Session topic


Title: The molecular tweezer CLR01 inhibits cell-free and cell-to-cell spread of cytomegalovirus by disruption of the viral envelope
ID: O 64
Type: Abstract talk
Talk time: 12 + 3 min
Session: Workshop 11
Antivirals and resistance II

Speaker: Jens von Einem (Ulm/DE)

Abstract - Text

Abstract text (incl. references and figure legends)

Introduction: Spread of infection by the Human Cytomegalovirus (HCMV) is facilitated by either cell-free virus or by direct cell-to-cell spread. Direct cell-to-cell spread cannot be blocked by neutralizing antibodies and is thus considered the most relevant mode of virus dissemination within the host. The molecular tweezer CLR01 (1) has recently been shown to inhibit infection of cells by enveloped viruses, including HCMV (2).

Objectives: We sought to clarify how CLR01 inhibits infection of cells by cell-free HCMV and tested the capability of CLR01 to block direct cell-to-cell spread of herpesviruses.

Materials & methods: Cryo-electron microscopy was used for visualization of effects of CLR01 on HCMV virions. Infection experiments were performed on human fibroblasts to investigate how CLR01 affects the different stages of virus entry. Focus expansion assays were conducted on fibroblasts in presence of CLR01 for up to 6 days to investigate direct cell-to-cell spread of herpesviruses.

Results: We show that the molecular tweezer CLR01 impairs the envelope of HCMV virions. The way CLR01 affects HCMV virions impairs not only attachment of virus particles to the cell surface but also subsequent entry steps into the cell. More importantly, CLR01 inhibits cell-to-cell spread of HCMV whereas production and release of virus particles from infected cells is unaffected. Furthermore, cell-to-cell spread of herpes simplex virus 1 and 2 is also inhibited by CLR01.

Conclusions: Our results characterize CLR01 as a small antiviral that selectively disrupts the HCMV envelope, presumably rendering virions non-infectious and thereby blocks virus dissemination by cell-free virus and the clinically more relevant cell-to-cell spread. Furthermore, our results suggest that targeting the viral envelope is an antiviral strategy that prevents direct cell-to-cell spread of HCMV and other herpesviruses.

(1) Zimmerman, Top. Curr. Chem., 1993; BFb0111281.

(2) Lump et al. Elife. 2015; 4:e05397.