Implication of the SETDB1-HUSH-MORC2 axis in the control of herpes simplex virus 1 latency

Description

The human body is colonized by numerous commensal microorganisms forming the human microbiota. The human microbiota is now recognized as an essential player in the health and physiology of its host. Efforts to describe the human microbiota have focused on its bacterial component, but it is becoming increasingly clear that many viruses also belong to the human microbiota. The viral component of the human microbiome therefore introduces a more recently accepted notion, that of the human virome, which corresponds to all viruses detected in humans. Among these viruses, we find the Herpesvirus family and in particular the herpes simplex virus 1 (HSV-1). This virus persists in the host organism in latent form within the trigeminal ganglia innervating the face. This latency is characterized by the absence of virus replication at the time of the initial infection, which results in transcriptional repression of the viral genome under the pressure of the intrinsic antiviral response. However, reactivation episodes are very frequent. This reactivation leads to variable clinical manifestations in the peripheral and central nervous system, with increasing degrees of severity ranging from simple epithelial damage to the face such as fever blisters, to keratitis that can lead to blindness, but also to fulminant encephalitis or even be a risk factor for Alzheimer’s disease.

The establishment of HSV-1 latency is controlled by PML nuclear bodies (PML NBs) but their exact involvement remains unclear. One of the major characteristics of the latency of the virus is the interaction between the viral genome and PML NBs forming structures called viral DNA-containing PML-NBs (vDCP NBs). The use of an infection model of primary human fibroblasts, which mimics the formation of vDCP NBs, combined with an immuno-FISH approach, allowed to show that vDCP NBs contain the SETDB1-HUSH-MORC2 entity. ChIP- qPCR experiments demonstrated the involvement of this axis in the latency of the HSV-1 genome via the deposition of the chromatin mark : trimethylation of lysine 9 of histone 3 (H3K9me3). Depletion experiments of the different components of this entity showed its involvement in the maintenance of HSV-1 latency, including in neurons derived from human induced pluripotent stem cells (huiPSDN). Finally, this study revealed the SETDB1-HUSH-MORC2 axis as a restriction factor of HSV-1 at the epigenetic level.