Photochemotherapy of viral lesions

Abstract

It has been known since the 1930’s that animal, plant and bacterial viruses could be inactivated by photodynamic reactions. The two human viral infections that have been studied most extensively for the application of photochemotherapy are those caused by herpes simplex (DNA-envelope) virus and by papilloma (DNA non-envelope) virus. Strains of both viruses are responsible for sexually transmitted infections that are a major clinical problem and are strongly correlated with anogenital cancer. In general, envelope viruses are more sensitive to PDT then non-envelope viruses. Herpes Simplex Virus (HSV) is rapidly inactivated in vitro by photodynamic treatment (PDT) with porphyrin photosensitizers including hematoporphyrin derivative (HPD). In contrast, papilloma viruses are relatively insensitive to PDT in vitro under the same conditions. Proteins and lipids in the envelopes of mature HSV virons appear to be the primary targets for negatively charged porphyrin photosensitizers in contrast to positively charged photosensitizers (quinone-imine dyes:methylene blue, neutral red; acridine dyes:proflavin, acridine orange) that are believed to intercalate in HSV and papilloma viral DNA and photodynamically destroy primarily guanine residues. Porphyrin photoinactivated HSV virons appear unable to bind or penetrate VERO cells as they do not produce cytopathic effects and neither new virus nor viral antigens are produced. In contrast, positively charged methylene blue, neutral red or acridine dye photoinactivated HSV initiates replication of both viral and cellular DNA. Although photodynamic inactivation by positively charged dyes inhibits viral replication, HSV photoinactivated by neutral red is capable of transforming hamster embryo fibroblasts. This unmasking of the oncogenic potential of HSV by photodynamic action associated with positively charged photosensitizers has been a serious impediment to the clinical application of PDT for the treatment of herpetic lesions. Because photoinactivation of HSV with negatively charged porphyrins appears to occur by altering viral envelope proteins and lipids, porphyrins may be superior photosensitizers for clinical applications as compared to the positively charged dyes which have the potential to unmask oncogenic or other pathobiological effects of the virus in unpredictable ways. We have studied the in vitro photoinactivation of HSV, type 1 (HSV-1) and the in vivo PDT of ocular HSV-1 lesions in rabbits with hydrophobic, two carboxyl porphyrins or hematoporphyrin derivative (HPD=Photofrin 1) and a high molecular weight fraction of HPD (DHE=Photofrin II) as well as hydrophilic tetraphenylporphine sulfonate (TPPS). We have also studied the effect of HPD-PDT on shope (rabbit) papilloma virus (SPV) in vitro and on viral lesions in vivo. The SPV is a non-envelope DNA virus and appears to be relatively resistant to inactivation by HPD-PDT; however, SPV lesions on Dutch belted rabbits are effectively treated by PDT as are human papilloma viral (HPV) lesions.It has been known since the 1930’s that animal, plant and bacterial viruses could be inactivated by photodynamic reactions. The two human viral infections that have been studied most extensively for the application of photochemotherapy are those caused by herpes simplex (DNA-envelope) virus and by papilloma (DNA non-envelope) virus. Strains of both viruses are responsible for sexually transmitted infections that are a major clinical problem and are strongly correlated with anogenital cancer. In general, envelope viruses are more sensitive to PDT then non-envelope viruses. Herpes Simplex Virus (HSV) is rapidly inactivated in vitro by photodynamic treatment (PDT) with porphyrin photosensitizers including hematoporphyrin derivative (HPD). In contrast, papilloma viruses are relatively insensitive to PDT in vitro under the same conditions. Proteins and lipids in the envelopes of mature HSV virons appear to be the primary targets for negatively charged porphyrin photosensitizers in contrast to positively charge...