Polyomaviruses: Structure, Entry, Replication, and Immune Evasion

Polyomaviruses are small, non-enveloped DNA viruses known for their ability to infect a wide range of hosts and their association with various diseases, including cancer. Understanding their biology is key to developing therapeutic strategies and preventative measures.

Viral Structure and Genome

Polyomaviruses have a simple, efficient structure with an icosahedral capsid made of 72 pentameric capsomers. The major structural protein, VP1, is essential for attaching to host cells, while minor proteins VP2 and VP3 are crucial for cell entry. The virus’s circular, double-stranded DNA genome, about 5,000 base pairs long, encodes early and late proteins. Early proteins, such as the large T-antigen and small t-antigen, are vital for viral replication and manipulation of the host cell cycle, potentially leading to oncogenic transformations. The late region encodes structural proteins necessary for assembling new viral particles. The non-coding control region contains the origin of replication and promoters for gene expression.

Host Range and Specificity

Polyomaviruses can infect a diverse array of hosts, from birds to mammals, including humans. This adaptability is influenced by the virus’s ability to bind to specific receptors on host cells. For example, the murine polyomavirus primarily infects rodents, while BK and JC viruses are more common in humans. Genetic variations and mutations allow these viruses to exploit new receptors or adapt to different environments. The binding to sialic acid-containing glycans on cell surfaces partly explains their wide host range. Subtle differences in receptor preference and affinity contribute to infection specificity, impacting which tissues or cell types are targeted. Other factors, such as immune status and genetic predispositions, influence susceptibility and disease severity.

Cell Entry Mechanisms

Polyomaviruses enter host cells by binding to specific cell surface receptors, facilitated by viral capsid proteins. Once attached, the virus uses endocytic pathways, such as clathrin-mediated endocytosis, to gain entry. As the virus moves through the endosomal pathway, acidification triggers conformational changes in the capsid, aiding genome release into the cytosol. The virus may hijack motor proteins to transport the genome to the nucleus, where replication occurs.

Viral Replication Process

Inside the nucleus, polyomaviruses initiate replication, relying on the host’s cellular machinery. The viral DNA serves as a template for transcription, with early genes encoding proteins that orchestrate the replication cycle. These proteins facilitate viral DNA replication and modulate the host cell cycle. As the host cell enters the S phase, the replication machinery duplicates the viral genome, using the cell’s DNA polymerases. The replicated genomes serve as templates for late gene transcription, encoding structural proteins for new virions.

Immune Evasion Strategies

Polyomaviruses have evolved mechanisms to evade the host immune system, enabling persistent infections. They can remain latent, minimizing protein expression to avoid immune recognition. Additionally, they interfere with antigen presentation pathways, downregulating MHC molecules to prevent cytotoxic T lymphocytes from identifying infected cells.

Oncogenic Potential and Pathogenesis

The oncogenic potential of polyomaviruses involves interactions between viral proteins and host cell regulators. The large T-antigen can inactivate tumor suppressor proteins, disrupting cell cycle control and promoting uncontrolled proliferation. In humans, BK and JC viruses are linked to significant diseases, particularly in immunocompromised individuals. BK virus can cause severe kidney complications, while JC virus leads to progressive multifocal leukoencephalopathy, a debilitating brain disease. Understanding the interplay between viral factors and host immune responses is essential for addressing these pathologies.