HSV-1 Remodels Host Telomeres to Facilitate Viral Replication

Abstract

Summary Telomeres protect the ends of cellular chromosomes. We show here that infection with herpes simplex virus 1 (HSV-1) results in chromosomal structural aberrations at telomeres and the accumulation of telomere dysfunction-induced DNA damage foci (TIFs). At the molecular level, HSV-1 induces transcription of telomere repeat-containing RNA (TERRA), followed by the proteolytic degradation of the telomere protein TPP1, and loss of the telomere repeat DNA signal. The HSV-1 encoded E3 ubiquitin ligase ICP0 is required for TERRA transcription and facilitates TPP1 degradation. shRNA depletion of TPP1 increases viral replication, arguing that TPP1inhibits viral replication. Viral replication protein ICP8 forms foci that coincide with telomeric proteins and ICP8 null virus failed to degrade telomere DNA signal. These findings suggest that HSV-1 reorganizes telomeres to form ICP8-associated pre-replication foci and promotes viral genomic replication.

Visualization of DNA G-quadruplexes in herpes simplex virus 1-infected cells

“…This evidence supports formation of viral G4s during viral replication. ICP8 has been recently shown to co-localize with telomeric foci (58) in the cell nucleus, however, no G4 dependence has been reported: it is thus unlikely that colocalization signals obtained in our experiments derive from telomeric G4s/ICP8 colocalization. Moreover, G4s in infected cells were much more abundant than those in mock-infected cells and their localization within the nucleus at different times p.i.…”

Corticosterone, inflammation, immune status and telomere length in frigatebird nestlings facing a severe herpesvirus infection

“…A previous study has underlined a major role of chronic infection in telomere shortening, showing how great reed warblers ( Acrocephalus arundinaceus ) infected with chronic malaria have an accelerated telomere shortening in comparison with uninfected individuals (Asghar et al ., 2015). Additionally, studies on humans have found herpesvirus to integrate into host telomeres and to cause telomere shortening and instability (Deng et al ., 2014; Huang et al ., 2014), in order to facilitate the release of viral genome from the chromosome (Huang et al ., 2014). In our study, we found longer telomeres in individuals with visible clinical signs in the second sampling period.…”

Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes

“…Telomere shortening may also increase TERRA expression (48), but it is not clear that senescent cells show a global increase in TERRA levels. We found that TERRA can be enriched in some cancer tissues (17) and is highly induced in cells after infection by herpes simplex virus 1 (HSV1) (47). TERRA has been shown to have several functions at telomeres, including recruitment of telomerase (48), inhibition of telomerase (49), assembly of DNA damage repair proteins (50), and maintenance of telomeric heterochromatin (12).…”

“…TERRA expression can be regulated by developmental and stress-related signals, including DNA damage and viral infection (7,(45)(46)(47). Telomere shortening may also increase TERRA expression (48), but it is not clear that senescent cells show a global increase in TERRA levels.…”