resulting inflammation. This combination of direct viral injury and immune-mediated destruction leads to edema, neuronal necrosis, and focal hemorrhage, which characterize the acute neurological disease and compromise the blood-brain barrier.
Spectrum of Neurological Disease
Herpes Simplex Encephalitis (HSE) is the leading cause of sporadic, non-epidemic encephalitis globally. HSE is overwhelmingly caused by HSV-1 in older children and adults, and it carries a high mortality rate of up to 70% if left untreated. Symptoms usually begin acutely with fever, headache, and a flu-like illness, rapidly progressing to severe neurological deterioration.
The preferential damage to the temporal and frontal lobes results in characteristic focal neurological deficits, including altered mental status, personality changes, memory loss, and seizures. Even with prompt antiviral therapy, survivors often experience long-term cognitive and neurological sequelae due to the extensive hemorrhagic necrosis. Neonatal encephalitis, often caused by HSV-2 acquired during birth, tends to be more generalized throughout the brain and is associated with profound neurological impairment.
Beyond HSE, HSV-2 is the most common cause of recurrent aseptic meningitis, often referred to as Mollaret’s meningitis. This condition is characterized by self-limiting, repeated episodes of headache, fever, and neck stiffness, with complete recovery between episodes. HSV-2 DNA is typically detected in the cerebrospinal fluid during these attacks. Other, less frequent conditions linked to HSV include transverse myelitis, which affects the spinal cord, and Bell’s palsy, a form of temporary facial paralysis.