The Human Cytomegalovirus Latency-Associated Gene Product Latency Unique Natural Antigen Regulates Latent Gene Expression

Abstract

Human cytomegalovirus (HCMV) infection can lead to either lytic or latent infection which is dependent on regulation of the viral major immediate early promoter (MIEP); suppression of the MIEP is pre-requisite for latency and is driven by repressive epigenetic modifications at the MIEP during latent infection. However, other viral genes are expressed during latency and this is correlated with activatory epigenetic modifications at latent gene promoters. Yet the molecular basis of the differential regulation of latent and lytic gene expression by epigenetics is unclear. LUNA, a latent viral transcript, has been suggested to be important for HCMV latency and also been shown to be important for efficient reactivation likely through its known deSUMOylase activity. Intriguingly, we and others have also observed that LUNA enhances latency-associated expression of viral UL138 gene. Here we now show that, in the absence of LUNA, the expression of multiple latency associated transcripts is reduced during latent infection which is correlated with a lack of activatory marks at their promoters. Interestingly, we also show that LUNA interacts with the haematopoietic transcription factor GATA-2, which is known to drive a number of latency-associated gene promoters, and that this interaction is dependent on the deSUMOylase domain of LUNA. Finally, we show that the deSUMOylase activity of LUNA is required for the establishment and/or maintenance of an open chromatin configuration around latency-associated gene promoters. As such, LUNA plays a key role in efficient latency-associated viral gene expression and carriage of viral genome during latent carriage.