Viral Infections

• Acellular: enter cells to ‘borrow’ metabolism
• Viral genome composed of capsids enclosed in a protein shell
• Capsids are icosahedral or helical
• Replication:
• Adsorption: attach to cell via electrostasis or cell receptors
• Penetration

• Cell enzymes remove the capsid and nucleic acid replication occurs (varies depending on DNA or RNA)

• DNA: mostly use host cell enzymes in the nucleus to make mRNA

• RNA: replication occurs in the cytoplasm. Cannot borrow host enzymes but use reverse transcriptase to make DNA from RNA

• Maturation
• New particles released by cell lysis or budding
• Transmission:
• Vertical: maternal to offspring
• CMV
• Rubella
• HSV
• Horizontal: from one individual to another
• HSV (again)
• Chronic infections
• Persistence: replication occurs at a slow rate
• Latency: no replication occurs but the viral genome integrates into host DNA
• Malignant and teratogenic change
• Evasive strategies
• Change antigens via point mutations or antigen shift

• Dodge complement: HSV produces a C3b binding molecule and EBV binds to complement receptors

HSV-1: Herpes stromal keratitis

• DNA
• Most common cause (globally) of ocular viral infection
• Life cycle
• Entry into host and replication at peripheral site
• Spread to axonal terminals of sensory neurones
• Retrograde intra-axonal transport to neuronal cell bodies in ganglia
• Latency in trigeminal ganglia
• Reactivation: antegrade transport of virus to the periphery
• The lytic pathway leads to cell lysis and particle release
• Infection often asymptomatic
• Oral and genital lesions
• Reactivation:
• UV radiation
• Fever
• Stress
• Menstruation
• Trauma 
• Primary infection: TLR9 involved in initial activation

VZV

• DNA
• Causes chicken pox: highly infectious, respiratory spread

• Becomes latent in ganglia especially the trigeminal (but also thoracic, lumbar and cervical)

• Reactivation (shingles):

• Immunosuppression (cell-mediated immunity is essential to maintain the virus in the latent state)

• X-ray

Viral retinitis

• Important cause of visual loss in immunosuppressed patients
• Most common:
• HSV
• VZV
• CMV
• LCMV: lymphocytic choriomeningitis virus
• EBV
• Rubella
• Measles
• West Niles
• Dengue
• Further explored in Part 2 package

CMV

• Extremely common but usually subclinical
• Double stranded DNA virus of the herpes family
• Primary infection: CD8 T-cell mediated (the virus becomes latent in lymphocytes)

• Most pathogenic after congenital infection and fetal abnormalities (due to infection DURING pregnancy. Infection prior to pregnancy may lead to reactivation but only an asymptomatic fetal infection)

• Owl’s eye inclusion bodies are a specific histopathological sign
• Clinical features:
• Chorioretinitis (in immunocompromised)
• Necrotizing retinitis can lead to retinal detachment
• Affects the posterior pole mostly
• Full thickness retinal necrosis seen histologically
• Keratitis
• Optic atrophy
• Cataract 
• Hydrocephalus
• Cytomegalic inclusion disease: strabismus
• Microcephaly and microphthalmia
• Jaundice (hepatitis), hepatosplenomegaly
• Intracranial calcification
• Treatment: oral ganciclovir

Hepatitis B virus

• DNA virus
• Oncogenic 
• Average incubation period is 60-90 days

• Outer coat: HBsAg (“Australia antigen”) raised in acute illness and in carriers

• Persistence of HbsAg increases the risk of chronic liver disease

• Inner core: HBeAg indicates acute infection or supercarrier status (increased infectivity)

• Anti-HBsAg: indicates previous infection or immunity (appears late). Reliable measure of non-infectivity.

• Anti-HB core (IgM/IgG): previous infection
• Primarily horizontal transmission via parenteral or sexual route
• HBeAg positive mothers can transmit vertically
• Vaccination uses HBsAg

HPV

• dsDNA
• More than 60 types
• Target epithelial cells
• A minority insert themselves into the genome and cause malignant change
• E2 gene contributes to HPV proliferation

• The E6 protein of HPV 16 and 18 causes p53 protein degradation (these are high-risk associated with conjunctival carcinoma)

• E7 protein inactivates the product of retinoblastoma tumour suppressor gene
• HPVs 6 and 11 cause conjunctival papillomata

Kaposi’s sarcoma

• Malignant tumour of the vascular endothelium

• Associated with Herpes hominis virus type 8 infection (HHV-8)

• More common in sexually transmitted HIV
• Usually seen when CD4 count <500 cells/microlitre
• Skin and palate are common sites
• Radiosensitive (cutaneous and lymph nodes) and chemosensitive (systemic)

• May be mistaken for subconjunctival haemorrhage (bright red, fleshy, violaceous nodular mass, commonly in the fornix).

• Ocular adnexal Kaposi’s typically presents as a pink-red conjunctival mass or blue-purple eyelid mass

Molluscum contagiosum

• Poxvirus: DNA
• Grows in the cytoplasm
• Possess enzymes allowing replication independent of the host
• Pearly white lesions of the skin (epidermal hyperplasia)
• Transmission by direct contact or sexually

Adenoviruses

• Numerous serotypes (dsDNA)
• No envelope

• Transmission by direct contact with virus in ocular secretions, instruments, eye drops etc.

• Can be cultured on HeLa cell lines
• A single infected cell can product 10000 virions every 30-36 horus
• Avoid immune defences:
• Disrupt MHC presentation by infected cells
• Suppress transcription encoding class I MHC
• Inhibition of cell lysis by TNF
• Can interact with retinoblastoma and p53 genes
• Serotypes 8, 19, 35 and subgroup D: epidemic keratoconjunctivitis (EKC)
• May be a severe follicular conjunctivitis with punctate keratitis
• Delayed presentation 7-10 days after inoculation
• True and pseudomembranes
• Subconjunctival hemorrhage
• Subepithelial infiltrates

• Steroids may prolong the disease course

• Contagious: while still hyperaemic and tearing

• Serotypes 3 and 7: pharyngoconjunctival fever
• Flu-like symptoms
• Skin papilloma

LCMV

• Single stranded RNA arenavirus and retrovirus

• Sources: ingestion of particles contaminated by mouse faeces, urine or saliva (rodent borne)

Measles

• Paramyxovirus (RNA)
• Clinical features (never subclinical):
• Fever
• Prodromal cough
• Coryza
• Conjunctivitis
• Rarely corneal scarring (typically with vitamin A deficiency)
• Can cause secondary bacterial infection
• Usually respiratory
• Rarely encephalitis
• More rarely: subacute sclerosing panencephalitis (SSPE).

• Slowly progressive and fatal encephalitis associated with chorioretinitis and maculopathy.

Rubella

• Togavirus (RNA)
• Transmission: droplet
• Subclinical in 80% of small children and 10% of adults
• The fetus is infected transplacentally, highest risk within the first 10 weeks

• Congenital abnormalities if infection during first trimester (when fetal organs developing)

• Transplacental spread to fetus
• Miscarriage or stillbirth

• Cataracts (2nd most common eye finding): pearly white nuclear opacifications

• Live virus particles can persist in the lens for many years

• They may be released after cataract surgery leading to a vigorous inflammatory response

• Microphthalmia

• Chorioretinitis leading to bilateral pigmentary retinopathy (most common ocular findings, ‘salt-and-pepper’ fundus. Not visually significant and ERG is normal)

• Corneal hydrops/clouding, keratoconus

• Glaucoma (3rd most common finding in eyes): does not occur simultaneously with cataract in congenital rubella! For some reason.

• Strabismus 
• Neural deafness
• Congenital heart defects eg. PDA
• Raised IgM indicates recent infection (IgG indicates previous infection)

Mumps

• Paramyxovirus (RNA)
• Clinical features
• Fever
• Parotitis
• Orchitis
• Pancreatitis
• Meningoencephalitis
• Dacroadenitis
• Extraocular palsies
• Recent infection: antibody to S antigen
• Previous infection: antibody to V antigen

Enteroviruses

• RNA viruses with icosahedral capsid
• Faecal-oral spread, direct contact, droplet
• Acute haemorrhagic conjunctivitis

HIV

• Single stranded RNA virus containing reverse transcriptase (exogenous virus ie. do not contain conserved cellular genes)

• Non-oncogenic cytocidal retrovirus
• HIV-1 and HIV-2 have different glycoprotein envelopes
• Type 1: urban centres, mainly transmitted via homosexuals and IVDUs
• Type 2: African, mainly heterosexually transmitted
• Weak virus: killed by strong acid and alkali, bleach and ethanol
• Pathogenesis

• CD4 receptors on T-helper cells act as receptors (although HIV can bind to macrophages, monocytes, microglia…)

• Binds to CD4 receptors with CCR5 or CXCR4 as co-receptors
• gag gene encodes the core nucleocapsid polypeptides
• Viral reverse transcriptase transcribes the ssRNA to DNA
• This is highly error prone, so new strains can be made
• The complementary DNA becomes part of the host genome: provirus
• Multinucleate cells form after infection leading to cell death (destroying CD4 cells)
• Cell mediated immune response fails (increased risk of infection and neoplasia)
• Decreases T cell dependent immunoglobulins

• Becomes latent in monocytes and macrophages (which also possess CD4 receptors) becoming invisible to immune defences

• Frequent mutations lead to changing glycoprotein envelopes and changing antigenicity
• ELISA (enzyme-linked immunosorbent assay) is a common diagnostic test in use
• Plate-based assay with quantitative and qualitative properties
• Can detect antigen or antibody, peptides, hormones, proteins
• Highly sensitive and specific

• Antigen or antibody is labelled with an enzyme which induces a colour change in a substrate

• Antibody profile varies depending on stage of disease eg. AIDS-related complex compared to full-blown AIDS

• ARC and AIDS: antibodies to gp41, gp120 and gp160 envelope glycoproteins
• Transition from ARC to AIDS: increase in p24 (a core protein) and reduced CD4:CD8 ratio
• NB: presence of p24 in the blood is one of the earliest signs of infection

Human T-lymphotropic virus type 1 (HTLV-1)

• Single stranded RNA

• Oncogenic retrovirus: T cell leukaemia, lymphoma (mycosis fungoides, Sezary syndrome), progressive myelopathy, uveitis

• Immortalises peripheral T cells in vitro via the tax gene
• Transmission: vertical and horizontal (sexual transmission or parenteral)
• Endemic in Japan, Africa, Caribbean 

TORCH viruses causing fetal abnormalities

• Toxoplasmosis
• Other (syphilis, HIV-1, Listeria)
• Rubella
• CMV
• Herpes viruses

Live vaccines

• Polio
• Yellow fever
• MMR