Evolutionary conflicts and adverse effects of antiviral factors

Abstract

Human cells are equipped with a plethora of antiviral proteins protecting them against invading viral pathogens. In contrast to apoptotic or pyroptotic cell death, which serves as ultima ratio to combat viral infections, these cell-intrinsic restriction factors may prevent or at least slow down viral spread while allowing the host cell to survive. Nevertheless, their antiviral activity may also have detrimental effects on the host. While the molecular mechanisms underlying the antiviral activity of restriction factors are frequently well investigated, potential undesired effects of their antiviral functions on the host cell are hardly explored. With a focus on antiretroviral proteins, we summarize in this review how individual restriction factors may exert adverse effects as trade-off for efficient defense against attacking pathogens.

Keywords: adverse effects; evolutionary biology; innate immunitya; restriction factors; viral pathogens.

Figure 1.. Antiviral factors targeting components of the virus.

The retroviral replication is exemplarily shown to illustrate antiviral host factors (violet) that directly target viral proteins, nucleic acids, and membranes during essentially all steps of the viral life cycle. While some factors successfully distinguish between self (blue, right panel) and non-self (pink, left panel), others may have unintended side effects on the host as they also target cellular factors. CpG: cytosine guanine dinucleotides; dsRNA: double-stranded ribonucleic acid; CAP0: 5′ mRNA cap with unmethylated ribose hydroxy-groups; CAP1: 5′ mRNA cap with methylated ribose hydroxy-group; IRES: internal ribosome entry site; PPP: 5′-triphosphate group without cap; abbreviations of protein names are explained in the text.

Figure 2.. Antiviral factors modulating virus-dependency factors.

Several antiviral host proteins (violet) suppress viral replication (left panel) by modulating the stability, localization, or activity of cellular factors (orange) involved in the viral replication cycle. Since these host factors also play important roles in the cell, their inhibition may be associated with detrimental side effects (right panel). dsRNA: double-stranded ribonucleic acid; tRNA: transfer ribonucleic acid; 25-HO-Chol.: 25-hydroxy-cholesterol; abbreviations of protein names are explained in the text.

Figure 3.. Dual role of endogenous retroviruses (ERVs).

ERV-derived regulatory elements (promoters, enhancers, repressors, insulators) and proteins (syncytin-1, syncytin-2, suppressyn, etc.) may have beneficial (left) or detrimental (right) effects on the host. Abbreviations are explained in the text.

Figure 4.. Long-term effects of antiviral proteins on host evolution.

Antiviral proteins (violet) exert selection pressure on host factors to limit similarities with viral factors. As a result, the emergence of antiviral cellular factors may be associated with constraints in host evolution.