Amyloidoses encompass a wide range of incurable animal diseases characterized by the deposition of amyloid fibrils either in localized organs (including the brain) or systemic tissues. Approximately 50 human proteins have been identified as contributors to amyloid fibril formation and are often linked to specific pathologies, like Alzheimer's disease (AD) and Parkinson's disease (PD). Recent successes using small molecules [1,2] or rationally designed peptides [3] hold promises for the discovery of future therapeutic approaches to prevent or even cure amyloidoses.

Most proteins, if not all, have the potential to undergo a transition to the amyloid state, the most energetically stable conformation possible [4] (Figure 1). The amino acid sequence contains the necessary information for structured proteins to adopt their native 3D structure, and for intrinsically disordered proteins (IDPs) to exist as disordered conformational ensembles. However, proteins also contain sequences, known as amyloid- or aggregation-prone regions (APRs), which drive the formation of an alternative structure (Figure 1). In this process, cellular stress typically causes partial unfolding of monomeric amyloidogenic precursors and exposure of APRs. The precursor then adopts an alternative β-rich conformation that results in aberrant assembly into straight, unbranched fibrils that are packed together to form steric zippers [5] (Figure 1). In the aggregates, the β-strands stack in perpendicular layers along the axis of the fibrils, creating the distinctive “amyloid fold”. The cross β-sheets, together with the connecting loops, constitute the “amyloid core”. Amyloids are typically detected using specific dyes such as thioflavin (ThT and ThS) and Congo Red.

IDPs can engage in the amyloid pathway, but unlike folded proteins, they do not require an unfolding step [6]. Approximately one-third of human proteins serving as precursors to human amyloidosis are intrinsically disordered, with Aβ peptides, α-synuclein, and Tau being illustrative examples.

Despite their role in protein misfolding diseases, amyloids are not systematically tied to pathologies and can have a functional role [7]. Increasing evidence suggests that viruses encode amyloidogenic proteins that form fibrillar aggregates (Figure 2). Several viral amyloids were shown to have functions that benefit the virus itself, supporting their classification as functional amyloids.

In this review, we focus on viral amyloids and the mechanisms driving their formation, and discuss the functional implications of amyloids for viral replication and the intricate interplay between viral amyloids, biological functions, virulence, and pathologies.