Inhibition of Adrenergic Receptors Reduces Genital HSV-1 Clinical Recurrences in Guinea Pigs

Herpes simplex virus 1 (HSV-1) establishes latency in both sensory and sympathetic neurons. Stress is strongly correlated with HSV-1 reactivation. The acute stress hormone epinephrine initiates HSV-1 reactivation in vitro upon activating at least two adrenergic receptors (ARs), including α2, β1, and/or β2-AR. To determine if blocking these receptors could reduce HSV-1 recurrences, we infected guinea pigs vaginally with HSV-1 (17+) and, after latency was established, treated them daily with atipamezole (specific α2-AR inhibitor), propranolol (nonspecific β-AR inhibitor), or atipamezole/propranolol combined. Clinical recurrences decreased in the treatment groups compared to untreated: atipamezole (29.3%, p = 0.123), propranolol (43.6%, p = 0.021), and atipamezole/propranolol (39.1%, p = 0.021). No significant differences were observed between groups in HSV-1 viral load in pelvic ganglia, or in transcription of the latency-associated transcript (LAT) in guinea pigs that were asymptomatic when euthanized, suggesting AR inhibitors did not affect latency. In guinea pigs euthanized during recurrences, viral DNA was similar between groups in sensory ganglia but reduced in sympathetic ganglia in treatment groups compared to untreated, suggesting that reactivation still occurred in sensory but was limited in sympathetic neurons in AR inhibitor-treated animals. The use of adrenergic beta blockers may be a useful therapeutic to reduce HSV-1 clinical recurrences.