Research Article

Structure of the herpes simplex virus 1 capsid with associated tegument protein complexes

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Science  06 Apr 2018:
Vol. 360, Issue 6384, eaao7298
DOI: 10.1126/science.aao7298

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Focusing in on herpesvirus

The herpesvirus family includes herpes simplex virus type 1 (HSV-1), which causes cold sores, and type 2 (HSV-2), which causes genital herpes. Herpesviruses comprise a large DNA genome enclosed in a large and complex protein cage called a capsid (see the Perspective by Heldwein). Dai and Zhou used electron microscopy to determine a high-resolution structure of the HSV-1 capsid bound to the tegument proteins that occupy the space between the capsid and the nuclear envelope. The structure suggests how these components may play a role in viral transport. Yuan et al. describe a higher-resolution structure of an HSV-2 capsid, providing insight into how the shell assembles and is stabilized.

Science, this issue p. eaao7298, p. eaao7283; see also p. 34

Structured Abstract

INTRODUCTION

Since Hippocrates first described the cutaneous spreading of herpes simplex lesions, many other diseases—chickenpox, infectious mononucleosis, nasopharyngeal carcinoma, and Kaposi’s sarcoma—have been found to be associated with the nine known human herpesviruses. Among them, herpes simplex virus type 1 (HSV-1, causes cold sores), type 2 (HSV-2, causes genital herpes), and varicella-zoster virus (causes chickenpox and shingles)—which all belong to the α-herpesvirus subfamily—can establish lifelong latent infection within our peripheral nervous system.

RATIONALE

A prominent feature of these neurotropic viruses is the long-range (up to tens of centimeters) axonal retrograde transport of the DNA-containing viral capsid from nerve endings at sites of infection (such as the lips) to neuronal cell bodies at the ganglia to establish latency or, upon reactivation, anterograde transport of the progeny viral particles from the ganglia to nerve terminals, resulting in reinfection of the dermis. Capsid-associated tegument complexes (CATCs) have been demonstrated to be involved in this cytoskeleton-dependent capsid transport. Because of the large size (~1300 Å) of HSV-1 particles, it has been difficult to obtain atomic structures of the HSV-1 capsid and CATC; consequently, the structural bases underlying α-herpesviruses’ remarkable capability of long-range neuronal transport and many other aspects of its life cycle are poorly understood.

RESULTS

By using cryo–electron microscopy, we obtained an atomic model of the HSV-1 capsid with CATC, comprising multiple conformers of the capsid proteins VP5, VP19c, VP23, and VP26 and tegument proteins pUL17, pUL25, and pUL36. Crowning every capsid vertex are five copies of heteropentameric CATC. The pUL17 monomer in each CATC bridges over triplexes Ta and Tc on the capsid surface and supports a coiled-coil helix bundle of a pUL25 dimer and a pUL36 dimer, thus positioning their flexible domains for potential involvement in nuclear egress and axonal transport of the capsid. The single C-terminal helix of pUL36 resolved in the CATC links the capsid to the outer tegument and envelope: As the largest tegument protein in all herpesviruses and essential for virion formation, pUL36 has been shown to interact extensively with other tegument proteins, which in turn interact with envelope glycoproteins. Architectural similarities between herpesvirus triplex proteins and auxiliary cementing protein gpD in bacteriophage λ, in addition to the bacteriophage HK97 gp5–like folds in their major capsid proteins and structural similarities in their DNA packaging and delivery apparatuses, indicate that the commonality between bacteriophages and herpesviruses extends to their auxiliary components. Notwithstanding this broad evolutionary conservation, comparison of HSV-1 capsid proteins with those of other herpesviruses revealed extraordinary structural diversities in the forms of domain insertion and conformation polymorphism, not only for tegument interactions but also for DNA encapsulation.

CONCLUSION

Our structure of the HSV-1 capsid with capsid-associated tegument proteins provides mechanistic insights into multiple aspects of the viral life cycle, including capsid assembly, nuclear egress, acquisition of tegument and envelope, and axonal transport in neuronal cells. The numerous molecular interactions and atomic details embodied in the structure make it a much-sought-after atlas for the search of antivirals targeting these critical steps of HSV-1 lytic replication.

Structure of the HSV-1 capsid with capsid-associated tegument proteins.

Surface view of a 4.2-Å resolution map of the icosahedral capsid, with a single facet shown in color. The structure of the vertex region (magnified view) was improved to 3.5-Å resolution by subparticle refinement. P, peripentonal; C, center; E, edge; Ta to Te, heterotrimeric triplexes composed of Tri1, Tri2A, and Tri2B.

Abstract

Herpes simplex viruses (HSVs) rely on capsid-associated tegument complex (CATC) for long-range axonal transport of their genome-containing capsids between sites of infection and neuronal cell bodies. Here we report cryo–electron microscopy structures of the HSV-1 capsid with CATC up to 3.5-angstrom resolution and atomic models of multiple conformers of capsid proteins VP5, VP19c, VP23, and VP26 and tegument proteins pUL17, pUL25, and pUL36. Crowning every capsid vertex are five copies of heteropentameric CATC, each containing a pUL17 monomer supporting the coiled-coil helix bundle of a pUL25 dimer and a pUL36 dimer, thus positioning their flexible domains for potential involvement in nuclear capsid egress and axonal capsid transport. Notwithstanding newly discovered fold conservation between triplex proteins and bacteriophage λ protein gpD and the previously recognized bacteriophage HK97 gp5–like fold in VP5, HSV-1 capsid proteins exhibit extraordinary diversity in forms of domain insertion and conformational polymorphism, not only for interactions with tegument proteins but also for encapsulation of large genomes.

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