Adenoviruses are non-enveloped viruses characterized by an icosahedral protein shell surrounding a linear double-stranded DNA genome. They are widespread in human populations and are commonly associated with self-limiting illnesses, such as respiratory infections and conjunctivitis, often referred to as “pink eye.” The virus engages in a highly coordinated life cycle, systematically exploiting the host cell’s internal machinery and resources. This process is strictly regulated, ensuring the efficient production of new infectious particles within the host cell’s nucleus. The entire cycle represents an intricate interplay of viral and cellular molecular components, orchestrated to maximize viral output.
Entry and Nuclear Genome Delivery
Attachment of the virion to the host cell surface occurs through receptor interactions. The knob domain of the viral Fiber protein initially binds to a primary receptor, most frequently the Coxsackievirus and Adenovirus Receptor (CAR) on the cell membrane. This initial tethering is strengthened by a secondary interaction involving the Penton base protein, which contains an Arginine-Glycine-Aspartic acid (RGD) motif that binds to cellular integrin proteins.
The co-engagement of these two distinct receptors triggers the host cell to internalize the virus via receptor-mediated endocytosis. Once enclosed within an endosome, the mildly acidic environment causes the virus to undergo a partial disassembly, which destabilizes the outer capsid. This structural change leads to the release of internal components, including the membrane-lytic protein VI, which facilitates the escape of the partially uncoated particle from the endosome into the cytoplasm.
The particle then associates with the host cell’s microtubule network and is transported toward the nucleus. Upon reaching the nuclear membrane, the particle docks at a nuclear pore complex (NPC). The final uncoating occurs at this complex, resulting in the dissociation of remaining capsid proteins and the injection of the viral DNA, which remains associated with viral core proteins, directly into the nuclear interior for replication and transcription.
Viral Gene Expression and DNA Replication
Once the viral DNA is delivered to the nucleus, the viral life cycle shifts to the expression of early genes. The earliest gene expressed is E1A, which serves as a transcriptional activator for almost all other viral genes. E1A’s function extends beyond transcription by targeting the host cell’s growth control mechanisms, notably the retinoblastoma protein (pRb).
By binding to pRb, E1A prevents it from repressing transcription factors like E2F, which activate genes necessary for DNA synthesis. This forces the normally quiescent host cell into the S-phase of the cell cycle for viral DNA replication. This forced proliferation, however, often triggers a cellular self-destruct mechanism called apoptosis.
To counteract this defense, the virus expresses the E1B protein, which functions to inhibit programmed cell death (apoptosis). The E1B-55K protein blocks the tumor suppressor protein p53, which would otherwise initiate apoptosis in response to the cell cycle deregulation caused by E1A. The E1B-19K protein, which is functionally analogous to the cellular Bcl-2 protein, also contributes to suppressing apoptosis, ensuring the host cell remains viable long enough to produce a full yield of new virions.
Following the early phase, the viral genome is replicated using a unique strategy known as protein-primed DNA replication. This process is independent of the typical RNA primers used by host cell DNA polymerases. Instead, a viral protein, the precursor Terminal Protein (pTP), acts as the primer by covalently attaching to the first nucleotide, deoxycytidine monophosphate (dCMP).
The pTP-dCMP complex then binds to the inverted terminal repeats (ITRs) at the ends of the linear viral genome, providing a free hydroxyl group to initiate DNA synthesis. The viral DNA polymerase, alongside the viral DNA-binding protein (DBP), proceeds to synthesize a new DNA strand, displacing the original strand. This mechanism allows the virus to replicate its linear genome end-to-end without losing genetic information.
Assembly and Virion Egress
The late phase of the infection begins after the onset of DNA replication and focuses on the production of structural proteins. Genes from the major late transcription unit (L1 to L5) are expressed, encoding the components of the icosahedral capsid, such as the Hexon, Penton base, and Fiber proteins. These proteins are synthesized in the cytoplasm and then transported back into the nucleus, where assembly takes place.
Within the nucleus, the newly synthesized capsid components self-assemble into empty procapsids. The viral DNA, which is already complexed with the viral core proteins like protein VII, is then packaged into the procapsids. Packaging also includes the precursor terminal protein (pTP) remaining covalently bound to the DNA ends.
The final step in assembly, known as maturation, involves the proteolytic cleavage of several precursor proteins within the virion by the virus-encoded protease (AVP). This cleavage transforms the unstable immature particle into a stable, infectious virion. The mature virions accumulate in the nucleus until the cell is overwhelmed and ruptures.
The final stage of the life cycle is the egress of the progeny virions from the host cell, which is accomplished through cell lysis. This physical disruption of the cell membrane and nuclear structure is often facilitated by the Adenovirus Death Protein (ADP), which aids in the destruction of the infected cell. The bursting of the cell releases thousands of newly formed, infectious adenovirus particles into the environment.