DNA	RNA	Oncogenic
Adenovirus	Rotavirus	HBV- hepatocellular carcinoma
Parvovirus	Enterovirus	Papovavirus
Herpesviruses (HSV, VSV, EBV, CMV)	HCV	EBV- Burkitt’s lymphoma, nasopharyngeal neoplasia
Pox viruses including Molluscum	MMR viruses	HPV: E6 protein inactivates p53
HBV	RSV	HTLV-1
HPV	Influenza
Papovavirus	LCMV
	HIV (retrovirus)
Dengue and yellow fever
HTLV-1 (retrovirus)	(NB: HIV is non-oncogenic)

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

Angiogenesis and lymphangiogenesis of normally avascular cornea occurs

Allows an adaptive immune response but impairs corneal transparency
Ring infiltrates in the corneal stroma represent antigen-antibody complexes

## 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

Management is supportive and topical steroids should only be used for vision threatening subepithelial infiltrates or conjunctival membranes

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