ABSTRACT Varicella zoster virus (VZV) is so well known as the cause of cutaneous varicella (chickenpox) and zoster (shingles) that it can be hard to imagine it as an enteric pathogen. VZV establishes latency during varicella and returns to the skin in zoster when the neurons in which VZV reactivates have cutaneous projections. Because a viremia occurs during varicella, VZV also infects and establishes latency in enteric neurons that do not innervate the skin. VZV can reactivate in enteric neurons to give rise to “enteric zoster”, which can occur without an associated rash. Because a rash may thus be absent, pain due to enteric zoster can be occult. We have found, however, that VZV DNA, which is absent from normal saliva, is detectable in saliva whenever an active (lytic) VZV infection is present in the body; thus, detection of salivary VZV is a non- invasive diagnostic tool that, in combination with enteric signs and symptoms, helps to identify GI disorders that involve VZV. We have found VZV transcripts and protein in endoscopic biopsies from patients with occult abdominal pain and salivary VZV DNA, which verifies that these patients have enteric zoster. These observations led us to investigate the potential association between VZV and achalasia in 15 patients. We found salivary VZV DNA in 12/15 subjects examined prior to myotomy and, subsequently, VZV transcripts in 13/15 of the resected myotomy specimens. The tissue also contained VZV-immunoreactive (gE, gH, ORF40p) neurons, nerve fibers, and multinucleated giant cells. To help determine whether this persistent VZV infection of esophageal neurons is causally related to achalasia, we now propose to conduct a clinical trial of valacyclovir to determine whether eradication of VZV alleviates achalasia symptoms and improves esophageal function. We also plan to quantify viral load in relation to achalasia phenotypes and employ next generation sequencing to look for a genetic basis of esophageal VZV reactivation. Finally, because mast cell accumulation and degranulation have been reported in the achalasia esophagus and verified in our preliminary data we will test the hypothesis that mast cell activation contributes to manifestations and/or painful symptoms of VZV- associated achalasia. To gain insight into mechanisms of achalasia pathogenesis, we will also determine whether VZV reactivates specifically in neurons thought to control relaxation of the lower esophageal sphincter (nitric oxide synthase) and/or the excitatory phase of esophageal peristalsis (choline acetyltransferase). Viral destruction of nitrergic inhibitory neurons could be a cause of failure of LES smooth muscle to relax and either or both of these neurons could contribute to the loss of peristalsis that accompanies achalasia.