Viruses follow a complex lifecycle, from attaching to host cells to releasing new viral particles. This process involves key stages like entry, uncoating, replication, assembly, and release. Each step presents unique challenges and opportunities for viral survival and spread.

Understanding these stages is crucial for developing effective antiviral strategies. By targeting specific points in the viral lifecycle, scientists can create drugs that disrupt replication and limit infection. This knowledge forms the foundation for combating viral diseases and preventing outbreaks.

Viral Replication Stages

Attachment and Entry

• Viral replication initiates with attachment involving specific interactions between viral surface proteins and host cell receptors
  • Determines viral tropism and host range
  • Examples: HIV gp120 protein binding to CD4 receptors, influenza hemagglutinin binding to sialic acid
• Penetration follows attachment through various mechanisms
  • Endocytosis (clathrin-mediated or caveolae-dependent)
  • Membrane fusion (pH-dependent or pH-independent)
  • Direct injection of viral genetic material
  • Examples: Influenza enters via endocytosis, HIV via membrane fusion

Uncoating and Replication

• Uncoating removes the viral capsid exposing the viral genome within the host cell
  • Facilitated by changes in pH, cellular enzymes, or viral proteins
  • Example: Adenovirus uses its own protease to partially digest capsid proteins
• Replication synthesizes viral genomic material and proteins using host cell machinery
  • Occurs in cytoplasm or nucleus depending on virus type
  • Involves transcription of viral genes, translation of viral proteins, and genome replication
  • Example: Hepatitis C virus replicates in cytoplasm, herpes simplex virus in nucleus

Assembly and Release

• Assembly packages newly synthesized viral genomes into capsids
  • Acquires envelope proteins for enveloped viruses
  • May involve scaffolding proteins or self-assembly mechanisms
  • Example: HIV Gag protein orchestrates virion assembly at the plasma membrane
• Release of mature virions occurs through various mechanisms
  • Cell lysis (non-enveloped viruses)
  • Exocytosis
  • Budding from host cell membrane (enveloped viruses)
  • Examples: Poliovirus released by cell lysis, influenza by budding

Molecular Processes in Replication

Attachment and Entry Mechanisms

• Attachment mediated by specific ligand-receptor interactions
  • Viral spike proteins or capsid components bind to host cell surface molecules
  • Example: SARS-CoV-2 spike protein binds to ACE2 receptors
• Penetration triggered by conformational changes in viral proteins
  • Activates cellular endocytosis pathways or initiates membrane fusion
  • Example: Influenza hemagglutinin undergoes pH-induced conformational change to mediate fusion

Genome Replication and Protein Synthesis

• Transcription of viral genes uses viral or host RNA polymerases
  • DNA viruses typically use host RNA polymerase II
  • RNA viruses often encode their own RNA-dependent RNA polymerases
• Translation of viral proteins hijacks host ribosomes and translation factors
  • Some viruses shut off host protein synthesis to prioritize viral protein production
• Genome replication strategies vary by virus type
  • DNA viruses use host or viral DNA polymerases
  • RNA viruses use viral RNA-dependent RNA polymerases
  • Retroviruses employ reverse transcriptase to convert RNA to DNA

Virion Assembly and Release Processes

• Coordinated production and localization of viral structural proteins and genomic material
  • May involve viral chaperones or host cell compartments
  • Example: Hepatitis B virus core particles assemble in the cytoplasm around pregenomic RNA
• Release mechanisms often hijack cellular transport systems
  • ESCRT pathway used by many enveloped viruses for budding
  • Some viruses induce cell death pathways to facilitate egress
  • Example: Influenza virus neuraminidase cleaves sialic acids to release virions from cell surface

Replication Stages: Comparisons

Replication Site and Genome Type

• DNA viruses typically replicate in host cell nucleus
  • Exceptions include poxviruses which replicate in cytoplasm
  • Utilize host DNA replication machinery
• RNA viruses usually replicate in cytoplasm
  • Exceptions include influenza viruses which replicate in nucleus
  • Carry their own RNA-dependent RNA polymerases
• Retroviruses have unique replication cycle
  • Reverse transcribe RNA genome into DNA
  • Integrate DNA into host genome
  • Example: HIV integrates its DNA into host chromosomes

Virus Structure and Release Mechanisms

• Enveloped viruses acquire lipid envelope by budding from cellular membranes
  • Examples: HIV, influenza, coronaviruses
• Non-enveloped viruses released through cell lysis
  • Examples: Poliovirus, adenovirus
• Latent infections established by some viruses
  • Viral genomes persist without active replication
  • Example: Herpesviruses maintain latency in neurons
• Rapid lytic cycles characteristic of other viruses
  • Continuous replication and release of virions
  • Example: Picornaviruses complete replication cycle in hours

Genetic Diversity and Replication Complexity

• Segmented genome viruses can reassort genetic material during coinfection
  • Leads to genetic diversity and potential emergence of new strains
  • Example: Influenza A virus with 8 RNA segments
• Viral replication machinery complexity varies greatly
  • Simple viruses rely heavily on host factors
  • Large DNA viruses encode many of their own replication proteins
  • Example: Bacteriophage T4 encodes over 100 proteins including its own DNA polymerase

Antiviral Targets in Replication

Entry and Uncoating Inhibitors

• Attachment and entry inhibitors block viral binding or prevent membrane fusion
  • Example: Enfuvirtide prevents HIV fusion with host cells
• Uncoating inhibitors disrupt capsid disassembly
  • Example: Amantadine blocks M2 ion channel in influenza A, preventing uncoating

Replication and Assembly Inhibitors

• Viral polymerase inhibitors target replication of viral genetic material
  • Example: Acyclovir inhibits herpesvirus DNA polymerase
• Protease inhibitors interfere with processing of viral polyproteins
  • Examples: Lopinavir for HIV, simeprevir for hepatitis C virus
• Assembly inhibitors prevent formation of mature viral particles
  • Example: Bevirimat disrupts HIV capsid maturation

Release Inhibitors and Host-Targeting Antivirals

• Egress inhibitors prevent release of newly formed virions
  • Example: Oseltamivir inhibits influenza neuraminidase, preventing viral release
• Host-targeting antivirals modulate cellular processes required for viral replication
  • Broader approach to antiviral therapy
  • Potential advantages in reducing viral resistance
  • Example: Cyclophilin inhibitors block essential host factors for HCV replication