Chapter 98
Host Defense and Immunologic Responses Associated With Viral Ocular Infections
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Because viruses must depend on host cell genetic and biosynthetic capabilities, outright killing of infected cells is not in the best long-term interest of any virus. Likewise, virus-infected cells express a variety of virus-specified proteins and glycoproteins that may initiate nonimmune and immune mechanisms that lead to the destruction of such cells. Again, this is not beneficial for the survival of the virus. Three viruses that infect many people, cause ocular infections, evoke immunologic responses, and have developed a variety of mechanisms that appear to ensure their continued presence in humans, and the current knowledge about immune responses associated with ocular viral infections will be discussed in this chapter.

The establishment of latency has enabled members of the herpesvirus family to survive within an infected person. It is becoming increasingly clear that viruses have the ability to redirect the biosynthetic machinery of an infected cell to help avoid destruction by inflammatory and other immune-directed responses. For example, during their lifetime, most persons are infected with cytomegalovirus (CMV, 60% to 80%), herpes simplex virus (HSV, 50% to 80%), and varicella-zoster virus (VZV, up to 100%)1–3; however, many persons do not manifest a significant illness at the time of primary infection, and only a few go on to develop a recurrent infection such as HSV corneal dendritic infection, VZV keratitis, or CMV retinitis. From these epidemiologic observations, it seems reasonable to conclude that these three viruses (and probably most others) have developed mechanisms that allow their successful use of infected host cell biosynthetic mechanisms, promote successful establishment of latency, and, under most circumstances, minimize infected host cell destruction by inflammatory and immune mechanisms. By the same token, the host, in its quest for survival, has developed mechanisms to recognize infected and transformed cells and destroy them. At most sites of viral infection there is inconsequential concomitant inflammatory damage to adjacent cells and tissues. The cornea, retina, and central nervous system are exceptions. In these sites, tissue destruction from direct viral effects or immune-mediated inflammatory responses may cause significant adverse functional consequences. In these tissues, immune responses appear to be modulated to minimize such damage. For example, the central corneal epithelium is devoid of immunologically important dendritic Langerhans cells.4 The down-regulation of immune responses after the intercameral introduction of antigen by the phenomenon known as anterior chamber associated immune deviation (ACAID) is likely an adaptation of nature to protect ocular structures from damage during immune responses.5

In the clinical management of ocular viral diseases, there are several challenges, including recognition of the viral agent, selection of an antiviral drug that either kills or prevents further growth of the virus, and use of therapies that modulate the local inflammatory processes to prevent irreversible damage, scarring, or neovascularization. These disease manifestations represent the extremes of the biologic processes that continually operate to allow these viruses to persist in nature.

Especially in humans, there are few opportunities to study the immunopathogenesis of ocular viral infections, mild or severe. As a result, many of the hypotheses regarding immunopathogenesis are based on the findings, and often the late stages, of the most severe human infections. These opportunities provide useful information but may not be representative of the most critical immunopathologic events occurring early in the clinical episode as the up-regulation of the immune and inflammatory pathways is initiated. Likewise, nonhuman animal models may provide incomplete or misleading information because human strains of HSV, CMV, and VZV do not ordinarily infect nonhuman species. Despite all of these limitations, this chapter will use and synthesize observations from human and experimental animal research to provide an idea of the inflammatory mechanisms and the immunopathogenesis of ocular infections caused by HSV, CMV, and VZV.

All three viruses are DNA viruses and are members of the herpesvirus family. Each causes significant ocular damage that may result in visual loss through a combination of direct viral effects and significant host inflammatory responses. This chapter focuses on the cellular and subcellular activities that accompany these infections and provide the biologic basis for the clinical manifestations and responses to therapy. In all inflammatory responses involving the eye, the roles of adhesion molecules expressed by various cell types (which, in turn, mediate accumulations of immune and inflammatory cells) and the roles of soluble cytokines released by a variety of cells under particular situations to act upon themselves and other cells in the immediate area are being elucidated. This evolving body of information is supplanting and enhancing the understanding of classical humoral and cellular immune responses that has been achieved over the past half century.

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The outcome of virus penetration into a given cell depends on the biologic behavior of the virus in that particular cell type. A virus can cause lysis of the infected cell with liberation of more infectious virus; it can become integrated into the biochemical and structural components of the infected cell, causing alteration or transformation; or it can persist within the cell without killing it or initiating a host immunologic response. These biologic variables can have a pronounced effect on the type and magnitude of the host immune response during a viral infection.

The mechanisms of spread of viruses from the originally infected cells to other susceptible cell types helps determine how and to what extent the host immune system is exposed to the virus and viral antigens. The mechanisms of spread include lysis of the cell and release of infectious particles into extracellular spaces, budding of viruses from infected cell surfaces into the extracellular spaces, and cell-to-cell spread without entry into any extracellular spaces. Another important biologic characteristic of different viruses is the mechanism(s) by which they present antigenic sites to the host immune system. Intact viruses are rarely presented to the immune system except during the viremic stage of primary infections. There are, however, a number of ways viruses can express antigenicity in a host. Among the types of presentations of viral antigens are whole virus or portions of virus, virus-specific proteins separate from the virus itself, a combination of host cell and viral antigens, and virus-altered host cell antigens. Any of these forms of antigen can be glycosylated by host enzymes to cause further alterations in the antigens. Thus, any viral infection may result in the presentation of a mosaic of antigens to the immune system.

Viremia may occur early in a primary infection, and the host response may be stimulated by various subunits of the whole virus. The initial host responses are mostly nonspecific and do not require immunologic memory. Usually the virus resides within infected cells and antigens are presented to the immune system in that context. The requirement for close proximity of the viral antigen and host major histocompatibility complex (MHC) antigens on the cell surface of antigen-presenting cells is critical.6

The composition of chemical antigens has been well studied.7 The most potent antigens are macromolecular proteins with a molecular weight of 100,000 daltons or more. Polysaccharides may be antigenic. Because a single macromolecule may have a few or many individual antigenic determinants, each composed of four to six amino acid or sugar residues, the possible number of antigenic determinants on a microorganism is great. The specific antigens recognized by the immune system may have a significant bearing on the nature of the host immune response and the clinical manifestations. Viruses may also infect and proliferate within cells of the immune system, including macrophages and B and T lymphocytes. These interactions may play an important role in immune responses to viral infections. For example, macrophages often play a vital role in the successful control of viral infections.8 However, macrophages are among the cell types involved in certain infections, and their involvement appears to play a role in the clinical course of infections such as those caused by lymphocytic choriomeningitis virus in mice and Aleutian disease virus in mink.9

There are also interactions between the immune system and latently infected host cells. These cells may have few or no virus-specific antigens on the cell surface; however, there is usually evidence of humoral and cellular immunity, and these play a role in controlling the number of cells that are latently infected. In immunocompetent mice with latent HSV infection, for example, 0.1% of dorsal root ganglion cells are infected. In immunocompromised mice, approximately 7% of these cells are infected.10 Thus, at some point even latently infected cells appear to express viral antigens in some manner that allows modulation of this aspect of infection by the immune system. All of these biologic responses help to control and eliminate viruses.

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In the evolutionary struggle between viruses and host immunologic responses, viruses have adopted clever ways to ensure their survival. The threats to the continued existence of viruses are multifaceted. Once a virus has infected a cell and cellsurface viral peptides are displayed in conjunction with class I MHC molecules, the virus must somehow elude antigen-specific cytotoxic T lymphocytes (CTLs) and by some mechanism(s) inactivate cytokines with antiviral or proinflammatory properties. Among the more obvious tactics is antigenic drift, which is a notable characteristic of varying strains of influenza viruses that, as a result, require new vaccines each year. Another tactic is for the virus to interrupt or modify viral antigen presentation and inhibit the initiation of immune responses. As an example of antigen modification of the immune response, one CMV protein has approximately 20% homology with the amino acid sequence of the variable portion of class I MHC antigen, and this CMV peptide blocks the transport of the class I MHC heterodimers to the cell surface.11 This results in defective antigen presentation to CTLs. Viruses may also redirect the production of cytokines to enhance their chances for survival. Another member of the herpesvirus family, Epstein-Barr virus, has a gene region that encodes a fully functional homologue of the anti-inflammatory cytokine IL-10.12 An additional strategy for the survival of both HSV and CMV is the interference with CTL recognition of virus-infected cells by a decrease in the surface expression of class I MHC on these cells.13,14

Knowledge regarding the range of possible adaptations by viruses is just unfolding, and it will be some time before the mechanisms within ocular tissues are elucidated. The reader is cautioned not to overinterpret papers reporting the expression of a particular cytokine in a tissue and the assignment of some specific function to it. The dynamic interactions among cytokines may not be accounted for in the search for a single cytokine or its receptor in a particular tissue.

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The hallmark of an immune response is its antigen specificity. The genetic control of immune responses resides with the genes in the immunoglobulin superfamily, which contains at least four families of proteins with similar molecular folding. These are involved in effective immune responses to specific antigens, including viruses. First, MHC glycoproteins are expressed on the surface of most nucleated cells, and antigen is displayed to cells of the immune system in conjunction with these glycoproteins. Second, T-cell receptor (TCR) proteins are expressed on the surface of T lymphocytes and recognize foreign antigen that is presented along with the MHC glycoproteins. Third, there are other TCR proteins that are required for T-lymphocyte function but are not antigen specific. Fourth, immunoglobulins (Igs) are produced by B lymphocytes and are responsible for specific antigen recognition in humoral immune mechanisms.

Characteristics of the presented antigen help determine the relative intensities of cellular and humoral immune responses. Other important determinants are the site of antigen presentation and the genetic makeup of the host. For example, some strains of HSV are more likely than others to cause the expression of high amounts of a particular envelope glycoprotein, glycoprotein D. Those with the greatest amounts of glycoprotein D cause the most severe stromal keratitis.15,16 However, viral nucleoproteins and polymerases, in addition to glycoproteins, can serve as antigens to initiate cellular immune responses.17 The type and intensity of the immune response against a particular virus are also influenced by the characteristics of the antigenpresenting cell and the class of MHC antigen that is adjacent to the viral antigen. For example, HSV antigen presented by corneal Langerhans cells plays a critical role in the activation of CD4 but not CD8 lymphocytes.18 In general terms, class I MHC molecules, which are polymorphic and widely expressed, present antigens to CD8 lymphocytes, which are predominantly CTLs, and the antigens have usually been synthesized within the presenting cell. In contrast, class II MHC molecules, which are less polymorphic and more restricted in expression, present antigens to CD4 lymphocytes, which typically function as helper cells, and the antigens are usually the product of the processing of soluble proteins by specialized antigen-presenting cells.

Virus-specific CTLs play a crucial role in the immune responses once they are generated (approximately 7 days after the onset of a primary infection and more rapidly after a secondary infection). These CTLs help in the elimination of virus and in the initiation and maintenance of inflammation in tissues such as the cornea. There are major CTL responses in humans to proteins expressed immediately upon infection with CMV, VZV, or HSV. Antigen-specific recognition by way of the TCR is followed by a series of activities, including signal transduction that leads to the calcium-dependent release of perforin from cytoplasmic granules of CTLs and the resultant lysis of an infected cell.

Natural killer (NK) cells look like large granular lymphocytes and mediate lysis of virus-infected cells early in an infection, with activity peaking by the third postinfection day. Interferon released in response to the viral infection elevates the cytotoxicity of NK cells. The killing mediated by NK cells is not characterized by conventional immunologic specificity. However, this early response is beneficial for the period before the generation of virus-specific CTLs.

Another type of cell-mediated immune response that can be demonstrated in vitro is called antibody-dependent cell-mediated cytotoxicity (ADCC). Either CTLs or NK cells can be effector cells. The virus-infected cell is coated with specific antibody, typically IgG, and after cell-cell attachment the target cell is killed. The role of ADCC in vivo is not clear.

The humoral immune effector mechanisms occur after a B cell is presented antigen by way of its receptor, which is a membrane-bound immunoglobulin. After this, the B cell differentiates into a mature plasma cell and produces antibodies specific for virus antigen. They are likely to be of the IgG or IgA classes, except for early in the response, when IgM antibodies may predominate. Specific antibodies from all three classes are capable of neutralizing the infectivity of the target virus. In addition, complexes of viruses and viral antigens with specific antibodies enhance phagocytosis by neutrophils and mononuclear cells. Complement also enhances the neutralization of viruses.

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In responding to viral infections, the effector cells need to gain access to specific sites of tissue involvement. The roles of cellular adhesion molecules and cytokines in the immune responses of viral infections and in the immunopathology occurring in infected tissues are in the process of being determined. These are vital issues for improved clinical management of viral infections and control of the concomitant tissue damage associated with the ensuing inflammation. Most general immunology textbooks provide reviews of these subjects. The emphasis in this section is on the probable roles of cellular adhesion molecules and cytokines in ocular tissues.

Cellular adhesion molecules are now recognized as an important characteristic that allows cells such as various types of leukocytes to come in contact with other cells (including virus-infected cells) and with specific extracellular matrix components. In cell-cell adhesion, the specific class of adhesion molecules on one cell type typically recognizes a different adhesion molecule class on the other in a ligand-receptor manner. A number of pathologic processes related to tissue damage, early nonspecific inflammatory reactions, and the production of cytokines can up-regulate local expression of adhesion molecules and facilitate leukocyte accumulation within blood vessels and specific tissue sites. A number of cytokines, including interleukin-1 (IL-1), interleukin-4 (IL-4), interferon-γ, and tumor necrosis factor-alpha (TNF-α), lead to the expression of a particular adhesion molecule, intercellular adhesion molecule-1 (ICAM-1), on vascular endothelial cells, epithelial cells, fibroblasts, and corneal endothelial cells.19–22 A receptor-ligand binding of ICAM-1 with lymphocyte function-associated antigen-1 (LFA-1), which is expressed by virtually all T cells, B cells, and monocyte/macrophages, can then take place.23,24 As the pathophysiologic response progresses, there can be a down-regulation of adhesion molecule expression as a key component in the resolution of inflammation.

Adhesion molecules are in the process of being classified by structure and function. Most are defined as integrins or selectins. Integrins are a fairly large family of related cell-surface heterodimers. They mediate a variety of cell-cell and cell-extracellular matrix adhesion activities. Adhesion molecules of the selectin family are structurally related proteins. Each selectin has one epidermal growth factor-like domain, several complement-binding protein-like domains, and a characteristic carbohydrate-binding domain. A number of other cell-surface molecules, including HLA classes I and II, are also recognized to have adhesion molecule properties.

The reports of adhesion molecule expression in viral ocular infections are limited. One study demonstrated considerable ICAM-1 immunoreactivity of corneal stromal keratocytes and endothelial cells, especially in areas of intense infiltration of leukocytes in corneas infected with HSV-1. In addition, there was enhanced expression of HLA-DR antigens throughout these corneas.25 Another study of diseased recipient corneal buttons, including those from two eyes with herpetic stromal keratitis, investigated immunoreactivity for adhesion molecules.26 Cells in the corneal stroma had significant immunoreactivity for ICAM-1, HLA-DR, LFA-1, platelet-endothelial cell adhesion molecule-1 (PECAM-1), and vascular cell adhesion molecule-1 (VCAM-1). In a similar study of diseased human corneas, enhanced ICAM-1 expression was found in corneas from patients with herpetic stromal keratitis and VZV keratitis.27 Expression of other adhesion molecules, namely E-selectin (which is also known as endothelial leukocyte adhesion molecule-1 [ELAM-1]) and VCAM-1, could be identified in areas of corneal neovascularization. It is probably reasonable to assume, until more data are accumulated and analyzed, that the inflammation associated with viral ocular infections involves up-regulated expression of adhesion molecules on infected resident cells and in adjacent blood vessels. Likewise, the diminution in the intensity of inflammation, at least in part, involves a subsequent decrease in the density of adhesion molecules. Because proinflammatory cytokines play a significant role in the regulation of adhesion molecules, approaches that decrease production of these cytokines may be useful in the control of tissue damage mediated by inflammatory cells. Studies of infections caused by other viruses and the involvement of other parts of the eye will help further elucidate the roles of adhesion molecules. In noninfectious causes of posterior uveitis, vascular endothelial cells of the retinal and choroidal blood vessels and the retinal pigment epithelium expressed ICAM-1; LFA-1 was found on infiltrating lymphocytes.28 Significant TNF-α immunoreactivity was found on inflammatory cells in all eyes. This also suggests that proinflammatory cytokines may cause the expression of adhesion molecules on resident cells.

As noted earlier, cytokines are produced by a variety of cell types and may up-regulate the production of adhesion molecules. These cytokines are low-molecular-weight proteins and are involved in many other biologic processes, including inflammation, immunity, cell growth, differentiation, and cellular repair. Most are produced and exert their effects in local tissue areas. They typically bind in a specific manner to certain cell types by way of receptors. In some instances, antagonists have been identified. Some cytokines down-regulate cellular processes, whereas others promote processes such as inflammation. Many laboratories are seeking to learn ways to use various cytokines and their antagonists to control local tissue reactions such as inflammation and tumor growth.

Several cytokines have been identified in ocular tissues, and inferences have been made regarding the role played by specific cytokines in particular disease processes. Because various cytokines and numerous cells may be involved in dynamic processes at any time, reports on assays of specific cytokines may portray only part of the total biologic control mechanisms involved. As more data are acquired, these possibilities will become more evident and more pieces of these biologic puzzles will fit into place. IL-1 is an activator of T lymphocytes and is produced by corneal and conjunctival as well as other cells.29 Corneal angiogenesis can be produced by applications of interleukin-2 (IL-2), a major T-lymphocyte growth factor, and interleukin-8 (IL-8), a chemotactic factor for neutrophils and lymphocytes.30,31 Evidence that corneal epithelial cells, stromal keratocytes, and endothelial cells produce a number of cytokines and growth factors and their receptors, including IL-1α and its receptor, epidermal growth factor and its receptor, basic fibroblast growth factor, and transforming growth factor beta-1, is based on identification of messenger RNA for each of these molecules.32–34 Likewise, cytokines can influence the biologic activities of resident ocular cells as well as up-regulate the expression of adhesion molecules. For example, human corneal stromal keratocytes exposed to interferon-γ, a cytokine produced by activated T lymphocytes, produce several different proteins.35

The exposure of corneal cells to proinflammatory cytokines such as IL-1α and TNF-α leads to the expression of genes for a number of other cytokines that might enhance or sustain an inflammatory response in infections such as HSV stromal keratitis. Among the expressed genes are those for granulocyte-macrophage colony-stimulating factor (which is a chemotactic and activating factor for such cell types as neutrophils and dendritic Langerhans cells), interleukin-6 (IL-6) (which enhances the differentiation of B lymphocytes into antibody-producing cells and in conjunction with IL-1α enhances the activation and proliferation of T lymphocytes), and IL-8 (which recruits T lymphocytes and nonspecific inflammatory cells to sites of inflammation).36–38 IL-8 also activates neutrophils and is capable of causing corneal neovascularization.31,39

Responses to intravitreal injections of some cytokines have been investigated. Experimental acute anterior uveitis has been described after intravitreal injections of IL-1, IL-2, IL-6, and IL-8.40–43 Such observations suggest that an infection that is associated with the local production of these cytokines will have an inflammatory component. Intraocular inflammation can also be produced by other mechanisms.

The roles played by cytokines in viral ocular infections are not fully established. There are some published observations that suggest that they are significant factors. For example, IL-2 has been detected in the vitreous of AIDS patients with viral retinitis.44 Stromal keratitis caused by HSV has been studied in a number of ways in attempts to elucidate the possible roles of cytokines in its pathogenesis. It is well established that immune responses play major roles in the inflammation and subsequent scarring. A murine model of herpetic infection demonstrated that the development and subsequent resolution of skin lesions are associated with an effective immune response involving II-2 and interferon-γ. In contrast, similar immune responses involving IL-2 and interferon-γ were important elements in the progression of herpetic stromal keratitis and scarring.45 One of the early inflammatory features of herpetic stromal keratitis is neutrophil infiltration. IL-8 is chemotactic for neutrophils. Cultured corneal stromal keratocytes infected with HSV-1 produce significant amounts of IL-8, which may play a vital role in the early accumulation of neutrophils. Interleukin-10 (IL-10) has a number of functions, including potent suppression of the effector functions of macrophages, T lymphocytes, and NK cells.46 Penetrating keratoplasty specimens removed from eyes with herpetic keratitis and incubated for 48 hours in a solution containing IL-10 showed decreased immunoreactivity for MHC HLA-DR antigen but no change in ICAM-1 immunoreactivity compared with control specimens.47 The possible role that this IL-10-induced down-regulation of HLA-DR antigen expression may have in human herpetic keratitis awaits further elucidation. In a murine model of HSV-1 corneal stromal keratitis, intracorneal and intraperitoneal injections of murine recombinant IL-10 resulted in a 35% incidence of blinding disease, compared with a 95% incidence in saline-treated control mice.48 Additionally, there were significant reductions in the corneal levels of the proinflammatory cytokines IL-2 and IL-6 in the mice treated with IL-10.

These data suggest that the therapeutic use of cytokines may be successful once the roles played by specific cytokines in particular infections are known. Such data also emphasize the crucial role of immune-mediated inflammatory responses in the pathologic processes caused by ocular viral infections.

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Many viruses can infect ocular tissues. In most instances the involvement is mild and transient with manifestations such as mild conjunctivitis or keratoconjunctivitis. These types of ocular involvement are especially common in infections caused by respiratory viruses, the rubella virus, the measles virus, and adenoviruses. On occasion there is an outbreak of adenoviral infection with significant ocular involvement. The role of immunologic responses in adenoviral infections is incompletely understood and is not considered in this chapter. The disease processes and immunologic responses associated with HSV, VZV, and CMV ocular infections are described. In these diseases, immunologic responses and interactions between viruses and cells of the immune system are partially defined. These responses are probably reasonably representative of those associated with other viral ocular diseases.49


Herpes simplex virus infections involving ocular tissues are a significant health problem. The sequelae of herpetic keratitis make it the leading infectious cause of blindness in the United States. On the basis of epidemiologic studies, it is estimated that there are 400,000 ocular HSV infections in this country per year.50 In a predominantly white population in Minnesota, there were 8.4 new cases of ocular herpes infections per 100,000 person years and an overall prevalence of 149 cases per 100,000 people.50 Primary infections with HSV are very common. Approximately 50% to 80% of the population of the United States has serologic evidence of HSV infection by age 30.2 At least 90% of primary infections are subclinical.

Primary infections with HSV-1 are typically spread to young children by close contact with infected adults. The few children who develop significant clinical disease usually have lip lesions and gingivostomatitis. They may also have malaise, fever, lymphadenopathy, and elevated white blood cell counts with lymphocytosis. A similar clinical picture can occur in adults with primary HSV-1 infection. Ocular involvement in primary HSV-1 infection is unusual. When it occurs, it is usually seen in conjunction with vesicles on the face and eyelids, with ensuing conjunctivitis and keratitis.

In contrast, HSV-2 primary infections are usually acquired by adults through venereal transmission. Previous HSV-1 infection does not necessarily protect against HSV-2 infection. Primary HSV-2 genital infections can range from no symptoms to a clinical picture of local vesicles and ulcers, malaise, fever, regional lymphadenopathy, and dysuria. Ocular involvement can occur in the form of conjunctivitis or keratitis. Approximately 20% have symptoms of meningitis. In some people, most notably newborns and immunodeficient persons, disseminated primary infection can occur; this may include severe herpetic meningitis and retinitis.

Because primary HSV infections are usually controlled before specific immunologic responses are generated, nonspecific responses are probably of major importance in controlling infection and possibly in minimizing the establishment of latency.49 In experimental HSV infections, nonspecific responses are also critical for the control of recurrent disease. The nonspecific immunologic responses of the ocular surface have been reviewed elsewhere.51 Likewise, the roles of these mechanisms for HSV infections at other sites have been reviewed.52,53

The various stages of HSV-host interactions are as follows:

  1. Development of primary infection at an epithelial site
  2. Dissemination or axonal spread of HSV to other sites, especially to sensory and autonomic ganglia
  3. Host control of the primary infection and limitation of HSV dissemination
  4. Establishment and maintenance of latency
  5. Breakdown of latency and establishment of recurrent infection at an epithelial site
  6. Host control of recurrent herpetic infections

The biologic basis of these steps has recently been reviewed.54

Development of Primary Infection at an Epithelial Site

Primary infections of cutaneous sites are of relatively short duration, and it is likely that nonspecific inflammatory mechanisms are operative shortly after the site becomes infected. Specific immunologic reactants are not demonstrable until several days after the peak of the clinical disease at the primary site. In contrast, secondary ocular infections have a more protracted clinical course. It may be up to 2 weeks or more from the onset of mild conjunctivitis to the development of a follicular response or keratitis. This allows more than ample time for the production of specific immunologic responses. For the most part, a primary HSV infection and the establishment of latency in the trigeminal ganglion by one HSV strain provide sufficient immunity to prevent further HSV infection. Recurrences, if any, are caused by reactivation of the latent strain.55,56 Reinfections with different exogenous strains are more likely in immunodeficient persons.

Dissemination or Axonal Spread of HSV to Other Sites

Primary herpetic infections involve viral replication within epithelial cells, direct spread to adjacent epithelial cells as well as to other cell types such as neurons, and possibly viremia. These various modes of spread probably depend on host factors and the biologic characteristics of the particular infecting HSV strain. In experimental studies, different animal species developed and disseminated HSV to various extents. The same is true for inbred strains within a species, such as mice.57,58 Sex, age, site of primary infection, and, in experimental animals, route of infection are important factors in the ability of HSV to disseminate. Newborns are especially likely to have viremia, as are immunodeficient persons, even when circulating antibody is present.59 In adults, most viral spread away from the primary site of infection is by way of neurons. The speed of viral transport within neurons is 2 to 10 mm/hour, which is similar to the speed of retrograde axonal transport.60 Thus, once HSV enters neurons, it can move rapidly to sensory and autonomic ganglia.

Host Control of Primary HSV Infections and Limitation of Dissemination

Three nonspecific reactants seem especially important in dealing with early primary herpetic infections. Macrophages, NK cells, and interferon are almost immediately available at the site and help to sequester the primary infection. There are several lines of evidence indicating that macrophages are important in natural resistance to HSV infections.53 Macrophages from adult animals are intrinsically resistant to HSV replication. They are often the predominant inflammatory cell at sites of primary infection. Resistance to HSV can be adoptively transferred by macrophages or by macrophages plus antibody, but not by antibody alone. Macrophages that have been activated by infection, exposure to interferon, or immunomodulating factors enhance HSV resistance. Conversely, macrophages from newborns readily support viral replication, and newborns are highly susceptible to severe, disseminated HSV infection. However, the role of macrophages in ocular infections is not fully understood.

The exact mechanisms by which macrophages destroy viruses are uncertain but appear to be nonspecific. These cells seem to reduce the amount of infectious virus by absorbing and ingesting viruses and rendering them incapable of replication.

Natural killer cells are also involved in the nonspecific responses to HSV.57 These cells make up approximately 4% of the population of peripheral blood mononuclear cells. In experimental systems, NK activity is augmented by the addition of interferon. Likewise, antibodies against interferon classes alpha, beta, or gamma significantly reduce NK cell cytotoxicity.61 Overall, the level of NK activation is associated with HSV virulence and its ability to grow in vivo.61 Low NK activity seems to correlate with patient susceptibility to severe HSV infections and to recurrent herpetic keratitis.

Interferon is the third of the nonspecific immunologic components.62 There are three major classes: alpha from leukocytes, beta from fibroblasts, and gamma from activated lymphocytes. Interferon inhibits the replication of HSV and limits virus production. It enhances the activity of NK cells and also activates macrophages, which, in turn, become more efficient at eliminating virus. The use of topical preparations of interferon to prevent or treat ocular HSV infections has been unsuccessful.

These nonspecific modalities act to curtail the primary infection and limit its dissemination to other organs and to distant sites where latency might become established. If the primary infection is prolonged, specific immunologic responses with the possibility of immunopathologic damage become operative.

Establishment and Maintenance of Latency

The sensory and autonomic ganglia are primary sites of latency.63,64 It appears that neurons are the key, if not the exclusive, cells for harboring latent HSV. Some reports suggest that skin and cornea may also serve as sites of latency.65–67 Both the ophthalmic division of the trigeminal nerve and the ganglia contain virus within 2 days of corneal infection. By 1 week postinfection, the other portions of the ipsilateral trigeminal ganglia and approximately 50% of the ipsilateral superior cervical ganglia are infected. Most ocular herpetic infections are the result of reactivation of latent virus in either the trigeminal or superior cervical ganglia. If cell bodies with axons to the eye are latently infected, their reactivation may lead to ocular herpetic diseases. The exact roles of nonspecific and specific immune responses in aiding or limiting the establishment of latency are not completely understood. For example, subunit vaccines containing HSV glycoprotein D induce host immunity that partially protects against the establishment of latency.68 However, the mechanism for this protection is not established. Once viral replication takes place within a cell, the death of that cell is almost inevitable. Latency requires a special relationship between the infected cell and virus. Perhaps antibody or cytokines from immune cells provide extracellular conditions that enhance this relationship, or perhaps cells containing latent virus are not altered significantly to allow recognition by the immune system.

Breakdown of Latency and Establishment of Recurrent Disease at an Epithelial Site

Viral shedding in saliva or tears without evident clinical disease suggests that latency may break down without concomitant clinically evident disease. However, clinically evident recurrent epithelial infection is the recognized sign of viral reactivation in a latent site. There are several theories that have been proposed to account for reactivation by some trigger mechanism.54 A popular supposition has been that a failure of immunologic control mechanisms in some way leads to recurrent herpetic infections. There is no body of evidence to suggest that a failure of humoral immune mechanisms is the cause. However, some studies do suggest that there is a relationship between changes in cellular immunity and recurrences. A breakdown in immune surveillance appears to play a central role.69

Host Control of Recurrent Herpetic Infections

Several cell-mediated immune mechanisms operate after herpetic infections. Triggering of T lymphocytes in all of these responses is controlled by a dual-recognition mechanism that requires the close proximity of viral antigens and MHC antigens. HSV-infected cells synthesize more than 60 distinct polypeptides. Many glycoproteins, including glycoprotein D, which is critical in the establishment of immunity, are expressed on the surfaces of infected cells and appear to play a role in the pathophysiology and immunopathology of these infections. Accessory cells such as dendritic Langerhans cells and macrophages play a key role in the presentation of viral antigens to the immune system. Populations of helper (CD4) and cytotoxic (CD8) lymphocytes determine the characteristics of the immune response. Antigen-presenting cells transport HSV antigen to lymphoid organs and present the HSV antigen in the context of class I MHC antigen to CD8 lymphocytes or in the context of class II MHC antigen to CD4 lymphocytes.70,71 Both of these presentations require the close proximity of the co-stimulator molecule known as B7 or some other molecule.72,73 Corneal Langerhans cells appear to play a critical role in the activation of CD4 lymphocytes in HSV-infected corneas.18 Cytokines also are likely involved. Once T-cell subsets are primed to recognize HSV-infected cells, a number of potential immune responses can occur. In viral infections, the generation of CD4 lymphocytes is important. The immunopathologic events leading to stromal keratitis and scarring are mediated by CD4 lymphocytes.74,75 Once generated, a cascade of events involving adhesion molecules and cytokines facilitates the establishment of intimate contact between these cells and HSV-infected cells, leading to their subsequent destruction as well as associated inflammation. These observations are of special interest because approximately 20% of people with herpetic keratitis develop stromal keratitis, which is the major cause of visual loss associated with these infections.50

Herpes simplex virus-specific antibodies contribute to the control of herpetic infections. There is not much free virus present in herpetic infections, but when it is present, neutralizing antibodies may play a role in eliminating it. In other situations, antibodies against HSV antigens diffuse into the corneal stroma from blood vessels. In some animal models, the interaction of these antibodies with specific antigen leads to complement binding and activation, which causes neutrophil chemotaxis and the formation of a Wesseley ring.76–78 In addition, there are in vitro experiments that suggest that antibodies against HSV may be involved in antibody-dependent cell-mediated cytotoxicity responses in the cornea.79


The incidence of herpes zoster in the United States is approximately 130 per 100,000 person years, with the incidence increasing in each decade beyond age 40.80 Approximately 12% to 25% of the cases involve the dermatologic distribution of the fifth cranial nerve. Approximately 20% of persons with herpes zoster ophthalmicus develop ocular complications, including keratitis, uveitis, secondary glaucoma, acute retinal necrosis syndrome, progressive outer retinal necrosis syndrome, and, rarely, panophthalmitis.81–85

In almost all patients who develop herpes zoster, the infection is caused by reactivation of latent VZV acquired during a childhood chicken pox infection. Sensory ganglia are the sites of latency. Cell-mediated immunity appears to play a crucial role in the prevention of recurrent infection. Herpes zoster infections are more common in older persons and may be associated with decreased competence of the immune system. In severely immunodeficient persons, recurrent herpes zoster infections are quite common. For example, approximately 35% of bone marrow transplant recipients develop herpes zoster. Likewise, VZV infections are seen quite frequently in AIDS patients. There appears to be a relatively frequent dynamic activation of latent VZV, which is usually handled by immunologic mechanisms in healthy people. However, immunodeficient persons may experience an overt recurrent herpes zoster infection after an episode of dynamic activation. Recovery from VZV infections correlates with the development of specific cell-mediated immune responses and local production of interferon-γ.86,87 Humoral immunity to VZV is at least partially protective against reinfection, but a decrease in cell-mediated immunity appears to be the crucial event leading to recurrence.88

Herpes zoster vesicles contain virus. Occasionally the virus is cultured from corneas with keratitis. The histopathologic hallmarks of VZV infections are perivascular and perineuronal accumulations of lymphocytes. Infected cells have intranuclear inclusions. There are few detailed immunologic studies on VZV infections because of a lack of animal models. Lymphocytes from persons who have had VZV infections demonstrate in vitro evidence of immunity when exposed to appropriate antigens. The perineuronal lymphocytic infiltration suggests that reactivation is associated with expression of VZV antigens along actively infected nerves. This infiltration persists for extended periods and probably accounts for the paresthesias and postherpetic neuralgia. Similar lymphocytic infiltrates are seen in blood vessel walls.


Cytomegalovirus infections have become of greater interest to ophthalmologists because of the frequent development of CMV retinitis in patients with AIDS. In general, these infections occur quite late in the course of AIDS when systemic CD4+ lymphocyte counts are greatly diminished.89 Studies suggest that humoral immune responses are not the main defense against CMV. In contrast, CD8+ T-cell-mediated immunity is strongly correlated with successful recovery from CMV infection.90 Some lines of evidence also suggest a significant role for NK-cell activity.90,91

The high incidence of serum antibodies against CMV in most parts of the world indicates that primary infections are quite common. Most infections are subclinical or very mild. Approximately 1% of infants in the United States are infected in utero. Although most congenital infections are also subclinical, some result in mental retardation and other problems; a portion of these may have significant ocular involvement. Overt adult CMV infections are usually in the context of immunodeficiency, and although they may be primary, most represent recurrent infection due to reactivation of latent virus. When there is impairment of the immune system, CMV may disseminate and cause infection at multiple sites, including lungs, liver, kidneys, salivary glands, spleen, central nervous system, and eyes. This widespread dissemination and proliferation of CMV in an immunocompromised host clearly illustrates the importance of immunologic processes in controlling this virus in the infected host.

Although persons with normal immunologic functions generally experience subclinical primary CMV infection and recover without sequelae, many of them secrete virus from involved organs such as the kidneys for prolonged periods. CMV may establish latency in some subsets of lymphocytes or cells of the monocyte/macrophage lineage; other sites in organs such as the salivary glands and kidneys may be involved as well. The virus is found in neutrophils and occasionally in lymphocytes and monocytes during viremia. CMV modulates immune reactivity as one of its mechanisms to avoid elimination from an infected host. In experimental CMV infections there is a transient suppression of cell-mediated immunity, suggesting that the virus itself causes temporary immunosuppression.66 When the host's cell-mediated immune responses return to normal, a quiescent latent state is established. This virus has the ability to alter cytokine production and class I MHC antigen expression in infected cells. For example, CMV causes increased production of interferon-β and TNF-α, which may increase inflammatory responses at sites of infection and increase tissue damage. CMV also induces production of transforming growth factor-beta 1, which may enhance the replication of CMV.92

In contrast to VZV infections, in which the intense immune response is responsible for tissue damage, CMV itself causes tissue necrosis. Ocular CMV infections involve the neurosensory retina, retinal pigment epithelium, and choroid. As the infection spreads, retinal vasculitis may be detected as well.81

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Numerous viral diseases occur in healthy persons. However, people with naturally occurring or induced immunodeficiency, especially if cell-mediated immunity is impaired, are at particular risk for the development of complications from infections caused by members of the herpesvirus family. This has been attributed to the spread of these viruses by fusion of infected cells with adjacent uninfected cells and the reactivation of these viruses from sites of latency. Without normal cell-mediated immunity, the herpesviruses are likely to cause significant damage. In contrast, other viral infections appear to be controlled by combinations of humoral and cell-mediated immune mechanisms. Members of the myxovirus and paramyxovirus families, such as the viruses causing mumps, measles, and influenza, spread by budding from cell surfaces and present both cell-surface antigens and extracellular virus to the immune system. Other viruses such as enteroviruses and rhinoviruses are spread by extracellular routes and are dealt with by humoral immune responses. Persons with many types of immunodeficiency are still able to avoid problems with these infections.

People with severe defects involving cellmediated immune mechanisms are at particular risk for developing severe infections with HSV, VZV, and CMV. Patients with Wiskott-Aldrich syndrome and people who are taking immunosuppressive drugs (such as transplant recipients) have increased risks for complications from HSV infections.93,94 Immunosuppression is also associated with frequent and severe VZV and CMV infections.95,96

Severe CMV infections are associated with AIDS; up to 40% of AIDS patients have CMV retinitis by the time of death.97–100

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Immunologic responses are operative during various stages of all infections. Some of the responses are nonspecific and others are highly specific. Adhesion molecules and cytokines play vital roles in the responses. These immune mechanisms act to limit the spread of infectious virus particles and to destroy infected host cells. Impairment of these responses may result in severe and disseminated disease. The immunopathologic responses are usually beneficial for the survival of the infected host. However, these responses may also result in significant tissue damage to structures such as the cornea and retina.
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