Introduction to Viruses in Ocular Disease: Definition, Structure, and Classification
James Chodosh
William G. Stroop
CONCEPTS AND DEFINITIONS
Viruses are small (10 to 400 microns in diameter) infectious units, each consisting of a nucleic acid genome and a protein capsid shell, with or without an external lipid envelope. Viruses lack the independent means for energy metabolism, molecular biosynthesis, or replication; only inside a permissive host cell are viral genes transcribed and viral progeny produced.
In 1966, the International Committee on Nomenclature of Viruses, later to become the International Committee on Taxonomy of Viruses (ICTV), set forth to classify the myriad of different viruses into groups. By agreement, virus orders are designated by the suffix –virales, families by –viridae, subfamilies by –virinae, and genera by –virus. Family members share a characteristic morphology, replicate in a similar fashion, and have relatively conserved nucleic acid sequences. The most recent report of the ICTV1 classified a total of 1 order, 71 families, 11 subfamilies, and 164 genera, including more than 4000 viruses.2 The only viral order so far designated, Mononegavirales, contains the families Filoviridae, Paramyxoviridae, and Rhabdoviridae. The viruses within this order express similar gene products and are thought to be phylogenetically related.3 As the genomic sequences of more viruses become known, some currently unclassifiable viruses may be placed and new phylogenetic relations appreciated.
CLASSIFICATION
The existence of communicable diseases from which no bacteria could be isolated led to the search for and eventual discovery of viruses. In the absence of any detailed knowledge of viruses beyond their associated clinical syndromes, initial schemes of viral classification grouped human viruses by the affected organ or other primarily clinical similarities. Thus, all viruses associated with hepatitis were grouped together. Although we now know that the hepatitis viruses are diverse, categorization of viruses by clinical criteria is still useful; clinicians create differential diagnoses based on constellations of clinical signs, possible modes of transmission, or specific target organs. Today, when presented with a possibly viral epidemic, epidemiologic clues such as the specific population infected, the geographic location, and the seasonal pattern of disease may allow a preliminary classification and assist in the selection of laboratory tests necessary to identify the virus.
Before the direct observation of viruses, early experiments showed that some infectious diseases could be transmitted by a filtrate of secretions from an infected animal using filter pore sizes small enough to exclude bacteria. Negative staining transmission electron microscopy now allows direct examination of virus size and morphology. Thin-section electron microscopy of infected tissues permits observation of events such as attachment, uncoating, replication, budding, and egress. In most cases, classification by ultrastructural appearance correlates with similarities in the genomic sequence. For example, the eight herpesviruses so far identified all have an identical electron microscopic appearance and a high degree of genomic homology. In generating a virus taxonomy, the ICTV considers multiple virus traits, including morphology, physical properties, nucleic acid type and strandedness, physical state of the genome, proteins expressed, antigenic properties, and serologic cross-reactivity, as well as biologic effects of infection.2 Viruses are then classified broadly by the type of nucleic acid, its strandedness (and if single-stranded, positive- or negative-sense), and the presence or absence of an external lipid bilayer envelope (Table 1).
TABLE 85-1. Classification of Virus Families by Nucleic Acid Type and Strandedness, and Presence of an Envelope | ||||||||||||||||||||||
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VIRAL STRUCTURE AND FUNCTION: IMPLICATIONS FOR PATHOGENESIS
VIRAL COMPONENTS
A virion is the entire viral infectious unit, including the nucleic acid, the capsid, and if present the envelope. Viral nucleic acids consist of either RNA or DNA. RNA viral genome may be either single- or double-stranded, and in the case of single-stranded viruses, either positive-sense (same polarity as mRNA) or negative-sense (opposite polarity to mRNA). Further, RNA viral genomes are either segmented, with discrete nucleic acid molecules, or nonsegmented, with all the genetic information on a single nucleic acid molecule. Finally, DNA and RNA genomes may be present either in a linear or circular (episomal) form. These characteristics of nucleic acid structure determine in large part the specific mechanics of viral replication.
The viral capsid is the protein shell that surrounds the viral nucleic acid. The capsid interacts internally with the genome to stabilize it, protects the genome from the external environment, and in the case of nonenveloped viruses, expresses on its surface the ligand for virus-host cell binding. The viral capsid proteins also assist in delivery of the viral genome to the intracellular site of viral replication. Thus, viral capsid structure is integrally related to many viral functions, in particular transmission, attachment, and entry into host target cells, but also virion assembly and egress. The capsid and nucleic acid together are referred to as the nucleocapsid. Occasionally, as with herpesviruses, the nucleocapsid is surrounded by an additional protein layer, the tegument.
Capsid structure is specified by the viral genome, and economy of genomic size frequently dictates a capsid of repeating protein subunits. Simplicity further dictates that subunits interact in symmetrical forms with conserved subunit interactions. Common capsid structural motifs include the icosahedron, with its 20 plane surfaces, and the helix.4 Electron microscopy and x-ray diffraction crystallography, in conjunction with nucleic acid and protein sequencing, are the principal techniques applied to delineation of capsid structure.
An envelope surrounds the capsid of some virus families. The envelope consists of viral genome-encoded glycoproteins embedded in a host cellderived lipid bilayer. Viral glycoproteins act as ligands (antigens) for neutralizing antibodies directed against the virus. In the initial stages of infection, envelope glycoproteins mediate attachment of the virus to its receptor on the host cell surface and fusion of the viral envelope with the host cell membrane. During viral replication, viral-encoded glycoproteins are targeted on a molecular level to specific membranes in the host cell to serve as sites of interaction between the viral nucleocapsid and the host cell membrane before budding. Cell membranes used by enveloped viruses include the nuclear envelope, endoplasmic reticulum, Golgi apparatus, and plasma membrane. Polarized epithelial cells, such as those found at mucosal surfaces, maintain tight intercellular junctions and possess biochemically and morphologically distinct apical and basolateral cell membranes. Because of differential targeting of viral glycoprotein into apical versus basolateral membranes, polarized cells typically release enveloped viruses from either the apical or basolateral cell surface. Virus shed apically into mucosal secretions such as the tear film creates the potential for transmission. Virus shed basolaterally may infect deeper tissues or disseminate.5
The viral envelope lipid bilayer is vulnerable to damage by ultraviolet light, detergents, alcohols, and general-use antiseptics. Enveloped viruses such as herpes simplex virus or human immunodeficiency virus are therefore intrinsically susceptible to the external environment. Nonenveloped viruses such as adenoviruses may be quite resistant to degradation, even under relatively harsh conditions.6
VIRAL TROPISMS: RECEPTOR BINDING AND EARLY EVENTS IN INFECTION
Viral tropisms for specific cell types and tissues are not random. Infection depends on the presence on the viral capsid surface (nonenveloped viruses) or envelope (enveloped viruses) of a ligand that can bind to a receptor on the target cell. Viral ligands are typically glycoproteins. Host cell virus receptors are diverse. Although viral ligand-host cell receptor interaction is essential for adsorption of the virus to the cell surface, the ligand receptor complex often also mediates subsequent internalization of the virus and uncoating of the capsid.
The polarized location of the virus receptor on epithelial tissues with distinct apical and basolateral cell surfaces and the changes in receptor expression during cell differentiation largely determine tissue susceptibility to infection in vivo. For example, virus receptor expression only on the basolateral surfaces of less differentiated epithelial cells would permit infection by virus presented across an underlying basement membrane, but not by virus present in mucosal fluids or on undamaged skin.
Viruses presumably evolved the capacity to bind existing constitutive host cell membrane components with essential primary cellular functions (Table 2). Therefore, binding of virus to a cell surface component subverts the natural function of that cellular molecule. For example, the B lymphocyte receptor for Epstein-Barr virus is the C3d complement receptor, CD21.7,8 Rhinoviruses bind to intercellular adhesion molecule-1 (ICAM-1),9,10,11 present on nasopharyngeal12 and conjunctival13 epithelial cells. Human papillomavirus (HPV) appears to bind the α6 component of the α6β4 integrin complex.14 Adenovirus type 2 uses the CAR protein for attachment15 and an integrin for internalization.16
TABLE 85-2. Selected Ocular Viruses and Their Possible Receptors | ||||||||||||||||
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In a classic lytic viral infection, virus replication diverts cellular protein production machinery over to the synthesis of viral proteins. However, before shutdown of host macromolecular synthesis, the cell may respond to viral infection by upregulation of specific genes. For instance, binding of cytomegalovirus to cells in vitro stimulates production of proto-oncogenes.17 Adenovirus binding stimulates the rapid induction of host cell-derived proinflammatory cytokines by the Raf/MAPK signal transduction pathway.18 The nonviral cellular function of the host cell virus receptor probably influences the initial molecular response to infection.
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