lec 12:Viral Molecular Biology: Structure, Replication, Entry, and Pathogenesis

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Viral Structure and Classification

Capsid and Nucleocapsid

The capsid is a protein shell that protects the viral nucleic acid genome from enzymatic degradation. The nucleocapsid consists of the capsid together with the genome. Viruses can be classified as naked viruses (lacking an envelope) or enveloped viruses (possessing a lipid membrane derived from the host cell).

Capsid protein: Encases and protects the viral genome.
Viral receptor-binding protein: Facilitates attachment to host cells.
Genome types: Viruses may have single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), or DNA genomes.

Diagram of naked and enveloped virus structure

Example: HIV is an enveloped virus, while poliovirus is a naked virus.

Viral Replication Cycle

Attachment

Viruses attach to host cells via specific proteins on their surface that bind to corresponding receptor molecules on the host cell membrane. This receptor specificity determines the host range and tissue tropism of the virus.

Lock-and-key interaction: Ensures only certain cells are susceptible to infection.
Example: HIV binds to CD4 receptors on T-helper cells; rhinoviruses bind to ICAM-1 receptors on respiratory cells.

HIV life cycle showing binding to CD4 cell

Entry (Penetration)

Viruses enter host cells through several mechanisms:

Membrane Fusion: Enveloped viruses fuse their membrane with the host cell membrane, releasing the viral core into the cytoplasm.

Membrane fusion entry mechanism

Endocytosis: Viruses are engulfed by the cell, forming a vesicle that transports the virus inside.

Endocytosis of virus into host cell

Genetic Injection: Bacteriophages inject their genetic material into bacteria, leaving the capsid outside.

Bacteriophage DNA injection mechanism

Uncoating

After entry, the virus sheds its protein coat to release its genetic material. Uncoating is often triggered by the acidic environment within cellular vesicles.

Viral uncoating mechanisms

Replication and Biosynthesis

Viruses hijack the host cell's machinery to produce viral proteins and replicate their genome. DNA viruses typically replicate in the nucleus, while most RNA viruses replicate in the cytoplasm.

Viral protein production: Viral genome directs synthesis of viral enzymes and structural proteins.
Genome replication: Host ribosomes and polymerases are used to make new viral genomes.

Viral replication and biosynthesis diagram Virus replication overview

Assembly (Maturation)

New viral proteins and genomes are assembled into immature virus particles. This process may occur in the nucleus or cytoplasm, depending on the virus.

Virus assembly mechanisms

Release (Egress)

Viruses exit the host cell by two main mechanisms:

Lysis: Host cell bursts, releasing viruses and killing the cell.
Budding: Enveloped viruses acquire their membrane by budding from the host cell, allowing continued virus production.

Viral budding process

Molecular Hurdles of the Host Cell

Barriers to Viral Infection

Eukaryotic cells present several molecular hurdles to viral infection:

Receptors and polymerases: Host cells lack viral-specific polymerases; viruses encode their own RNA-dependent RNA polymerases.
Actin remodeling: Actin cytoskeleton affects viral entry, movement, and egress.
Ribosome and mRNA compatibility: Host translation machinery is restricted to monocistronic RNAs; viruses use alternative splicing, segmented genomes, or polyproteins.
Virus–host mRNA competition: Viruses evolve mechanisms to dominate protein synthesis in the host cell.

Cellular barriers to viral infection

Genetic Diversity and Mutation

Error-Prone RNA Polymerases

RNA viruses mutate rapidly because their RNA polymerases lack proofreading ability, leading to high genetic diversity and adaptability.

Mutation rate: Higher in RNA viruses than DNA viruses.
Implication: Rapid evolution and emergence of new viral strains.

Antiviral Therapies

Targets for Antiviral Drugs

Effective antiviral drugs must target essential viral processes without being toxic to the host. Common targets include viral polymerases, proteases, and entry mechanisms.

Specificity: Drugs must distinguish viral from host functions.
Example: Reverse transcriptase inhibitors for HIV.

Mechanisms of Viral Entry and Spread in the Body

Preferred Routes of Entry

Viruses enter hosts through skin or mucous membranes, including the respiratory tract, gastrointestinal tract, genital tract, conjunctiva, and placenta.

Respiratory tract: Most frequent route; viruses enter via inhaled droplets.
Gastrointestinal tract: Viruses must resist acidic conditions; entry via contaminated food or water.
Genital tract: Entry through abrasions or infection of reproductive cells.
Conjunctiva: Entry via the eye's surface tissue.
Placenta: Bloodborne viruses can cross to the fetus.

Routes of viral entry

Respiratory Tract Entry

Viruses such as rhinoviruses, coronaviruses, and influenza viruses commonly enter via the respiratory tract.

Respiratory tract anatomy

Gastrointestinal Tract Entry

Viruses entering through the gastrointestinal tract must survive harsh digestive conditions. Common examples include norovirus and rotavirus.

Table of gastrointestinal viruses and symptoms

Genital Tract Entry

Sexually transmitted viruses infect through the genital tract, often via micro-abrasions or direct infection of epithelial cells.

Table of genital tract viruses and symptoms

Conjunctiva Entry

The conjunctiva is a thin, transparent tissue covering the eye. Viruses can cause conjunctivitis and other ocular diseases.

Conjunctiva of the eye Severe conjunctivitis

Other Routes of Entry

Viruses may enter through skin breaches, bone marrow or organ transplants, transfusions, or iatrogenic induction.

Mechanisms of Viral Spread and Pathogenesis

Routes of Transmission

Viruses spread between hosts via respiratory droplets, gastrointestinal (fecal-oral) route, skin breaches, genital contact, and vertical transmission (mother to child).

Vertical transmission: Includes transplacental, perinatal, and postnatal routes.
Zoonosis: Transmission from animals to humans; bushmeat is a major source.

Viral Infections and Pregnancy

Viruses can cross the placenta, causing severe outcomes such as spontaneous abortion, stillbirth, neonatal death, or congenital malformations.

Placental anatomy and viral transmission

Spread Within the Host

Viruses may spread locally or systemically after entry:

Local spread: Virus spreads to neighboring cells via extracellular release or cell fusion.
Systemic spread: Dissemination via bloodstream (hematogenous spread) or nerves (neurotropic spread).

Skin infection example Hematogenous spread diagram Neurotropic spread diagram

Virus Exit: Shedding

Shedding and Zoonosis Potential

Viruses are shed from their routes of entry or primary replication sites. Zoonotic viruses with segmented genomes are emerging pathogens (e.g., hantaviruses, arenaviruses, SARS, MERS, rabies, Ebola).

Survival of Viruses in the Environment

Factors Affecting Survival

Virus survival depends on composition, presence in human/animal wastes, temperature, humidity, and pH. Enteric viruses are more stable in water than bacteria.

Human Viruses in Water Environments

Humans are exposed to enteric viruses via contaminated shellfish, crops irrigated with wastewater, and polluted recreational/drinking water.

Groundwater Safety

Groundwater can be contaminated by viruses, as illustrated by outbreaks such as the 2007 norovirus incident in Wisconsin.

Groundwater contamination diagram

Patterns of Viral Disease

Types of Viral Infection

Viral infections can follow four patterns:

Acute infection: Rapid onset and resolution.
Acute infection followed by persistent latent infection: Virus remains dormant and can reactivate.
Chronic infection: Continuous shedding of virus.
Slow infection: Gradual progression over time.