A Preclinical Model for Studying Herpes Simplex Virus Infection

Abstract

Herpes simplex virus (HSV) infections can cause considerable morbidity. Currently, nucleoside analogues such as acyclovir are widely used for treatment. However, HSV infections resistant to these drugs are a clinical problem among immunocompromised patients. To provide more efficient therapy and to counteract resistance, a different class of antiviral compounds has been developed. Pritelivir, a helicase primase inhibitor, represents a promising candidate for improved therapy. Here, we established an HSV-1 infection model on microneedle-pretreated human skin ex vivo. We identified HSV-1especific histological changes (e.g., cytopathic effects, multinucleated giant cells), down-regulation of nectin-1, nuclear translocation of NF-kB (p65), interferon regulatory factor 3 (IRF3), and signaling of the IFN-inducible protein MxA. Accordingly, this model was used to test the potency of pritelivir compared with the standard drug acyclovir. We discovered that both drugs had a comparable efficacy for inhibiting HSV-1 replication, suggesting that pritelivir could be an alternative therapeutic agent for patients infected with acyclovir-resistant strains. To our knowledge, we present a previously unreported ex vivo HSV-1 infection model with abdominal human skin to test antiviral drugs, thus bridging the gap between in vitro and in vivo drug screening and providing a valuable preclinical platform for HSV research.

Tracking Mechanisms of Viral Dissemination In Vivo

“…, 41. , 42. ]), but the administrative and technical difficulties in obtaining human-derived samples, associated with the complicated methods required to image and genetically manipulate them, makes such an approach cumbersome to implement in cell biology studies.…”

“…With current ethical concerns regarding animal research, non-animal models mimicking complex 3D environments have been developed. Human explants probably represent the most relevant alternative to measure physiological viral infection ex vivo (see, for instance [40][41][42]), but the administrative and technical difficulties in obtaining human-derived samples, associated with the complicated methods required to image and genetically manipulate them, makes such an approach cumbersome to implement in cell biology studies. In contrast, stem cell-derived organoids represent attractive alternatives to study physiological viral dissemination in-a-dish [43,44].…”

Human Skin Explants Recapitulate Key Features of HSV-1 Infections

“…These differences in murine and human physiology underscore the need for models of infection that faithfully mimic pathogenesis in humans. Tajpara et al (2019) describe an ex vivo infection model in human skin that can be used to study HSV pathogenesis and test the efficacy of antiviral compounds. Discarded human abdominal skin samples obtained from plastic surgery procedures were subjected to microneedle treatment to overcome the mechanical barrier function of the stratum corneum (Tajpara et al, 2018).…”

Engineering a Model to Study Viral Infections: Bioprinting, Microfluidics, and Organoids to Defeat Coronavirus Disease 2019 (COVID-19)

“…For example, Tajpara et al . developed a model based on the microneedle-pretreated human abdominal skin explant to test antivirals and their combinations against human simplex virus (HSV-1) infection[ 67 ]. Zhu et al .…”