DNA Viruses: Papovaviruses
Human papillomaviruses (HPV) are small, nonenveloped, double-stranded DNA viruses with an icosahedral capsid. Persistent viral infection of susceptible epithelial cells induces cellular proliferation and can lead to malignant transformation. Papillomavirus proteins can induce transformation of the cell and loss of senescence. HPV subtypes 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 HPV-containing basal epithelial cells mature and differentiate into superficial epithelial cells, they become permissive for complete viral gene expression and produce infectious virus. Neoplastic transformation due to HPV 6 or 11 is very rare. In contrast, HPV 16 and 18 stereotypically integrate their viral genome into host chromosomal DNA, and this in turn is associated with malignant transformation and squamous cell carcinoma. Recently implemented immunization strategies specifically targeted against HPV oncogenes may result in a decreased incidence of these tumors in the future.
Verrucae and papillomas are caused by papillomavirus infection of the skin and conjunctival epithelium (Fig 4-22). Venereally acquired conjunctival papillomas resemble those on the larynx and urogenital tract. Papillomavirus-associated conjunctival intraepithelial neoplasia and squamous cell carcinoma share many histologic features with similar lesions in the uterine cervix. Another neoplasm, Kaposi sarcoma of the skin or conjunctiva, is associated with infection by human herpesvirus type 8. These entities are discussed in greater detail in Chapter 8.
Figure 4-22 Conjunctival papillomas. (Courtesy of Elmer Y. Tu, MD.)
RNA Viruses
Picornaviruses are negative-sense, single-stranded RNA viruses with an icosahedral capsid and no envelope. Members of the family picornaviridae include the enteroviruses (poliovirus, coxsackievirus, echovirus, and enterovirus) and the rhinoviruses, the single most common etiology of the common cold.
Togaviruses are positive-sense, single-stranded RNA with no envelope. Togaviruses with general medical and ophthalmic importance include rubella, encephalomyelitis, yellow fever, and dengue viruses.
Orthomyxoviruses such as influenza virus are negative-sense, single-stranded RNA viruses with an enveloped helical icosahedral capsid. Structurally similar to the orthomyxoviruses, paramyxoviruses of ocular importance include mumps virus, measles (rubeola) virus, parainfluenza virus, respiratory syncytial virus, and Newcastle disease virus (a cause of follicular conjunctivitis in poultry handlers). The paramyxovirus envelope contains hemagglutinin-neuraminidase protein spikes and a hemolysin, which mediate viral fusion with the host cell membrane.
Eye infections due to RNA viruses present to the ophthalmologist less often than those due to DNA viruses, and they most commonly manifest as follicular conjunctivitis associated with an upper respiratory tract infection. However, certain RNA virus infections may cause pathologic changes in virtually any ocular tissue. For example, influenza virus can induce inflammation in the lacrimal gland, cornea, iris, retina, optic nerve, and other cranial nerves.
In measles (rubeola) virus (a paramyxovirus) infection, the classic triad of postnatally acquired measles—cough, coryza, and follicular conjunctivitis—can be observed. Mild epithelial keratitis may be present. Less common are optic neuritis, retinal vascular occlusion, and pigmentary retinopathy. Measles keratopathy, a major source of blindness in the developing world, typically presents as corneal ulceration in malnourished, vitamin A–deficient children. (For further information on the ocular effects of vitamin A deficiency, see Chapter 3.) A rare and fatal complication of measles virus infection, subacute sclerosing panencephalitis (SSPE), occurs in approximately 1 per 100,000 cases, often years after clinically apparent measles.
Mumps virus (a paramyxovirus) infection may result in dacryoadenitis, sometimes concurrent with parotid gland involvement. Follicular conjunctivitis, epithelial and stromal keratitis, iritis, trabeculitis, and scleritis have all been reported within the first 2 weeks after onset of parotitis.
Rubella virus (a togavirus), when acquired in utero, may cause microphthalmos, corneal haze, cataracts, iris hypoplasia, iridocyclitis, glaucoma, and salt-and-pepper pigmentary retinopathy. Congenital ocular abnormalities due to rubella are much worse when maternal infection ensues early in pregnancy. Measles, mumps, and rubella are all uncommon in places where childhood immunization is regularly performed.
Corneal biopsy and impression cytology have been useful in helping in the early diagnosis of rabies virus infection. Rabies virus can be transmitted via corneal transplant. Acute hemorrhagic conjunctivitis (AHC), caused by enterovirus type 70 and coxsackievirus A24 variant, and, less commonly, adenovirus type 11, is one of the most dramatic ocular viral syndromes. Sudden onset of follicular conjunctivitis associated with multiple petechial hemorrhages of bulbar and tarsal conjunctiva characterizes AHC. The hemorrhages may become confluent and appear posttraumatic. Eyelid edema, preauricular adenopathy, chemosis, and punctate epithelial keratitis may be associated with infection. AHC is highly contagious and occurs in large and rapidly spreading epidemics. In approximately 1 out of 10,000 cases due to enterovirus type 70, a polio-like paralysis follows; neurologic deficits are permanent in up to one-third of affected individuals.
Retroviruses are positive-sense, single-stranded enveloped RNA viruses that encode a viral enzyme, reverse transcriptase, that assists in conversion of the single-stranded RNA genome into a circular double-stranded DNA molecule. The viral nucleic acid then integrates into host cell chromosomal DNA.
The retrovirus of greatest medical importance is human immunodeficiency virus (HIV), the etiologic agent of AIDS. HIV enters the human host via sexual contact at mucosal surfaces, through breast-feeding, or via blood-contaminated needles. Sexually transmitted infection is facilitated by uptake of HIV by dendritic cells at mucosal surfaces. CD4+ T lymphocytes are a primary target of the virus, as are dendritic cells and monocyte-macrophages. Infection of these cell types induces predictable defects of innate and acquired (both humoral and cellular) immunity. Primary viremia
results in an infectious mononucleosis-like HIV prodrome, followed by seeding of the peripheral lymphoid organs and development of a measurable immune response. Infected patients may remain otherwise asymptomatic for several years, but CD4+ T lymphocytes are progressively depleted. Clinical immunodeficiency eventually develops.
AIDS-related ocular disorders include HZO, molluscum contagiosum, keratoconjunctivitis sicca, microsporidial keratoconjunctivitis, HIV neuropathy, cryptococcal optic neuritis, retinal microvasculopathy, choroiditis and retinitis due to syphilis, mycobacteria, pneumocystosis, toxoplasmosis, CMV, HSV, and VZV. For more information regarding HIV, see BCSC Section 1,
Update on General Medicine, and Section 9, Intraocular Inflammation and Uveitis.
Cunningham ET Jr, Margolis TP. Ocular manifestations of HIV infection. N Engl J Med. 1998;339(4):236–244.
Lai TY, Wong RL, Luk FO, Chow VW, Chan CK, Lam DS. Ophthalmic manifestations and risk factors for mortality of HIV patients in the post-highly active anti-retroviral therapy era. Clin Experiment Ophthalmol. 2011;39(2):99–104.
Zaidman GW, Billingsley A. Corneal impression test for the diagnosis of acute rabies encephalitis. Ophthalmology. 1998;105(2):249–251.