The Latency-Associated Transcript Inhibits Apoptosis via Downregulation of Components of the Type I Interferon Pathway during Latent Herpes Simplex Virus 1 Ocular Infection

Tormanen, Kati; Allen, Sariah J.; Mott, Kevin R.; Ghiasi, Homayon

doi:10.1128/jvi.00103-19

Cited by 29 publications

(34 citation statements)

References 83 publications

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“…However, on days 2 and 4 p.i., WT mice infected with LAT(Ϫ) virus had higher virus titers than the other three groups ( in the eyes of infected mice. Recently, we reported that LAT downregulates components of the type I IFN pathway in ocularly infected mice (27). As we reported previously (12,19), we did not detect any difference in virus titers between LT␣ Ϫ/Ϫ mice infected with LAT(ϩ) and LAT(Ϫ) virus ( Fig.…”

Section: Resultssupporting

confidence: 79%

The Absence of Lymphotoxin-α, a Herpesvirus Entry Mediator (HVEM) Ligand, Affects Herpes Simplex Virus 1 InfectionIn VivoDifferently than the Absence of Other HVEM Cellular Ligands

Wang

Hirose

Ghiasi

2019

J Virol

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Previously, we reported that the absence of herpesvirus entry mediator (HVEM) decreases latency but not primary infection in ocularly infected mice. Recently, we reported that similar to the absence of HVEM, the absence of HVEM ligands (i.e., LIGHT, CD160, and B and T lymphocyte attenuator [BTLA]) also decreased latency but not primary infection. Similar to LIGHT, CD160, and BTLA, another member of tumor necrosis factor (TNF) superfamily, lymphotoxin-␣ (LT␣), also interacts with HVEM. To determine whether LT␣ decreases latency in infected mice, we ocularly infected LT␣ Ϫ/Ϫ mice with latency-associated transcript-positive [LAT(ϩ)] and LAT(Ϫ) viruses using similarly infected wild-type (WT) mice as controls. In contrast to WT C57BL/6 mice, LT␣ Ϫ/Ϫ mice were highly susceptible to ocular herpes simplex virus 1 (HSV-1) infection, independent of the presence or absence of LAT. Survival was partially restored by adoptive transfer of CD4 ϩ , CD8 ϩ , or total T cells. Infected LT␣ Ϫ/Ϫ mice had significantly higher corneal scarring than WT mice, and adoptive T cell transfer did not alter the severity of eye disease. In contrast to results in WT mice, the amount of latency was not affected by the absence of LAT. The amount of LAT RNA in LT␣ Ϫ/Ϫ mice infected with LAT(ϩ) virus was similar to that in WT mice, and adoptive T cell transfer did not alter LAT RNA levels in LT␣ Ϫ/Ϫ infected mice. Increased latency in the absence of LT␣ correlated with upregulation of HVEM, LIGHT, CD160, and BTLA transcripts as well as with an increase in markers of T cell exhaustion. The results of our study suggest that LT␣ has antipathogenic and anti-inflammatory functions and may act to protect the host from infection. IMPORTANCE Recently, we evaluated the effects of HVEM and its ligands (LIGHT, CD160, and BTLA) on HSV-1 infectivity. However, the effect of LT␣, another member of the TNF superfamily, on HSV-1 latency and eye disease is not known. Here, we demonstrate increased latency and corneal scarring in LT␣ Ϫ/Ϫ infected mice, independent of the presence of LAT. In addition, infected mice were highly susceptible to HSV-1 infection, and survival was partially but not significantly restored by adoptive T cell transfer. These results suggest that the absence of LT␣ affects HSV-1 infectivity differently than the absence of HVEM, LIGHT, CD160, and BTLA.

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Section: Resultssupporting

confidence: 79%

The Absence of Lymphotoxin-α, a Herpesvirus Entry Mediator (HVEM) Ligand, Affects Herpes Simplex Virus 1 InfectionIn VivoDifferently than the Absence of Other HVEM Cellular Ligands

Wang

Hirose

Ghiasi

2019

J Virol

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“…However, the mechanism of LAT against apoptosis is still not fully understood. LAT down-regulates the activation of apoptotic caspases 3, 8 and 9 [19]. In vitro, the cleavage of caspase 8 and 9 was inhibited in wild type HSV infected nerve 2A cells, while LAT deletion mutant viruses did not [37], indicating that the function of LAT was achieved by inhibiting the activation of pro-apoptotic caspases.…”

Section: Introductionmentioning

confidence: 95%

“…LAT may promote HSV activation by inhibiting apoptosis [19]. To some extent, the survival of neuronal cells can be achieved [60] [61].…”

Section: Current Theory Of Lat Mediated Hsv Reactivationmentioning

confidence: 99%

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The Role, Mechanism and Transcriptional Regulation of LAT in Herpes Simplex Virus Latency and Reactivation

Zhang¹,

Wang²,

Cheng³

et al. 2020

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Herpes simplex virus (HSV) infection in the human body can be latent in neurons for long time and be reactivated leading to recurrence at high rate. Currently there is no effective clinical strategy for the prevention and treatment of the disease relapse. HSV LAT gene is expressed in large quantities and lytic genes are turned off leading to HSV latency. Disruption of the gene expression is thought to cause HSV reactivation and disease relapse. To reveal the essence of HSV latency and reactivation, we summarized and innovatively classified the role, mechanism and transcriptional regulation of LAT in HSV latency and reactivation. This review may have important implications for future studies on HSV latency and reactivation, HSV disease prevention and treatment, and safer and more effective oncolytic HSVs (oHSVs).

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“…LAT is the only HSV-1 transcript abundantly expressed during latency (20,21). It is well established that LAT controls apoptosis (22)(23)(24)(25)(26)(27)(28)(29), which likely occurs via the type I interferon (IFN) pathway (30). In addition, LAT is responsible for CD8 ϩ T cell immune exhaustion, which is also essential for latency establishment (31,32).…”

mentioning

confidence: 99%

Expression of Murine CD80 by Herpes Simplex Virus 1 in Place of Latency-Associated Transcript (LAT) Can Compensate for Latency Reactivation and Anti-apoptotic Functions of LAT

Jaggi

Matundan

Tormanen

et al. 2020

J Virol

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High rates of wild-type (WT) herpes simplex virus 1 (HSV-1) latency reactivation depend on the anti-apoptotic activities of latency-associated transcript (LAT). Replacing LAT with the baculovirus inhibitor of apoptosis protein (cpIAP) or cellular FLIP (FLICE-like inhibitory protein) gene restored the WT latency reactivation phenotype to that of a LAT-minus [LAT(−)] virus, while similar recombinant viruses expressing interleukin-4 (IL-4) or interferon gamma (IFN-γ) did not. However, HSV-1 recombinant virus expressing cpIAP did not restore all LAT functions. Recently, we reported that a similar recombinant virus expressing CD80 in place of LAT had higher latency reactivation than a LAT-null virus. The present study was designed to determine if this CD80-expressing recombinant virus can restore all LAT functions as observed with WT virus. Our results suggest that overexpression of CD80 fully rescues LAT function in latency reactivation, apoptosis, and immune exhaustion, suggesting that LAT and CD80 have multiple overlapping functions. IMPORTANCE Recurring ocular infections caused by HSV-1 can cause corneal scarring and blindness. A major function of the HSV-1 latency-associated transcript (LAT) is to establish high levels of latency and reactivation, thus contributing to the development of eye disease. Here, we show that the host CD80 T cell costimulatory molecule functions similarly to LAT and can restore the ability of LAT to establish latency, reactivation, and immune exhaustion as well as induce the expression of caspase 3, caspase 8, caspase 9, and Bcl2. Our results suggest that, in contrast to several other previously tested genes, CD80-expressing virus can completely compensate for all known and tested LAT functions.

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The Latency-Associated Transcript Inhibits Apoptosis via Downregulation of Components of the Type I Interferon Pathway during Latent Herpes Simplex Virus 1 Ocular Infection

Cited by 29 publications

References 83 publications

The Absence of Lymphotoxin-α, a Herpesvirus Entry Mediator (HVEM) Ligand, Affects Herpes Simplex Virus 1 InfectionIn VivoDifferently than the Absence of Other HVEM Cellular Ligands

The Absence of Lymphotoxin-α, a Herpesvirus Entry Mediator (HVEM) Ligand, Affects Herpes Simplex Virus 1 InfectionIn VivoDifferently than the Absence of Other HVEM Cellular Ligands

The Role, Mechanism and Transcriptional Regulation of LAT in Herpes Simplex Virus Latency and Reactivation

Expression of Murine CD80 by Herpes Simplex Virus 1 in Place of Latency-Associated Transcript (LAT) Can Compensate for Latency Reactivation and Anti-apoptotic Functions of LAT

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