An Inquiry into the Molecular Basis of HSV Latency and Reactivation

Roizman, Bernard; Whitley, Richard J.

doi:10.1146/annurev-micro-092412-155654

Cited by 189 publications

(197 citation statements)

References 71 publications

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“…LAT is a stable intron derived from a much longer precursor RNA (pLAT) (3,6). In a fraction of neurons infected with HSV-1, the virus reactivates and is transported anterograde to a site at or near the portal of entry, where it replicates and becomes available for transmission to another individual by physical tissue contact (7,8). Knowledge is scant regarding the mechanisms by which HSV-1, a potentially virulent virus, can remain silent in neurons for the life of the host or reactivate from latency.…”

mentioning

confidence: 99%

Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia

Shu

Zhou

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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A key property of herpes simplex viruses (HSVs) is their ability to establish latent infection in sensory or autonomic ganglia and to reactivate on physical, hormonal, or emotional stress. In latently infected ganglia, HSVs express a long noncoding RNA, a latency-associated transcript (LAT), which plays a key role in maintaining latently infected neurons, but not viral proteins. To investigate the events leading to reactivation, we examined the use of ganglionic organ cultures that enable rapid reactivation in medium containing antibody to nerve growth factor (NGF) or delayed reactivation in medium containing NGF and epidermal growth factor (EGF). Here we report the discovery that activating transcription factor 3 (ATF3), a stress response protein, profoundly affects the interaction of HSV with its host. Specifically, (i) ATF3 is induced by stress, such as inhibition of protein synthesis or infection; (ii) in infected cells, ATF3 enhances the accumulation of LAT by acting on the response elements in the promoter of the LAT precursor RNA; (iii) ATF3 is induced nearly 100-fold in ganglionic organ cultures; and (iv) ATF3 plays a key role in the maintenance of the latent state, inasmuch as expression of ATF3 bereft of the C-terminal activation domain acts as a dominant negative factor, inducing HSV gene expression in ganglionic organ cultures harboring latent virus and incubated in medium containing NGF and EGF. Thus, ATF3 is a component of a cluster of cellular proteins that together with LAT maintain the integrity of the neurons harboring latent virus.

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mentioning

confidence: 99%

Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia

Shu

Zhou

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…17 Periodically, dormant HSV-1 may reactivate from latency, and virus particles are then transported along sensory neurons to the skin or other mucosa, causing recurrent HSL. 18 Although HSV-1 allows itself to be silenced in neurons, reactivated virus may prevail by overcoming various host defenses 19 to cause disseminated disease, 18,20 which will be discussed later. An important cellular defense mechanism against HSV-1 infection is the lysosome degradation pathway of autophagy, which constitutes a quality control of intracellular entities of eukaryotic cells.…”

Section: Herpes Simplex Virus Type-1 Primary Infectionmentioning

confidence: 99%

Autophagy interaction with herpes simplex virus type-1 infection

O’Connell

Liang

2016

Autophagy

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More than 50% of the U.S. population is infected with herpes simplex virus type-I (HSV-1) and global infectious estimates are nearly 90%. HSV-1 is normally seen as a harmless virus but debilitating diseases can arise, including encephalitis and ocular diseases. HSV-1 is unique in that it can undermine host defenses and establish lifelong infection in neurons. Viral reactivation from latency may allow HSV-1 to lay siege to the brain (Herpes encephalitis). Recent advances maintain that HSV-1 proteins act to suppress and/or control the lysosome-dependent degradation pathway of macroautophagy (hereafter autophagy) and consequently, in neurons, may be coupled with the advancement of HSV-1-associated pathogenesis. Furthermore, increasing evidence suggests that HSV-1 infection may constitute a gradual risk factor for neurodegenerative disorders. The relationship between HSV-1 infection and autophagy manipulation combined with neuropathogenesis may be intimately intertwined demanding further investigation.

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“…Herpes simplex virus type 1 (HSV-1) establishes lifelong latency within sensory neurons and can periodically reactivate to facilitate virus shedding at peripheral sites, often asymptomatically (Roizman & Whitley, 2013;Wagner & Bloom, 1997). Much has been learnt from small animal models of herpes simplex virus (HSV) latency both at the molecular and immunological level (Efstathiou & Preston, 2005;Nicoll et al, 2012b;Wagner & Bloom, 1997) but our understanding of latency within single neurons in vivo has been hampered by the lack of amenable systems to identify and isolate live cells from the infected host.…”

Section: Introductionmentioning

confidence: 99%

Analyses of herpes simplex virus type 1 latency and reactivation at the single cell level using fluorescent reporter mice

Proença

Nelson

Nicoll

et al. 2016

Journal of General Virology

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Herpes simplex virus type 1 (HSV-1) establishes a latent infection in sensory neurons from which the virus can periodically reactivate. Whilst latency establishment is thought to result from a failure to express immediate-early genes, we have previously shown that subpopulations of the latent neuronal reservoir have undergone lytic promoter activation prior to latency establishment. In the present study, we have investigated the biological properties of such latently infected neuronal subpopulations using Ai6 fluorescent reporter mice. Using this system we have determined that prior ICP0 or TK promoter activation does not correlate with increased latent virus DNA loads within individual cells and that neurons with evidence of historical lytic cycle promoter activity exhibit a comparable frequency of reactivation to that of the general latent cell population. Comparison of viral DNA content within cells harbouring latent HSV-1 genomes and those undergoing the earliest stages of reactivation has revealed that reactivation can initiate from cells harbouring a wide range of HSV-1 genome copies, but that exiting latency is biased towards cells bearing higher latent virus DNA loads.

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An Inquiry into the Molecular Basis of HSV Latency and Reactivation

Cited by 189 publications

References 71 publications

Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia

Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia

Autophagy interaction with herpes simplex virus type-1 infection

Analyses of herpes simplex virus type 1 latency and reactivation at the single cell level using fluorescent reporter mice

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