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.

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

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),^9–11 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

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.

FUNDAMENTALS OF VIRAL INFECTION, REPLICATION, AND PATHOGENESIS

Viruses may infect the human host via the placenta and birth canal, through ingestion of breast milk, by inhalation of airborne secretions, through contaminated food, by insect bite or inadvertent passage with intravascular injections, and by intimate or sexual contact. Ocular infection by viruses most often follows direct contact with virus externally from infected secretions in the birth canal (herpes simplex virus, HPV), on fomites (adenovirus), or airborne particles (rhinovirus), or is acquired during viremia (human cytomegalovirus, measles virus). Other mechanisms of ocular viral infection include extension from contiguous adnexal disease (herpes simplex virus), spread from the upper respiratory tract via the nasolacrimal duct (rhinovirus), and transplacental passage of infectious virus (rubella virus). Rarely, ocular infection may disseminate elsewhere (enterovirus 70).¹⁹ A classification of viruses infecting the human eye and adnexa is presented in Table 3.

TABLE 85-3. Classification of Viruses Affecting the Human Eye

The objective of infection for a virus is the generation of viral progeny. The synthesis of viral-encoded proteins is essential to the ability of the virus to replicate and determines the effect of viral infection on the cell. Although differences exist between enveloped and nonenveloped viruses in the mechanics of infection, the replicative cycle of all viruses can be summarized in six stages (Fig. 1):

1. Attachment
   
2. Penetration
   
3. Uncoating
   
4. Replication
   
5. Assembly
   
6. Release.
   

Host cell receptors may be protein, glycoprotein, lipid, or carbohydrate.²⁰ After adsorption, penetration occurs by endocytosis or translocation, or in the case of enveloped viruses, fusion of the envelope with the host plasma membrane. Virus capsid components play an active role in transport of the virus into the cell. Uncoating, or shedding of capsid components, typically occurs in the cell cytoplasm. Replication takes place in the nucleus for most DNA viruses and in the cytoplasm for most RNA viruses. Mechanisms of viral replication are summarized in Figure 2. Assembly of the virus, the process by which capsid is added to newly replicated genome, typically occurs in the cytoplasm. Release occurs by budding or lysis.

Transcription of viral nucleic acid to produce the enzymatic and structural proteins necessary for replication varies with the type of viral genome. With the exception of the positive-sense single-stranded picornaviruses, alphaviruses, and flaviviruses, it is necessary first to transcribe an mRNA. DNA viruses that replicate in the cell nucleus can use cell-derived polymerases; otherwise, generation of a viral-encoded RNA polymerase is required. Lastly, because eukaryotic host cells do not recognize internal initiation sites within mRNA molecules, posttranslational modifications of viral proteins by cellular or viral enzymes are often used to produce the individual proteins necessary for replication and maturation.

Assembly of infectious virus and subsequent release of virus from the cell are tightly linked processes and largely determine the outcome of infection. The assembly of nonenveloped viruses in the cell nucleus or cytoplasm typically exposes the cell to capsid components that may inhibit cellular function and cause cell death. To acquire envelopes, viruses encode proteins for insertion into host cell membranes that then act as binding targets for immature virions. Egress of the virus via budding sometimes leads to cell lysis (herpesviruses).

Viruses cause disease by a broad array of mechanisms, including altered cellular metabolism caused by viral gene products, altered host gene expression mediated by interactions between viral proteins and the host genome, and host immune response to viral infection of the cell. The end results of viral infection may be frank destruction of host tissues; disrupted function on cellular, tissue, organ, or systemic levels; recurrent disease from intermittent viral expression over time; neoplastic transformation; or immunologically mediated disease.

VIRAL IMMUNOPATHOGENESIS

Virus infections are limited by natural killer cells, B lymphocyte-derived antibodies, and effector T lymphocytes. Unlike B and T lymphocytes, natural killer cells act without antigen specificity or immunologic memory. Interferon-stimulated natural killer cells limit the extent of viral infection early on, before the machinery of acquired antigen-specific immunity has fully engaged. Additionally, activated natural killer cells attack cells with reduced MHC class 1 expression to counter viral evasion of MHC class 1 presentation (see below).

Antibodies neutralize free virus in blood or mucosal secretions. They also mediate cell death of infected cells through complement-mediated killing and by antibody-dependent cell-mediated cytotoxicity. Viral neutralization by antibody depends on recognition of viral epitopes present on virus surfaces such as envelope glycoproteins or, in the case of nonenveloped virus, surface capsid proteins. High quantities of virus-antibody immune complexes in the blood can induce immune complex-mediated immunopathology at distant tissue sites.

CD8+ cytotoxic T lymphocytes (CTLs) typically recognize viral epitopes in the context of MHC class 1 molecules expressed on the surface of virusinfected cells and are critical to the elimination of virus-infected cells. All nucleated cells express class 1 molecules, so any virus-infected cell may be a target for CTLs. Killing occurs through a directional release of perforin and granzymes with a minimum of bystander damage. However, stimulation of T-cell immunity may be accompanied by production of tumor necrosis factor and other cytokines that have deleterious effects at local and systemic levels.

Some viruses possess the means to evade the host's immune system. A herpes simplex virusencoded protein, ICP47, successfully competes with antigenic viral peptides for transport into the endoplasmic reticulum, where peptides are loaded onto the MHC complex.²¹ Thus, herpes simplex virus-infected cells can be resistant to CTL lysis. Similarly, human cytomegalovirus-encoded US11 dislocates MHC molecules into the cytosol, where they are degraded by cell proteases.²² These and other examples of the means by which ocular viruses may evade the immune system are presented in Table 4.

TABLE 85-4. Ocular Viruses and Molecular Means by Which They Evade Host Immunity

Certain viruses produce homologues of human proteins that can influence host immunity. Epstein-Barr virus encodes a homologue of human IL-10.²³ Expression of viral IL-10 by infected cells inhibits interferon-γ production and T-cell immunity and results in enhanced survival of virus-infected cells. Human herpesvirus 8 encodes a structural homologue of IL-6, suggested to influence the pathogenesis of Kaposi sarcoma.²⁴ Human cytomegalovirus encodes a homologue for a human chemokine receptor, providing the capacity to divert host cell-derived chemokines and thereby prevent inflammation and viral clearance.²⁵

Viral infections have been implicated in autoimmune disease induction by several mechanisms.²⁶ Some viruses stimulate polyclonal B-cell activation and lead to excessive deposition of immune complexes in sensitive tissues. The altered cytokine milieu associated with viral infection can stimulate autoreactive T cells, resulting in inadvertent damage to normal tissues. Inflammation of immunologically sequestered tissues, such as those in the central nervous system or the eye in the mature adult, could expose previously hidden epitopes and lead to local hyperimmunologic responsiveness, with devastating functional consequences. Finally, shared antigenic determinants between virus and host can lead in genetically susceptible persons to immunologic recognition of self-epitopes (molecular mimicry),²⁷ with immune-mediated damage at distant and ostensibly normal sites.

Viruses that infect the eye or its adnexa produce stereotypic pathologic changes in ocular target tissues. Infection of the eyelid skin by viruses typically induces the formation of vesicles and ulceration. Infection of the conjunctiva results in increased numbers of conjunctival lymphoid follicles and enlargement of the corresponding draining lymph nodes. Although clinical teaching traditionally emphasizes the disparity in appearance of epithelial keratitis with different viral etiologies, viral infection of the corneal epithelium invariably causes punctate epithelial cytopathic effect, evident biomicroscopically as isolated swollen epithelial cells (punctate epithelial keratitis) and loss of individual epithelial cells (punctate epithelial erosions). When extensive, the punctate erosions may coalesce to form confluent epithelial ulcers (dendritic, dendritiform, and geographic ulcers).²⁸ Corneal stromal infection results in white blood cell recruitment to the site of infection,²⁹ with resultant stromal infiltration. Retinal infection leads to retinal necrosis. Viral encephalitis, encephalomyelitis, and meningitis may lead to cranial nerve inflammation and dysfunction of vision or extraocular motility.

OUTCOMES OF VIRAL EYE INFECTION: LATENCY, CARCINOGENESIS, LOSS OF FUNCTION

Although many viruses cause self-limited infections with complete clearance of the virus, some persist indefinitely in the host. For example, adenoviruses persist within nasopharyngeal lymphoid tissue, Epstein-Barr virus in nasopharyngeal epithelial cells and B lymphocytes, herpes simplex and varicella zoster viruses in sensory ganglia, and HPV in skin and mucosal epithelia. Persistent infections may consistently or intermittently produce infectious virus. When not productive of infectious virus, the infection is said to be latent. In latent infections, only limited viral gene expression occurs. Interestingly, latent infection frequently occurs in cell types poorly permissive for lytic infection by the virus. Such is the case with sensory neurons and herpes simplex virus, B lymphocytes and Epstein-Barr virus, and basal skin epithelial cells and HPV. Latent infections tend to occur in slow-cycling cells. HPV and Epstein-Barr virus both persist as circular episomes within the cell nucleus andcan replicate as necessary to maintain themselves on cell division.

Persistent viral infection of susceptible cells can lead to malignant transformation. Viral proteins, whether directly through interaction with the host genome or by interaction with cellular proteins, can induce transformation of the cell and loss of senescence. Perhaps the most elegant example of tumor induction is by HPV.³⁰ HPV tropisms for skin and mucosa derive in part from tissue-specific gene expression.³¹ HPV types 6 and 11 are maintained in a latent state within basal epithelial cells as circular episomes with very limited viral gene transcription and low copy number. Early viral gene products stimulate cell growth and lead to a skin wart or a conjunctival papilloma. As basal epithelial cells containing HPV mature and differentiate into superficial epithelial cells, they become permissive for complete viral gene expression and produce infectious virus. Neoplastic transformation from HPV type 6 or 11 is rare. In contrast, HPV types 16 and 18 stereotypically integrate their viral genome into host chromosomal DNA, and this in turn has been strongly associated with malignant transformation and squamous cell carcinoma. In the episomal state, transcription of HPV proto-oncogenes E6 and E7 is effectively repressed by the HPV E2 gene product. When HPV genome integrates into host cell chromosomal DNA, the circular (episomal) viral DNA molecule breaks at a recombination site within the E2 open reading frame, resulting in a truncated E2 protein and disinhibition of E6 and E7 transcription. The E6 protein binds to and initiates the degradation of cellular p53 tumor suppressor gene. The E7 protein displaces cellular pRB from its complex with cellular E2F transcription factor. E2F then activates transcription of genes that initiate the cell cycle. Hence, increased cellular levels of E6 and E7 proteins contribute to the malignant phenotype of squamous epithelium infected with HPV types 16 and 18.

The results of viral infection depend on a complicated array of factors. The presence of viral receptors on host cells at a surface exposed to infectious virus, the permissiveness of the cell to the viral gene cycle, the capacity of the host to eliminate the virus balanced against the damage to host tissue caused by the immune response, and finally the fine function of the tissue all determine the functional and anatomic derangements associated with viral infection. For a virus like herpes simplex, tropic for almost all ocular tissues, the outcome of ocular infection varies with the tissue infected. Herpes simplex virus infection of the conjunctiva is self-limited and leaves no visual deficit, whereas infection of the corneal stroma may result in varying degrees of vision loss, and infection of the retina may result in complete loss of useful vision. In contrast, HPV ocular tropism is limited to the conjunctiva, limbus, and eyelid skin. Blinding sequela of HPV infection occurs with malignant transformation of infected tissues.

As classification of viruses proceeds on a molecular genetic level, the mechanisms by which viruses infect ocular cells, destroy critical ocular structures, evade the immune system, and induce cancer will be better understood.

1. Virus Taxonomy: 6th Report of the International Committee on Taxonomy of Viruses. Arch Virol Suppl 10:1, 1995

2. Murphy FA: Virus taxonomy. In Fields BN, Knipe DM, Howley PM et al (eds): Fields Virology, p. 15. Vol. 2, 3d ed. Philadelphia, Lippincott-Raven, 1996

3. Pringle CR: The order Mononegavirales. Arch Virol 117: 137, 1991

4. Harrison SC, Shehel JJ, Wiley DC: Virus structure. In Fields BN, Knipe DM, Howley PM et al (eds): Fields Virology, p. 59. Vol. 3, 3d ed. Philadelphia, Lippincott-Raven, 1996

5. Gan Y-J, Chodosh J, Largaespada D, Morgan A, Sixbey JW: Epithelial cell polarization is a determinant in the infectious outcome of immunoglobulin A—mediated entry by Epstein-Barr virus. J Virol 71:519, 1997

6. Gordon YJ, Gordon RY, Romanowski E, Araullo-Cruz TP: Prolonged recovery of desiccated adenoviral serotypes 5, 8, and 19 from plastic and metal surfaces in vitro. Ophthalmology 100:1835, 1993

7. Frade R, Barel M, Ehlin-Henriksson B, Klein G: gp140, the C3d receptor of human lymphocytes, is also the Epstein-Barr virus receptor. Proc Nat Acad Sci USA 82:1490, 1985

8. Nemerow GR, Wolfert R, McNaughton ME, Cooper NR: Identification and characterization of the Epstein-Barr virus receptor on human B lymphocytes and its relationship to the C3d complement receptor (CR2). J Virol 55:347, 1985

9. Greve JM, Davis G, Meyer AM et al: The major human rhinovirus receptor is ICAM-1. Cell 56:839, 1989

10. Staunton DE, Merluzzi VJ, Rothlein R, Barton R, Marlin SD, Springer TA: A cell adhesion molecule, ICAM-1, is the major surface receptor for rhinoviruses. Cell 56:849, 1989

11. Tomassini JE, Graham D, Dewitt CM, Lineberger DW, Rodkey JA, Colonno RJ: cDNA cloning reveals that the major group rhinovirus receptor on HeLa cells is intercellular adhesion molecule 1. Proc Natl Acad Sci USA 86:4907, 1989

12. Winther B, Greve JM, Gwaltney JM et al: Surface expression of intercellular adhesion molecule 1 on epithelial cells in the human adenoid. J Infect Dis 176:523, 1997

13. Bouchard CS, Lasky JB, Cundiff JE, Smith BS: Ocular surface upregulation of intercellular adhesive molecule-1 (ICAM-1) by local interferon-gamma (IFN-gamma) in the rat. Curr Eye Res 15:203, 1996

14. Evander M, Frazer IH, Payne E, Qi YM, Hengst K, McMillan NAJ: Identification of the α₆ integrin as a candidate receptor for papillomaviruses. J Virol 71:2449, 1997

15. Bergelson JM, Cunningham JA, Droguett G et al: Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science 275:1320, 1997

16. Wickham TJ, Mathias P, Cheresh DA, Nemerow GR: Integrins alpha_v beta₃ and alpha_v beta₅ promote adenovirus internalization but not virus attachment. Cell 73:309, 1993

17. Albrecht T, Boldogh I, Fons MP: Receptor-initiated activation of cells and their oncogenes by herpes-family viruses. J Invest Dermatol 98:S29, 1992

18. Bruder JT, Kovesdi I: Adenovirus infection stimulates the Raf/MAPK signaling pathway and induces interleukin-8 expression. J Virol 71:398, 1997

19. Higgins PG: Enteroviral conjunctivitis and its neurological complications. Arch Virol 73:91, 1982

20. Knipe DM: Virus-host cell interactions. In Fields BN, Knipe DM, Howley PM et al (eds): Fields Virology, p. 273. Vol. 10, 3d ed. Philadelphia, Lippincott-Raven, 1996

21. York IA, Roop C, Andrews DW, Riddell SR, Graham FL, Johnson DC: A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Cell 77: 525, 1994

22. Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL: The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84:769, 1996

23. Moore KW, Viera P, Fiorentino DF, Trounstine ML, Khan TA, Mosman TR: Homology of cytokine synthesis inhibitory factor (IL-10) to Epstein-Barr virus gene BCRFI. Science 248:1230, 1990

24. Neipel F, Albrecht J-C, Ensser A et al: Human herpesvirus 8 encodes a homolog of interleukin-6. J Virol 71:839, 1997

25. Chee MS, Satchwell SC, Preddie E, Weston KM, Barrell BG: Human cytomegalovirus encodes three G protein-coupled receptor homologues. Nature 344:774, 1990

26. Barnett LA, Fujinami RS: Molecular mimicry: A mechanism for autoimmune injury. FASEB J 6:840, 1992

27. Fujinami RS, Oldstone MBA: Amino acid homology between the encephalitogenic site of myelin basic protein and virus: Mechanism for autoimmunity. Science 230:1043, 1985

28. Chodosh J, Miller D, Stroop WG, Pflugfelder SC: Adenoviral epithelial keratitis. Cornea 14:167, 1995

29. Oakes JE, Monteiro CA, Cubitt CL, Lausch RN: Induction of interleukin-8 gene expression is associated with herpes simplex virus infection of human corneal keratocytes but not human corneal epithelial cells. J Virol 67:4777, 1993

30. Ahmed R, Morrison LA, Knipe DM: Persistence of viruses. In Fields BN, Knipe DM, Howley PM et al (eds): Fields Virology, p. 219. Vol. 8, 3d ed. Philadelphia, Lippincott-Raven, 1996

31. Steinberg BM, Auborn KJ, Brandsma JL, Taichman LB: Tissue site-specific enhancer function of the upstream regulatory region of human papillomavirus type 11 in cultured keratinocytes. J Virol 63:957, 1989

32. Shieh MT, WuDunn D, Montgomery RI, Esko JD, Spear PG: Cell surface receptors for herpes simplex virus are heparan sulfate proteoglycans. J Cell Biol 116:1273, 1992

33. WuDunn DW, Spear PG: Initial interaction of herpes simplex virus with cells is binding to heparan sulfate. J Virol 63:52, 1989

34. Comptom T, Nowlin DM, Cooper NR: Initiation of human cytomegalovirus infection requires initial interaction with cell surface heparan sulfate. Virology 193:834, 1993

35. Higa HH, Rogers GN, Paulson JC: Influenza virus hemagglutinins differentiate between receptor determinants bearing N-acetyl-N-glycollyl- and N-O-diacetylneuraminic acid groups. Virology 144:279, 1985

36. Weis W, Brown J, Cusack S, Paulson JC, Skehel JJ, Wiley DC: Structure of the influenza virus hemagglutinin complexed with its receptor, sialic acid. Nature 333:426, 1988

37. Eppstein DA, Marsh YV, Schreiber AB, Newman SR, Todaro GJ, Nestor JJ Jr: Epidermal growth factor receptor occupancy inhibits vaccinia virus infection. Nature 318: 663, 1985

38. Friedman HM, Cohen GH, Eisenberg RJ, Seidel CA, Cines DB: Glycoprotein C of herpes simplex virus 1 is an inhibitor of the complement cascade. Nature 309:633, 1984

39. Reyburn HT, Mandelbolm O, Vaels-Gomez M, Davis DM, Pazmany L, Strominger JL: The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 386:514, 1997

40. Levitskaya J, Coram M, Levitsky V et al: Inhibition of antigen presentation by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 375:685, 1995

41. Burgert H-G, Kvist S: An adenovirus type 2 glycoprotein blocks cell surface expression of human histocompatibility class I antigens. Cell 41:987, 1985

42. Gooding LR, Elmore LW, Tollefson AE, Brady HA, Wold WSM: A 14,700 mw protein from the E3 region of adenovirus inhibits cytolysis by tumor necrosis factor. Cell 53:341, 1988

43. Katze MG, Krug RM: Translational control in influenza virus-infected cells. Enzyme 44:265, 1990

44. Beattie E, Tartaglia J, Paoletti E: Vaccinia virus encoded elF-2 alpha homolog abrogates the antiviral effect of interferon. Virology 183:419, 1991