Cytomégalovirus humain, mutations de résistance et nouvelles cibles thérapeutiques

Abstract : Human cytomegalovirus (HCMV) is an important opportunistic pathogen for immunecompromised patients and is the leading cause of congenital viral infection. Although they are effective, using of conventional molecules is limited by the emergence of resistance and their toxicity. Then it becomes necessary to develop new treatments. Study of new mutationsemerging under antiviral treatment is therefore essential. Introduction of these new mutations, by « en passant » mutagenesis, into an artificial bacterial chromosome containing the viral genome allows us, after transfection into human cells, testing antivirals sensitivity of the recombinant. Different mutations of resistances have been characterized. In order tohighlight new antiviral targets, bioinformatics and recombinant viruses production allowed to identify potential functional patterns essential for viral replication within terminase and helicase-primase complex. Thus, we have shown that pUL56 subunit of the terminase complex belongs to the LAGLIDADG Homing Endonuclease family. Indeed, pUL56 contains aLATLNDIERFL motif and a DNA binding motif. Alpha technology using purified proteins allowed to validate the essential character of the WMVVKYMGFF fragment of pUL56 for the interaction with pUL89. Finally, we highlighted the residues involved in ATP binding within the helicase and in the stabilization of zinc within the primase. Thus, understanding of these proteins structure could allow us to better understand their role within the viral replication process and the development of new therapies targeting these domains.
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Gaëtan Ligat. Cytomégalovirus humain, mutations de résistance et nouvelles cibles thérapeutiques. Maladies infectieuses. Université de Limoges, 2017. Français. ⟨NNT : 2017LIMO0046⟩. ⟨tel-01941721⟩

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