Adenoviruses are a common type of virus that can cause a range of illnesses, from respiratory infections like the common cold to gastrointestinal issues. These non-enveloped viruses, characterized by their protein capsid and double-stranded DNA genome, infect various cell types in humans and other animals.
Viral Entry and Initial Steps
Adenoviruses begin by attaching to a host cell. The virus uses specialized fiber proteins to bind to specific receptors on the surface of human cells, such as the coxsackievirus adenovirus receptor (CAR) or CD46. A secondary interaction then occurs, where the penton base protein interacts with integrin molecules, particularly alpha-v integrins. This co-receptor interaction stimulates the cell to internalize the virus.
The host cell then engulfs the virus through a process called receptor-mediated endocytosis, often involving clathrin-coated pits. Inside the endosome, the acidic environment of this compartment causes conformational changes in the viral capsid, leading to partial disassembly. This also releases protein VI, a multifunctional inner capsid protein with membrane lytic properties.
The partially uncoated virus then escapes the endosome and moves through the cytoplasm towards the cell’s nucleus, often utilizing cellular microtubules and motor proteins like dynein. Upon reaching the nuclear pore complex, the virus undergoes a final uncoating step, shedding more of its capsid layers. This releases the viral double-stranded DNA genome into the nucleus for replication.
Replication and Protein Synthesis
Once the viral DNA enters the host cell’s nucleus, the adenovirus begins to utilize cellular machinery. The viral gene expression program occurs in two distinct phases: early and late, defined by the onset of viral DNA replication. In the early phase, genes like E1A, E1B, E2, E3, and E4 are expressed.
These “early” proteins serve several purposes, including altering the expression of host proteins necessary for DNA synthesis, activating other viral genes, and suppressing the host’s antiviral defenses. For instance, E1A proteins induce cell cycle progression in non-dividing cells and stimulate the expression of other viral genes, while E1B proteins help prevent apoptosis. The host’s RNA polymerase II is used to transcribe the viral genes into messenger RNA (mRNA).
Following the production of early proteins, viral DNA replication commences around 6 hours post-infection. The viral DNA polymerase, using a unique strand displacement mechanism, copies the viral genome multiple times. A terminal protein covalently bound to the 5′ end of the adenovirus genome acts as a primer for this replication.
After DNA replication, the “late” genes are expressed, primarily encoding the structural proteins needed to build new virus particles. These late transcripts are translated into proteins using the host cell’s ribosomes in the cytoplasm. These newly synthesized structural proteins, such as hexon, penton base, and fiber proteins, are then transported back into the nucleus for assembly.
Assembly and Release
The final stages of the adenovirus life cycle involve the assembly of new virus particles within the host cell’s nucleus. The newly replicated viral DNA genomes and the newly synthesized structural proteins are brought together in viral replication compartments. These compartments serve as organizing hubs for the assembly process.
Inside the nucleus, the viral DNA condenses and is packaged into the protein shells formed by the major capsid proteins. This process results in the formation of complete, infectious adenovirus particles, known as virions. The virions undergo a maturation process that involves proteolytic processing of several precursor proteins, transforming immature capsids into infection-competent particles.
Once a sufficient number of new virions have been assembled, they exit the host cell by causing the cell to burst. This process, known as lysis, is facilitated by viral proteins such as the adenovirus death protein (ADP), also known as E3-11.6K, which helps mediate the destruction of the nuclear membrane. Lysis releases thousands of new viral particles, allowing them to infect neighboring cells and continue the infection cycle.
Why Understanding the Life Cycle Matters
Understanding the adenovirus life cycle informs several practical applications. Knowledge of each step helps scientists understand how these viruses cause illness, leading to the development of targeted treatments. By identifying the specific mechanisms of viral entry, replication, and protein synthesis, researchers can pinpoint vulnerabilities to interrupt the infection process.
Insights into viral replication and immune responses also inform the design of vaccines. Adenovirus vectors, modified to be replication-defective by removing genes like E1 and E3, have been used widely as vaccine platforms. These vectors can deliver foreign antigens to the host, triggering a robust immune response, as demonstrated in the development of some COVID-19 vaccines.
Adenoviruses are also engineered as “delivery vehicles” for gene therapy. With their replication genes removed, these modified viruses can efficiently introduce beneficial genes into human cells. Their ability to transduce both dividing and non-dividing cells and carry significant genetic material makes them a suitable tool for delivering therapeutic genes in various medical applications, including cancer therapies.