A viral lncRNA tethers HSV-1 genomes at the nuclear periphery to establish viral latency

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ABSTRACT Herpes simplex virus 1 (HSV-1) produces a long noncoding RNA, the latency-associated transcript (LAT), that mediates silencing of the virus in neurons through unknown mechanisms. Here, we show that the LAT binds both the cellular transmembrane protein 43 (TMEM43) and HSV-1 genomes in human neurons. Additionally, loss of TMEM43 prior to infection results in a decreased ability of the virus to establish latency, mirroring phenotypes of LAT promoter mutant viruses which are also defective in establishing latency. These data support a unique mechanism whereby the LAT binds TMEM43 and the HSV genome to localize HSV-1 genomes to the nuclear periphery to repress lytic viral transcription and establish viral latency and suggests that TMEM43 may play a similar role in regulating cellular genes. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes lifelong latency in neuronal cells. Following a stressor, the virus reactivates from latency, virus is shed at the periphery and recurrent disease can occur. During latency, the viral lncRNA termed the latency-associated transcript (LAT) is known to accumulate to high abundance. The LAT is known to impact many aspects of latency though the molecular events involved are not well understood. Here, we utilized a human neuronal cell line model of HSV latency and reactivation (LUHMES) to identify the molecular-binding partners of the LAT during latency. We found that the LAT binds to both the cellular protein, TMEM43, and HSV-1 genomes in LUHMES cells. Additionally, we find that knockdown of TMEM43 prior to infection results in a decreased ability of HSV-1 to establish latency. This work highlights a potential mechanism for how the LAT facilitates the establishment of HSV-1 latency in human neurons.

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