# Identification of the human cytomegalovirus gHgLgO trimer as the central player in virion infectivity

## TL;DR

This study identifies the gHgLgO complex as a key player in human cytomegalovirus infectivity, challenging previous assumptions about other viral proteins.

## Contribution

The study reveals that gHgLgO, not previously known for this role, is essential for virus particle infectivity by interacting with host cell heparan sulfate proteoglycans.

## Key findings

- The gHgLgO complex is crucial for HCMV infectivity by interacting with host cell heparan sulfate proteoglycans.
- The gHgLgO complex plays a role in virion tethering, a function previously attributed to gB and gM/gN complexes.
- Incorporating gHgLgO into vaccine development could improve HCMV vaccine efficacy.

## Abstract

Glycoproteins in the viral envelope of human cytomegalovirus (HCMV) orchestrate virion tethering, receptor recognition and fusion with cellular membranes. The glycoprotein gB acts as fusion protein. The gHgL complexes gHgLgO and gHgLpUL(128,130,131A) define the HCMV cell tropism. Studies with HCMV lacking gO had indicated that gHgLgO, independently of binding to its cellular receptor PDGFRα, plays an important second role in infection. Here, we identified a gO mutation which abolished virus particle infectivity by preventing the interaction of gHgLgO with host cell heparan sulfate proteoglycans (HSPGs). We could not only show that gHgLgO – HSPG interactions are a genuine second role of gHgLgO, but also that gHgLgO is a main player in determining the infectivity of HCMV virus particles. This challenges long-accepted textbook knowledge on the role of gB and gMgN complexes in virion tethering. Additionally, it adds the gHgLgO complex to the antigens of interest for future HCMV vaccines or treatments.

Life threatening diseases in immunocompromised individuals and severe damage of unborn children after intrauterine infection with HCMV strongly ask for a vaccine efficiently preventing HCMV disease. Numerous trials with vaccines predominantly targeting HCMV virion glycoproteins have been performed but none of them met the requirements for a license. The CMV gHgLgO glycoprotein complex has been shown to be crucial for virion infectivity and infection of first target cells in vivo, but also due to an incomplete understanding of the mechanisms determining its role in infection, it was never considered as a vaccine antigen. By using a highly specific HCMV gO mutant, we could here show that, besides binding the entry receptor PDGFRα, the gHgLgO complex determines particle infectivity by tethering virus particles to cell surface HSPGs. This role has for a long time been attributed to the glycoproteins gB and gM/gN. Our data challenge this. Complementation of vaccine antigens like gB or the gHgLpUL(128,130,131A) complex, which have already been used in vaccine trials, with the until now neglected gHgLgO complex might take the anti-HCMV vaccine development a step forward.