Viral and host heterogeneity and their effects on the viral life cycle

Abstract

Traditionally, the viral replication cycle is envisioned as a single, well-defined loop with four major steps: attachment and entry into a target cell, replication of the viral genome, maturation of viral proteins and genome packaging into infectious progeny, and egress and dissemination to the next target cell. However, for many viruses, a growing body of evidence points towards extreme heterogeneity in each of these steps. In this Review, we reassess the major steps of the viral replication cycle by highlighting recent advances that show considerable variability during viral infection. First, we discuss heterogeneity in entry receptors, followed by a discussion on error-prone and low-fidelity polymerases and their impact on viral diversity. Next, we cover the implications of heterogeneity in genome packaging and assembly on virion morphology. Last, we explore alternative egress mechanisms, including tunnelling nanotubes and host microvesicles. In summary, we discuss the implications of viral phenotypic, morphological and genetic heterogeneity on pathogenesis and medicine. This Review highlights common themes and unique features that give nuance to the viral replication cycle.

Fig. 1. Heterogeneity in the virus replication cycle.

a | Traditional depiction of the viral replication cycle with its series of defined, uniform steps, using human metapneumovirus (HMPV) as an example. HMPV virions bind to a target receptor and fuse with the host cell membrane (step 1). After fusion, viral RNA is replicated in cytoplasmic replication organelles (step 2) and viral proteins are produced and undergo assembly with the viral RNA (step 3). Homogeneous mature virus particles undergo egress through the cellular membrane (step 4). b | Evidence of substantial heterogeneity in the viral replication cycle is accumulating. Entry can be impacted by the presence of post-translational modification of receptors, including glycosylation (step 1). Upon entry, HMPV replication organelles can traffic along actin-containing nanotubes across tight junctions of the lung epithelium (step 2). Variation in assembly (step 3) and egress (step 4) lead to the maturation of heterogeneous virus particles from the cell. Similar heterogeneity has been observed in many different viruses.

Fig. 2. Heterogeneity in glycosylation of entry receptors.

a | Differences between individual hosts can affect viral entry, such as heterogeneous host populations (left) that carry differentially modified viral receptors. In the example shown, hepatitis C virus (HCV) has different affinities for variants of its co-receptor, scavenger receptor class B type I (SR-BI). The glycosylated wild-type (WT) T175 variant (top) binds HCV, and the unmodified T175A variant found in human SR-BI (bottom) does not. b | Furthermore, species-level determinants of viral entry exist. Middle East respiratory syndrome coronavirus (MERS-CoV) differs in its affinity for different variants of the receptor dipeptidyl peptidase 4 (DPP4). Humans, camels and bats carry unmodified DPP4 (left), which binds MERS-CoV, whereas the glycosylated DPP4 variants found in mice, ferrets and guinea pigs (right) do not support infection. *Additional determinants exist.

Fig. 3. Heterogeneity in influenza virus particle morphology.

a | Traditionally, all pleomorphic influenza virus particles were thought to comprise viral components only. This traditional influenza virus particle is shown, displaying spherical morphology and consisting of haemagglutinin (HA), neuraminidase (NA), matrix (M1) and viral genomic material. b | Careful studies of virions have revealed a revised architecture consisting of an influenza virion that encases several components of host exosomes. c | Influenza virus also assumes a filamentous morphology of variable length with polarized NA proteins. ANXA, annexin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; UBB, ubiquitin.