This case illustrates the appearance of HSV-1 viral strains resistant to acyclovir . Acyclovir is a potent and highly selective antiviral nucleoside analog, which remains one of the standard treatments of HSV infections in both immunocompetent and immunocompromised hosts. To become active and inhibit viral DNA synthesis acyclovir must be phosphorylated to acyclovir monophosphate by specific HSV-1 thymidine kinases (tk) and then phosphorylated to acyclovir triphosphate, the active form of acyclovir able to inhibit viral DNA-polymerases, by host cell kinases.
Previous studies indicate that antiviral resistance develops at a stable low rate in pools of HIV. Acyclovir-resistance is based principally on three different mechanisms . Two mechanisms involve a deficiency of viral tk genes, the third shows drug resistance with normal expression of tk. These mutants have either an altered tk enzyme or a mutation in their DNA polymerase gene .
NGF is a member of the neurotrophin gene family which also includes neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4) and brain-derived neurotrophic factor (BDNF). Neurotrophins exert their biological functions by binding to high affinity transmembranous receptors belonging to the trk family of receptor tyrosin kinase including trkA, trkB and trkC and p75 .
TrkA is the receptor of NGF and consists of a 140 KD molecule, which modulates not just neuronal survival but also the migration and proliferation of other cell lines .
NGF is a polypeptide that is essential for the survival and growth of sympathetic and sensorial system neurons and for CNS neuronal differentiation . The production of NGF and the ubiquitous presence of its specific receptors have also been demonstrated in the ocular surfaces . The mechanism of action of NGF on the ocular surface to heal corneal neurotrophic ulceration is not well defined. It may be that NGF restores a deficit of synthesis or release of endogenous NGF . A direct mechanism may involve the sensory innervation and the proliferation and differentiation of epithelial cells . An indirect mechanism could be related to the increase of those neuropeptides that promote epithelial healing or the release of cytokines.
In vitro and in vivo studies  have shown how the depletion of NGF causes a reactivation of HSV-1. This reactivation is the consequence of the loss of balance between the cytokine produced by the corneal epithelial inflammation and the resulting reduction in the NGF-trkA complex signals . Topical administration of NGF has therefore a mainly anti-inflammatory effect blocking the action of the cytokine and restoring the normal transmission of the NGF-trkA complex towards the nerve endings .
The case presented here is the first described in the medical literature in which a corneal herpetic ulcer, resistant to antiviral therapy, was treated with NGF. Although the use of NGF for the treatment of this type of disorder is still under debate, we believe that its use in selected cases of herpetic keratitis resistant to acyclovir therapy must be investigated on a larger number of cases to confirm our result.