Viral Infections: an overview

Dr. Gerrard Uy

Defining a Virus

• Viruses consist of a nucleic acid surrounded by one or more proteins

• obligate intracellular parasites: they can replicate only within cells

• Many human viruses are simply composed of a core and a capsid

• Genes: contain either DNA or RNA

RNA Viruses DNA Viruses

Picornaviruses Poliovirus Coxsackievirus Echovirus Enterovirus Rhinovirus Hepatitis A virus

Herpesviridae Herpes simplex virus types 1 and 2b

Varicella-zoster virusc Epstein-Barr virusd Cytomegaloviruse Human herpesvirus 6 Human herpesvirus 7

Calciviridae Norwalk agent Hepatitis E virus

Hepadnaviridae Hepatitis B virus

Togaviridae Rubella virus Eastern equine encephalitis virus Western equine encephalitis virus

Papovaviridae Human papillomaviruses JC virus BK virus

Flaviviridae Yellow fever virus Dengue virus St. Louis encephalitis virus West Nile virus Hepatitis C virus Hepatitis G virus

Poxviridae Variola (smallpox) virus Orf virus Molluscum contagiosum virus

RNA Viruses DNA Viruses

Coronaviridae Coronaviruses

Adenoviridae Human adenoviruses

Rhabdoviridae Rabies virus Vesicular stomatitis virus

Parvoviridae Parvovirus B19

Filoviridae Marburg virus Ebola virus

Paramyxoviridae Parainfluenza virus Respiratory syncytial virus Newcastle disease virus Mumps virus Rubeola (measles) virus

Orthomyxoviridae Influenza A, B, and C viruses

Bunyaviridae Hantavirus California encephalitis virus Sandfly fever virus

Viral Infection• Transmission– capsid and envelope of a virus protect its genome – Most common viral infections are spread by • direct contact• by ingestion of contaminated water or food• by inhalation of aerosolized particles

– Animals are important reservoirs and vectors for transmission of viruses causing human disease

Viral Infection

• Primary Infection– usually lasts from several days to several weeks• enterovirus, mumps virus, measles virus, rubella virus,

rotavirus, influenza virus, AAV, adenovirus, HSV, and VZV are cleared from almost all sites within 3–4 weeks• AAV, EBV, or cytomegalovirus (CMV) can last for

several months• HBV, HCV, hepatitis D virus (HDV), HIV, HPV, and

molluscum contagiosum virus extend beyond several weeks

Viral Infection

• Primary Infection– Disease manifestations usually arise as a

consequence of viral replication and the resultant inflammatory response

– are cleared by nonspecific innate and specific adaptive immune responses

– host is usually immune to the disease manifestations of reinfection by the same virus

Persistent and Latent Infections

– HCV RNA polymerase and HIV reverse transcriptase have high mutation rates

– generation of variant genomes that evade the host immune response facilitates persistent infection

– DNA viruses: lower mutation rates• ability to establish latent infection and to reactivate

from latency

Persistent and Latent Infections

• latency is defined as a state of infection in which the virus is not replicating

• HPVs establish latent infection in basal epithelial cells

Persistent and Latent Infections

• Herpesviruses: latent infection is established – in nonreplicating neural cells (HSV and VZV)– in replicating cells of hematopoietic lineages [EBV

and probably CMV, HHV-6, HHV-7, and Kaposi's sarcoma–associated herpesvirus (KSHV, also known as HHV-8)].

Persistent Viral infections and Cancer

– estimated to be the root cause of as many as 20% of human malignancies

– Most hepatocellular carcinoma is now believed to be caused by chronic inflammatory, immune, and regenerative responses to HBV or HCV infection

– Almost all cervical carcinoma is caused by persistent infection with "high-risk" genital HPV strains

– EBV infection also plays a role in the long-term development of certain B lymphocyte and epithelial cell malignancies

Resistance to Viral Infections

• Initial response is not virus-specific• Physical– cornified layers of the skin and by mucous

secretions that continuously sweep over mucosal surfaces

• Cellular– IFNs are induced and confer resistance– cytokines may be chemotactic to inflammatory

and immune cells

Resistance to Viral Infections

• By 7–10 days after infection, virus-specific antibody responses develop

• virus-specific HLA class II–restricted CD4+ helper T lymphocyte responses, and virus-specific HLA class I–restricted CD8+ cytotoxic T lymphocyte responses• Antibody and complement can also lyse virus-infected

cells that express viral proteins on their surface

• host inflammatory and immune response contributes to the symptoms, signs, and other pathophysiologic manifestations of viral infection

Diagnostic Virology

• Serology• Viral Isolation

• Acute- and convalescent-phase sera with rising titers of antibody to virus-specific antigens

• shift from IgM to IgG antibodies

Diagnostic Virology

• ELISA (Enyme-Linked Immunosorbent Assay)– generally use specific viral proteins that are most

frequently targeted by the antibody response– amount of antibody can then be quantitated by

the intensity of a color reaction mediated by the linked enzyme

• Virus isolation– depends on the collection of specimens from the

appropriate site – the rapid transport of these specimens in the

appropriate medium to the virology laboratory– Rapid transport maintains viral viability and limits

bacterial and fungal overgrowth.

Treatment

• Multiple steps in the viral life cycle can be effectively targeted by antiviral drugs– synthesis of the HIV provirus– block maturation of the HIV polyprotein – preventing a conformational change required for

virus fusion– preventing release of viral RNA early during

infection– Prevent efficient release of mature virions

Immunization

• Smallpox• Poliovirus• Measles• Influenza• Chickenpox• HBV• Mumps, rubella

Guillain-Barre Syndrome

Guillain-Barre Syndrome

• Acute, frequently severe, and fulminant polyradiculopathy

• Autoimmune in anture• Males have higher risk than females

Clinical Manifestation

• Rapidly evolving areflexic motor paralysis with or without senosry disturbance

• Usual pattern is ascending paralysis – “rubbery legs”

• Weakness evolves over hours to days• Associated with tingling dysesthesias in the

extremities• Legs are usually more affected than the arms

Clinical Manifestation

• Pain in the neck, shoulder, back or diffusely over the spine is common in the early stages

• Most patients require hospitalization and ~30% require mechanical ventilation

• Bladder dysfunction may occur in severe cases• Once clinical worsening stops and reaches a

plateau (almost always within 4 weeks of onset), further progression is unlikely

Antecedent Events

• Approximately 70% occur 1-3 weeks after an acute infectious process, usually respiratory or gastrointestinal

• Organisms that may be responsible:– Campylobacter jejuni– CMV or Epstein barr virus– Mycoplasma pneumoniae

Immunopathogenesis

• Acute inflammatory demyelinating polyneuropathy (AIDP) – most common type of GBS

• Both CMI and humoral immunity contribute to tissue damage

• Antibodies to gangliosides

Subtypes of GBS

• AIDP– Rapid recovery, anti-GM1 antibodies

• Acute Motor axonal neuropathy (AMAN)– Anti GD1a antibodies

• Acute Motor sensory anxonal neuropathy (AMSAN)– Recovery slow

• Miller Fisher syndrome– Anti GQ1b antibodies

Pathophysiology

• In the demyelinating forms of GBS, the basis for flaccid paralysis and senosry disturbance is conduction block, axonal connections remain intact

Laboratory Features

• CFS findings:– Elevated CSF protein– Without accompanying pleocytosis– Csf is often normal when symptoms have been

present for <48 hrs

Diagnosis

• Diagnosis is made by recognizing the pattern of rapidly evolving paralysis with areflexia, absence of systemic symptoms and characteristic antecedent events

• Required diagnostic criteria– Progressive weakness of 2 or more limbs due to

neuropathy– Areflexia– Disease course < 4 weeks– Exclusion of other causes

Treatment

• Treatment should be initiated as soon after the diagnosis as possible

• ~ 2 weeks after the first motor symptoms, immunotherapy is no longer effective

• IVIg (2g/kg) or plasmapheresis (40-50 ml/kg plasma exchange 4x/week)

Prognosis

• Approximately 85% of patients with GBS achieve full functional recovery within several months to a year

• Mortality rate is <5% in optimal settings• Death usually result from secondary

pulmonary complications