A cultured affair: HSV latency and reactivation in neurons

doi:10.1016/j.tim.2012.08.005

Trends in Microbiology

Volume 20, Issue 12, December 2012, Pages 604-611

https://doi.org/10.1016/j.tim.2012.08.005 Get rights and content

After replicating in surface epithelia, herpes simplex virus type-1 (HSV-1) enters the axonal terminals of peripheral neurons. The viral genome translocates to the nucleus, where it establishes a specialized infection known as latency, re-emerging periodically to seed new infections. Studies using cultured neuron models that faithfully recapitulate the molecular hallmarks of latency and reactivation defined in live animal models have provided fresh insight into the control of latency and connections to neuronal physiology. With this comes a growing appreciation for how the life cycles of HSV-1 and other herpesviruses are governed by key host pathways controlling metabolic homeostasis and cell identity.

Section snippets

Herpesviruses rely on latency for long-term persistence

All herpesviruses use two contrasting infection strategies: productive (or lytic) replication and latency, constituting fundamentally different viral gene expression programs with contrary goals and outcomes. Latency maintains the viral genome for long periods without producing infectious progeny, but allows the virus to re-engage in productive replication, a process known as reactivation. This ensures long-term persistence as well as dissemination to new host cells or organisms. During latency

Establishment and maintenance of latency

The sensory neurons of the trigeminal ganglia (TG) innervate the lips, gingiva, and eyes, and are the principal site for HSV-1 latency in humans, although sympathetic and sensory neurons from the vestibular, geniculate, spiral, and sacral ganglia are also documented sites 2, 3. Viruses access the neurons through axon terminals and release the capsid, containing the viral linear double-stranded DNA genome, into the cytoplasm (Figure 1a). From there, the genome is transported over a comparatively

Reactivation: a race to the finish with multiple hurdles

To reactivate, a latent episome must extensively reorganize its chromatin, ensure that levels of IE gene expression are sufficient to overcome the virus-encoded miRs, and contend with antagonistic host responses. For every HSV-1 genome that produces infectious progeny, it is likely that a greater number will have begun the process but failed at some point. As viral activity increases, the likelihood of a strong counter-response from the host grows, and progression to each successive stage may

Importance of an active signaling program to maintain latency in neurons

It has been known for more than a century that applying trauma to a nerve to treat chronic pain (trigeminal neuralgia) can elicit an outbreak of herpetic lesions in the associated dermatome [62]. This eventually led to the realization that sensory ganglia are the source of reactivating virus, and that reactivation is most likely is due to loss of trophic support. Neurotrophins are growth factors that function in the nervous system to promote survival, proliferation, differentiation, axonal

Peeling back the layers of host control

Environmental triggers that cause HSV-1 reactivation in people include emotional stress, fever, UV exposure, hormonal changes, dental surgery, and cranial trauma. Whether these stimuli act directly on the infected neuron, or through some of many other cell types present in the ganglion, is unknown. The emerging consensus is that latency is intrinsic to neurons but that, in the context of a living host, there are additional inputs or layers that involve other cell types (Figure 2). Ganglia are

Concluding remarks

Many aspects of latency and reactivation need to be explored further (Box 1), and this will undoubtedly benefit from the increasing acceptance of cultured neuron models. The lack of simple methods to detect latent virus in live cells has made it particularly difficult to study the temporal or spatial relationships between known events. Do viruses first replicate in the neurons that support latency, explaining the presence of multiple episomes? Do all genomes engage in active lytic gene

Acknowledgments

This is a very active field with an extensive literature and we apologize to our many colleagues whose findings could not be cited directly. Work performed in our laboratories was supported by grants from the National Institutes of Health (AI073898, GM61139, S10RR017970, T32AI007647, and T32AI07180), the Vilcek Foundation, and a collaborative project grant from the New York University Langone Medical Center.

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Trends in Microbiology

ReviewA cultured affair: HSV latency and reactivation in neurons

Section snippets

Herpesviruses rely on latency for long-term persistence

Establishment and maintenance of latency

Reactivation: a race to the finish with multiple hurdles

Importance of an active signaling program to maintain latency in neurons

Peeling back the layers of host control

Concluding remarks

Acknowledgments

Biochim. Biophys. Acta

Virology

Mol. Cell

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Mol. Cell

Cell

Vaccine

Cell Host Microbe

Trends Biochem. Sci.

Cell

Mol. Cell

Curr. Opin. Neurobiol.

Mol. Immunol.

Cell Host Microbe

Cell Stem Cell

Herpesvirus infections of the nervous system

Nat. Clin. Pract. Neurol.

Latent herpes simplex virus type 1 in human vestibular ganglia

Acta Otolaryngol. Suppl.

Isolation of latent herpes simplex virus from the superior cervical and vagus ganglions of human beings

N. Engl. J. Med.

Entry of herpes simplex virus type 1 (HSV-1) into the distal axons of trigeminal neurons favors the onset of nonproductive, silent infection

PLoS Pathog.

An inquiry into the mechanisms of herpes simplex virus latency

Annu. Rev. Microbiol.

ICP0 is required for efficient reactivation of herpes simplex virus type 1 from neuronal latency

J. Virol.

Evidence that the herpes simplex virus type 1 ICP0 protein does not initiate reactivation from latency in vivo

J. Virol.

During latency, herpes simplex virus type 1 DNA is associated with nucleosomes in a chromatin structure

J. Virol.

Herpes simplex virus latency-associated transcript is a stable intron

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

MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs

Nature

The relationship of herpes simplex virus latency associated transcript expression to genome copy number: a quantitative study using laser capture microdissection

J. Neurovirol.

The herpes simplex virus type 1 latency associated transcript locus is required for the maintenance of reactivation competent latent infections

J. Neurovirol.

Influence of herpes simplex virus 1 latency-associated transcripts on the establishment and maintenance of latency in the ROSA26R reporter mouse model

J. Virol.

Viruses, microRNAs, and host interactions

Annu. Rev. Microbiol.

An acutely and latently expressed herpes simplex virus 2 viral microRNA inhibits expression of ICP34.5, a viral neurovirulence factor

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

Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease

Nat. Rev. Neurosci.

The abundant latency-associated transcripts of herpes simplex virus type 1 are bound to polyribosomes in cultured neuronal cells and during latent infection in mouse trigeminal ganglia

J. Virol.

The stable 2-kilobase latency-associated transcript of herpes simplex virus type 1 can alter the assembly of the 60S ribosomal subunit and is exported from nucleus to cytoplasm by a CRM1-dependent pathway

J. Virol.

Identification of herpes simplex virus type 1 proteins encoded within the first 1.5 kb of the latency-associated transcript

J. Neurovirol.

Chromatin control of herpes simplex virus lytic and latent infection

Nat. Rev. Microbiol.

Checkpoints in productive and latent infections with herpes simplex virus 1: conceptualization of the issues

J. Neurovirol.

Transcription of the herpes simplex virus latency-associated transcript promotes the formation of facultative heterochromatin on lytic promoters

J. Virol.

Herpesviral latency-associated transcript gene promotes assembly of heterochromatin on viral lytic-gene promoters in latent infection

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

Specific histone tail modification and not DNA methylation is a determinant of herpes simplex virus type 1 latent gene expression

J. Virol.

The Polycomb complex PRC2 and its mark in life

Nature

Epigenetic analysis of KSHV latent and lytic genomes

PLoS Pathog.

Review
A cultured affair: HSV latency and reactivation in neurons