Viral replication and pathogenesis

Viral infection 

Viral replication  and pathogenesis

Steps of viral replication 

General phases in animal virus multiplication cycle:

1.     Adsorption – binding of virus to specific molecule on host cell

2.     Penetration – genome enters host cell

3.     Uncoating – the viral nucleic acid is released from the capsid

4.     Synthesis – viral components are produced

5.     Assembly – new viral particles are constructed

6.     Release – assembled viruses are released by budding (exocytosis) or cell lysis

1. Adsorption

The virus becomes attached to the cells, and at this stage, it can be recovered in the infectious form without cell lysis by procedures that either destroy the receptors or weaken their bonds to the virions. Animal viruses have specialized attachment sites distributed over the surface of the virion e.g. orthomyxoviruses and paramyxoviruses attach through glycoprotein spikes, and adenoviruses attach through the penton fibers. Adsorption occurs to specific cellular receptors. Some receptors are glycoproteins, others are phospholipids or glycolipids. These are usually macromolecules with specific physiological functions, such as complement receptors for EBV. Whether or not receptors for a certain virus are present on a cell depends on the species, the tissue and its physiological state. Cells lacking specific receptors are resistant. Attachment is blocked by antibodies that bind to the viral or cellular sites involved.  

2. Penetration

Penetration rapidly follows adsorption, and the virus can no longer be recovered from the intact cell. The most common mechanism is receptor mediated endocytosis, the process by which many hormones and toxins enter cells. The virion is endocytosed and contained within a cytoplasmic vacuole.  

3. Uncoating

A key step in uncoating is the acidification of the content of the endosome to a pH of about 5, owing to the activity of a proton pump present in the membrane. The low pH causes rearrangement of coat components, which then expose normally hidden hydrophobic sites. They bind to the lipid bilayer of the membrane, causing the extrusion of the viral core into the cytosol. For influenza virus, the acid-sensitive component is the core HA₂ unit of the haemagglutinin, for adenoviruses, it is the penton base.

4. Viral Nucleic Acid Replication

Virulent viruses, either DNA and RNA, shut off cellular protein synthesis and disaggregate cellular polyribosomes, favouring a shift to viral synthesis. The mechanism of protein synthesis shut-off varies even within the same viral family. 

Replication and Protein Production

•         Varies depending on whether the virus is a DNA or RNA virus

•         DNA viruses generally are replicated and assembled in the nucleus

•         RNA viruses generally are replicated and assembled in the cytoplasm

–        Positive-sense RNA contain the message for translation

–        Negative-sense RNA must be converted into positive-sense message

Release

•         Assembled viruses leave host cell in one of two ways:

–        Budding – exocytosis; nucleocapsid binds to membrane which pinches off and sheds the viruses gradually; cell is not immediately destroyed

–        Lysis – non enveloped and complex viruses released when cell dies and ruptures

Transmission routes (Viral Entry)

1. Skin – through cut or vectors
2. Conjunctiva and other mucous membranes - rather exposed site and relatively unprotected
3. Respiratory tract -
4. Gastrointestinal tract -
5. Genitourinary tract -

Course of Viral Infection

• Primary Replication
• The place of primary replication is where the virus replicates after gaining initial entry into the host. either  localized at the site of entry or spread to become a systemic infection.
• Systemic Spread
• Apart from direct cell-to-cell contact, the virus may spread via the blood stream and the CNS.
• Secondary Replication
• Secondary replication takes place at susceptible organs/tissues following systemic spread.

Viral  Pathogenesis

 Viral pathogenesis is the process by which a viral infection leads to disease. Infections depend on number of viral and host factors.

 a-Acute Infection

- Recovery with no residue effects

-Recovery with residue effects e.g. acute viral encephalitis leading to neurological sequelae.

- Death

-  Proceed to chronic infection

b-  Chronic Infection

- Silent subclinical infection for life e.g. CMV, EBV

- A long silent period before disease e.g. HIV, SSPE, PML

- Reactivation to cause acute disease e.g. herpes and shingles.

- Chronic disease with relapses and exacerbationsتفاقم .g. HBV, HCV.

-  Cancers e.g. EBV, HTLV-1, HPV, HBV, HCV, HHV-8

Immunopathogenesis

Although the immune response is essential to control the virus infection, it is also a major contributor to the disease signs and symptoms. It takes energy to combat a viral infection, and many protective immune responses also cause cell damage. Interferon and cytokines not only mobilize the body’s defenses against the virus, but also cause the flu-like symptoms of fever, malaise, headache, muscle ache, and lack of appetite. Inflammation, rashes, and tissue destruction can be the consequence of cell-mediated immune responses causing peripheral damage as they kill infected cells to combat the virus. Immune complexes between viral antigen and antibody can lead to hypersensitivity reactions as with the arthritis that accompanies adult infection by the B19 parvovirus or the rubella (German measles) virus. The large amount of viral antigen particles (HBsAg) during hepatitis B infection can cause glomerulonephritis.