engleski

A novel cationic amphiphilic porphyrin-based photosensitizer effectively inhibits replication of HSV-1 by several different mechanisms

Herpes simplex virus 1 (HSV-1) is very important and common human pathogen, widely known as the causative agent of cold sores. HSV-1 is also the leading infectious cause of blindness and the most common cause of sporadic encephalitis. Antiviral treatment of HSV-1 infections largely relies on nucleoside analogs such as acyclovir (ACV) and its derivates. However, prevalence of ACV resistant viruses is increasing and thus the development of novel strategies to treat HSV-1 infections is necessary. Photodynamic therapy (PDT) is an approach that employs a nontoxic photosensitizer (PS) that can be excited by light and produce reactive oxygen species (ROS) and HSV-1 is frequently used as a model enveloped virus to study novel photoactive compounds. In our study we investigated the potency of TMPyP3-C17H35, an amphiphilic porphyrin based PS, to inhibit HSV-1 replication in cultured cells. First, we have determined the concentration range at which the light activated compound does not exert a significant toxicity on Vero cells by using standard MTT and proliferation assays. Such sub- toxic concentrations of TMPyP3-C17H35, were then used to test its antiviral properties in a variety of different experiments. We show that TMPyP3- C17H35 inhibits replication of HSV-1 in a dose dependent manner and that its activity strongly depends on the activation by light. Virus yields in treated and irradiated cells were more than thousand times lower than in cells equally treated by not irradiated compound or not treated at all. Moreover, we show that treatment of cells prior to infection effects expression of genes of all expression- kinetics classes, including immediate early gen ICP0, indicating an early block in virus replication. However, in experiments where cells were treated after infection we observed a strong effect of TMPyP3-C17H35 on virus replication only when cells were treated shortly after infection, i.e. up to 30 min post entry. These results indicate that the activated compound efficiently blocks HSV-1 replication intracellularly, inhibits early replication events and strongly decreases infectivity of free virions probably by damaging internalized virus capsids, disrupting internalization to nucleus or triggering intrinsic immunity. Taken together, our results show that activated TMPyP3-C17H35 inhibits HSV- 1 infection by several different mechanisms and might offer a novel approach in therapy against HSV-1.

HSV-1 ; photodynamic therapy ; TMPyP3-C17H35

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