Fueling Replication – how herpes viruses get to cellular DNA building blocks
Human cytomegalovirus (CMV) belongs to the herpesvirus family and is of clinical importance, especially during pregnancy or in immunosuppressed patients such as transplant recipients. Research teams led by the virologists Thomas Gramberg (University Hospital Erlangen) and Michael Schindler (University Hospital Tübingen) report in the latest issue of the renowned journal Nature Microbiology how CMV ensures the supply of essential DNA building blocks for the replication of the viral genome, the so-called nucleotides.
In detail, the virus blocks the cellular enzyme SAMHD1, which regulates the provision of nucleotides through its activity. Normally, this protects the cell from infectious pathogens and ensures proper genome replication and repair, which also prevents the development of tumors. Thus, the knowledge gained in these studies is an important basis for novel therapies against DNA viruses and cancer.
The researchers were able to show that both human and murine CMV code for a protein, namely the viral kinase pUL97 or M97, which modifies SAMHD1 and thus inactivates it. „In infected mice that were genetically manipulated in such a way that they did not express SAMHD1, we found a strongly increased CMV replication,“ explains Janina Deutschmann, PhD student in the laboratory of Prof. Gramberg and first author of the mouse study. „The effect was even more pronounced when the viruses no longer encoded the kinase M97 to inactivate SAMHD1,“ she continues. Dr. Ramona Businger, first author of the second study in Prof. Schindler’s laboratory, also investigated the effects in the human system. „A drastic increase in SAMHD1 phosphorylation was observed in primary human immune cells after CMV infection. We were able to directly relate this to the activity of the viral kinase pUL97,“ explains Dr. Businger.
However, there are also differences between humans and mice. While murine CMV seems to switch off SAMHD1 only by its kinase, its human counterpart also targets the production of SAMHD1. This shows how important this factor is for virus replication. It is also known that other viruses, and probably also tumor cells, have to inactivate SAMHD1 as well in order to multiply efficiently. Based on these findings, the researchers now hope to jointly develop novel approaches to fight viral infectious agents and tumor diseases.
Prof. Dr. Michael Schindler
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Businger et al., Human cytomegalovirus overcomes SAMHD1 restriction in macrophages via pUL97, www.nature.com/articles/s41564-019-0557-8
Deutschmann et al., A viral kinase counteracts in vivo restriction of murine cytomegalovirus by SAMHD1, www.nature.com/articles/s41564-019-0529-z