Trillions and Trillions: Herpes Simplex Virus–1 Hepatitis in an Immunocompetent Adult

Ikuta, Kevin S; Roychoudhury, Pavitra; Xie, Hong; McClurkan, Christopher L.; Walkiewicz, Magdalena; Makhsous, Negar; Huang, Meei‐Li; Beru, Yodit N.; Alam, Mariam; Shepherd, Amanda; Lamotte, Eric D; Patel, Kevin; Morris, Amy; Ҫoruh, Başak; Lei, Yu; Bhattacharya, Renuka; Cheng, Richard; Walter, Roland B.; Limaye, Ajit P.; Lockwood, Christina M.; Holland, Steven M.; Rakita, Robert M.; Koelle, David M.; Greninger, Alexander L.

doi:10.1093/ofid/ofz465

Cited by 4 publications

(3 citation statements)

References 11 publications

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“…Neonatal HSV is also sometimes due to HSV-1 but with lower burden than HSV-2 (8) and has recently been associated with maternal primary infection and lack of transplacental antibody (8)(9)(10). Other severe manifestations that are less likely to reflect ganglion biology include childhood HSE and HSV hepatitis in the immunocompetent person, usually related to primary infection and/or defective innate immunity (11,12) In immune suppressed persons, recurrent infections can be prolonged, severe, or systemic from epithelial to visceral sites. Host adaptation by HSV-1 is profound and leads to differences in clinical syndromes between humans and model organisms, albeit the host and viral genetic basis is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man

et al. 2021

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Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen. HSV-1 genomes persist in trigeminal ganglia neuronal nuclei as chromatinized episomes, while epithelial cells are typically killed by lytic infection. Fluctuations in anti-viral responses, broadly defined, may underlay periodic reactivations. The ganglionic immune response to HSV-1 infection includes cell-intrinsic responses in neurons, innate sensing by several cell types, and the infiltration and persistence of antigen-specific T-cells. The mechanisms specifying the contrasting fates of HSV-1 in neurons and epithelial cells may include differential genome silencing and chromatinization, dictated by variation in access of immune modulating viral tegument proteins to the cell body, and protection of neurons by autophagy. Innate responses have the capacity of recruiting additional immune cells and paracrine activity on parenchymal cells, for example via chemokines and type I interferons. In both mice and humans, HSV-1-specific CD8 and CD4 T-cells are recruited to ganglia, with mechanistic studies suggesting active roles in immune surveillance and control of reactivation. In this review we focus mainly on HSV-1 and the TG, comparing and contrasting where possible observational, interventional, and in vitro studies between humans and animal hosts.

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Section: Introductionmentioning

confidence: 99%

Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man

et al. 2021

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“…Ninety‐seven of those were included in the analysis, representing a total of 119 independent patients (Figure 1). The cases were extracted from 86 clinical cases 9‐35,37‐48,50‐54,56‐63,65‐71,73,75‐77,80‐83,85‐100,102,103 and 11 case series 36,49,55,64,72,74,78,79,84,101,113 . Figure 1 shows the case selection flow diagram.…”

Section: Resultsmentioning

confidence: 99%

Neurotoxicity associated with acyclovir and valacyclovir: A systematic review of cases

et al. 2021

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What is known and objective Acyclovir and valacyclovir are commonly used antivirals with good general tolerance. Despite their good safety profile, they can cause systemic adverse effects, such as neurotoxicity, which are less frequent and known. The objective of this review was to collect all the reported cases of neurotoxicity associated with acyclovir and valaciclovir published in the literature and characterize their clinical course and interventions. Methods A systematic review of cases was carried out following the guidelines established by “Preferred Reporting Items for Systematic Reviews and Meta‐Analyses” (PRISMA). The research was carried out using the PubMed‐Medline and Embase databases, between July 1984 and March 2021. Results and discussion A total of 119 cases with neurotoxicity mainly related to acyclovir (n = 88; 73.9%), followed by valaciclovir (n = 35; 29.4%) were analysed. 49.6% (n = 59) were men with a mean age of 59.5 years ± 21.1 (0.5–88). In 83.3% of the cases, renal impairment was documented and 57.1% (n = 68) with end‐stage renal disease. The administered dose was higher than the renal adjustment recommendations in 59.7% of the cases. The global mean of onset of symptoms was 3.1 days ± 4.3 (0.2–28) after the start of antivirals. The mean recovery time was 9.8 days ± 21.7 (0.2–180). 74.4% of the patients had a recovery of ≤7 days, 15.9% between 8 and 15 days and 9.8% > 15 days. What is new and conclusion The neurotoxicity induced by acyclovir and its derivative valacyclovir is a poorly known and rare adverse effect that can occur mainly in patients with advanced age and impaired renal function. The most characteristic symptoms are confusion, altered level of consciousness, hallucinations, agitation and dysarthria. The basis of treatment is the discontinuation of the antiviral, and in some cases, it may require additional clearance by dialysis.

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“…Severe HSV-1 infection is often associated with systemic distribution of HSV-1 ( 5 ). This may trigger an innate immune response ( 6 ), contribute to the severity of primary disease, cause organ damage ( 7 – 9 ) and increase the mortality of patients ( 5 ). Of note, HSV-1 DNA has been detected in up to 50% of intensive care unit patients, in particular in patients with sepsis or septic shock or with COVID-19 ( 10 – 15 ).…”

Section: Introductionmentioning

confidence: 99%

AMPK protects endothelial cells against HSV-1 replication via inhibition of mTORC1 and ACC1

Doshi,

Spengler,

Godbole

et al. 2023

Microbiol Spectr

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Herpes simplex virus type 1 (HSV-1) is a widespread contagious pathogen, mostly causing mild symptoms on the mucosal entry side. However, systemic distribution, in particular upon reactivation of the virus in immunocompromised patients, may trigger an innate immune response and induce damage of organs. In these conditions, HSV-1 may infect vascular endothelial cells, but little is known about the regulation of HSV-1 replication and possible defense mechanisms in these cells. The current study addresses the question of whether the host cell protein AMP-activated protein kinase (AMPK), an important metabolic sensor, can control HSV-1 replication in endothelial cells. We show that downregulation of the catalytic subunits AMPKα1 and/or AMPKα2 increased HSV-1 replication as monitored by TCID 50 titrations, while a potent AMPK agonist, MK-8722, strongly inhibited it. MK-8722 induced a persistent phosphorylation of the AMPK downstream targets acetyl-CoA carboxylase (ACC) and the rapamycin-sensitive adaptor protein of mTOR (Raptor) and, related to this, impairment of ACC1-mediated lipid synthesis and the mechanistic target of the rapamycin complex-1 (mTORC1) pathway. Since blockade of mTOR by Torin-2 as well as downregulation of ACC1 by siRNA also decreased HSV-1 replication, MK-8722 is likely to exert its anti-viral effect via mTORC1 and ACC1 inhibition. Importantly, MK-8722 was able to reduce virus replication even when added after HSV-1. Together, our data highlight the importance of endothelial cells as host cells for HSV-1 replication upon systemic infection and identify AMPK, a metabolic host cell protein, as a potential target for antiviral strategies against HSV-1 infection and its severe consequences. IMPORTANCE Herpes simplex virus type 1 (HSV-1) is a common pathogen that causes blisters or cold sores in humans. It remains latent in infected individuals and can be reactivated multiple times. In adverse conditions, for instance, in immunocompromised patients, HSV-1 can lead to serious complications such as encephalitis, meningitis, or blindness. In these situations, infection of endothelial cells lining the surface of blood vessels may contribute to the manifestation of disease. Here, we describe the role of AMP-activated protein kinase (AMPK), a potent regulator of cellular energy metabolism, in HSV-1 replication in endothelial cells. While downregulation of AMPK potentiates HSV-1 replication, pharmacological AMPK activation inhibits it by limiting the availability of required host cell macromolecules such as proteins or fatty acids. These data highlight the role of metabolic host cell proteins as antiviral targets and reveal activation of endothelial AMPK as a potential strategy to protect from severe consequences of HSV-1 infection.

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Trillions and Trillions: Herpes Simplex Virus–1 Hepatitis in an Immunocompetent Adult

Cited by 4 publications

References 11 publications

Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man

Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man

Neurotoxicity associated with acyclovir and valacyclovir: A systematic review of cases

AMPK protects endothelial cells against HSV-1 replication via inhibition of mTORC1 and ACC1

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