What triggers the reactivation of herpes simplex virus (HSV) that causes cold sores?

Cold Sore Reactivation Mechanism

After primary HSV-1 infection, the virus establishes lifelong latency in sensory ganglia (specifically the trigeminal ganglion for oral infections), and reactivates in response to specific physiological triggers that disrupt the balance between viral suppression and lytic gene expression. 1

Establishment of Latency

• Following primary HSV-1 infection (which may be asymptomatic or cause gingivostomatitis), the virus travels via retrograde axonal transport to establish latency in the sensory ganglia 1
• During latency, the virus exists in a non-replicating episomal form in neuronal nuclei, with viral lytic genes suppressed and only latency-associated transcripts (LATs) expressed 1, 2
• The virus remains dormant in these neurons indefinitely, maintaining the capacity for periodic reactivation 3

Reactivation Triggers

The most well-established triggers for HSV-1 reactivation include:

• Ultraviolet light exposure - UV-B radiation is a potent stimulus that induces reactivation through mechanisms involving neural pathways, with lesions typically developing 4-5 days post-exposure at or near the UV-exposed site 1, 4
• Fever - Elevated body temperature disrupts the latency-maintenance mechanisms 1
• Psychological stress - Stress-related hormonal changes, particularly glucocorticoids, can trigger reactivation 1, 2
• Menstruation - Hormonal fluctuations during the menstrual cycle serve as a reactivation stimulus 1
• Immunosuppression - Conditions causing low lymphocyte counts or T-cell dysfunction increase reactivation frequency 1, 5
• Physical trauma or local tissue injury - Including procedures like radiation therapy 6, 7

Molecular Mechanisms of Reactivation

• Different triggers activate distinct cellular signaling pathways that converge on viral gene expression changes 3
• Heat stress and glucocorticoids (like dexamethasone) can induce reactivation through mechanisms independent of the heat shock protein response alone 2
• The reactivation process involves transition from latency-associated transcript expression to lytic-phase mRNA and protein production, first detectable in neurons approximately 24 hours after the triggering stimulus 2
• Viral replication begins in the neuronal cell bodies within the ganglia, followed by anterograde transport of newly produced virions back to the mucocutaneous site 2

Clinical Progression After Reactivation

• Prodromal phase: Itching, burning, and/or paresthesia occur 12-24 hours before visible lesions, representing viral replication and migration along sensory nerves 1
• Lesion evolution: Erythema → papule → vesicle → pustule → ulcer → crust, with complete healing typically within 7-10 days 1
• Peak viral shedding: Occurs within the first 24 hours after lesion onset when most lesions are vesicular, followed by progressive decline as lesions ulcerate and crust 1

Important Clinical Considerations

• Reactivation frequency varies widely from once every few years to multiple times monthly, with individual variation in trigger sensitivity 1
• In immunocompromised patients, reactivations produce more severe, prolonged, and extensive lesions that may involve the oral cavity or extend across the face 1, 5
• The timing and anatomical distribution of recurrent lesions typically coincide with the site of primary infection, reflecting the specific ganglia harboring latent virus 1, 4
• Smokers paradoxically report fewer outbreaks than nonsmokers, though the mechanism remains unclear 1, 5