The use of nerve growth factor in herpetic keratitis: a case report
© Mauro et al; licensee BioMed Central Ltd. 2007
Received: 04 August 2007
Accepted: 31 October 2007
Published: 31 October 2007
We evaluate the role of nerve growth factor (NGF) eye drops to treat a herpetic corneal ulcer resistant to systemic and local acyclovir treatment in an HIV-positive patient.
A 68 year old HIV-positive male presented with a herpetic corneal ulcer which was treated unsuccessfully with acyclovir. Acyclovir sensitivity of herpes simplex virus was tested with a dye uptake assay and we found that the herpes simplex virus isolated was resistant to acyclovir. We started eye drop therapy with NGF and the corneal herpetic ulcer healed in 23 treatment days.
The case presented here is the first described in the literature in which a herpetic corneal ulcer was successfully treated with NGF. We recommend that trials of NGF therapy in herpetic keratitis should be carried out on a larger number of acyclovir resistant cases.
Herpes simplex virus (HSV-1) infections of the eye, and in particular keratitis, are quite frequent in people with acquired immunodeficiency syndrome  and are generally treated with acyclovir. Recently, there has been a progressive increase in the number of cases resistant to acyclovir  due to the development of viral strains resistant to the drug and the appearance of a gene tk mutation . Experimental studies have recently demonstrated that nerve growth factor (NGF) is able to block HSV-1 reactivation  and is also able to repair neurotrophic corneal ulcers . On the basis of this, we decided to use NGF eye drops to treat a corneal herpetic ulcer in an HIV-positive patient, where the herpes simplex virus was resistant to systemic and local acyclovir treatment.
On the basis of the persistence of the corneal herpetic ulcer we decided to discontinue the topical and systemic acyclovir therapies and to trial topical treatment with NGF eye drops. Before treatment the patient was informed of the procedures and the aim of the therapy and he signed a written consent form. The institutional ethics committee of the S. Orsola-Malpighi Hospital also approved the study.
Treatment consisted of murine NGF purified from sub maxillary glands and produced in the laboratories of the Institute of Neurobiology & Molecular Medicine (CNR-EBR, Roma, Italy).
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.
Mauro Cellini, MD (Department of Surgery and Transplant – Ophthalmology Service) examined the patient and received the informed written consent from the patientfor publication of the manuscript and any accompanying images.
We thank Dr. Luigi Aloe (Institute of Neurobiology & Molecular Medicine CNR-EBR, Roma, Italy) for the supply of nerve growth factor for this study.
- Shuler J, Engstrom R, Holland G: External ocular disease and anterior segment disorders associated with AIDS. Int Ophthalmol Clin. 1998, 29: 98-104. 10.1097/00004397-198902920-00007.View ArticleGoogle Scholar
- Erlich KS, Mills J, Chatis P: Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1989, 320: 293-296.View ArticlePubMedGoogle Scholar
- Nugler F, Colin JN, Aymard M, Langlois M: Occurrence and characterization of acyclovir-resistant herpes simplex virus isolates: report on a two-year sensitivity screening survey. J Med Virol. 1992, 36: 1-12.View ArticleGoogle Scholar
- Kriesel JD: The roles of inflammation, STAT transcription factors, and nerve growth factor in viral reactivation and herpes keratitis. DNA and cell biology. 2002, 21: 475-481. 10.1089/10445490260099773.View ArticlePubMedGoogle Scholar
- Bonini S, Lambiase A, Rama P, Caprifoglio G, Aloe L: Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology. 2000, 107: 1347-1351. 10.1016/S0161-6420(00)00163-9.View ArticlePubMedGoogle Scholar
- McLaren C, Ellis MN, Hunter GA: A colorimetric assay for the measurement of the sensitivity of herpes simplex viruses to antiviral agents. Antiviral Res. 1983, 3: 223-234. 10.1016/0166-3542(83)90001-3.View ArticlePubMedGoogle Scholar
- Andrei G, Snoeck R, De Clercq E, Esnouf R, Fiten P, Opdenakker G: Resistance of herpes simplex virus type 1 against different phosphonylmethoxyalkyl derivatives of purines and pyrimidines due to specific mutations in the viral DNA polymerase gene. J Gen Virol. 2000, 81: 639-648.View ArticlePubMedGoogle Scholar
- Yamamoto M, Sobue G, Yamamoto K: Expression of mRNAs for neurotrophic factors (NGF, BDNF, NT-3, and GDNF) and their receptors (p75NGFR, trkA, trkB, and trkC) in the adult human peripheral nervous system and nonneural tissues. Neurochem Res. 1996, 21: 929-938. 10.1007/BF02532343.View ArticlePubMedGoogle Scholar
- Lambiase A, Bonini S, Micera A, Rama P, Bovini S, Aloe L: Expression of nerve growth factor receptors on the ocular surface in healthy subjects and during manifestation of inflammatory diseases. Invest Ophthalmol Vis Sci. 1998, 39: 1272-1275.PubMedGoogle Scholar
- Kriesel J, Jones B, Hwang I, Dahms K, Spruance S: Signal transducers and activators of transcription(STATs) are detectable in mouse trigeminal ganglion neurons. J Interferon Cytokine Res. 2001, 21: 445-450. 10.1089/107999001750277934.View ArticlePubMedGoogle Scholar
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