Evolutionary conflicts between viruses and restriction factors shape immunity

Abstract

Host restriction factors are potent, widely expressed intracellular blocks to viral replication that are an important component of the innate immune response to viral infection. However, viruses have evolved mechanisms that antagonize restriction factors. Through evolutionary pressure for both host survival and virus replication, an evolutionary 'arms race' has developed that drives continuous rounds of selection for beneficial mutations in the genes encoding restriction factors and their viral antagonists. Because viruses can evolve faster than their hosts, the innate immune system of modern-day vertebrates is for the most part optimized to defend against ancient viruses, rather than newer viral threats. Thus, the evolutionary history of restriction factors might, in part, explain why humans are susceptible or resistant to the viruses present in the modern world.

Figure 1. Mechanisms of viral antagonism of host restriction factors.

a | Degradation. The lentiviral accessory protein Vpx antagonizes the host restriction factor SAMHD1 (SAM domain- and HD domain-containing protein 1) by targeting it for degradation^,. Vpx bridges SAMHD1 to an E3 ubiquitin (Ub) ligase complex, which ubiquitylates SAMHD1, thus targeting SAMHD1 for degradation by the proteasome. b | Mislocalization and sequestration. The HIV-1 accessory protein Vpu antagonizes the host restriction factor tetherin by promoting its mislocalization, which leads to functional downregulation. Vpu interacts with tetherin at the plasma membrane and facilitates its trafficking to early endosomes. Tetherin is then either sequestered in the trans-Golgi network, where it is unable to restrict viral budding from the cell surface, or degraded in lysosomes. c | Mimicry. The poxvirus accessory protein K3L antagonizes the host RNA-activated protein kinase (PKR) pathway by acting as a mimic of the PKR substrate, eukaryotic initiation factor 2 subunit-α (eIF2α). PKR is activated by binding to double-stranded RNA and induces an antiviral signalling pathway that leads to the inhibition of protein translation. By competing for PKR binding, K3L prevents the phosphorylation of eIF2α, thus pre-empting the antiviral response of host protein translation shut-off.

Figure 2. Genetic conflict between virus and host.

a | A host restriction factor (blue) that is antagonized by a viral factor (green) cannot restrict viral replication, and the host is susceptible to viral infection. This exerts a fitness cost on the host, and escape mutations will be selected for in the host factor. In return, when the host factor restricts viral replication, a fitness cost is exerted on the virus. Mutations that allow the virus to regain restriction factor antagonism (for example, by re-forming a protein–protein interface between the viral antagonist and the host factor) are selected for in the virus. This back-and-forth fitness adaptation in the virus and host leads to a conflict that is visible on the genetic level. b | Over time, in the absence of genetic conflict, most genes evolve under negative (purifying) selection. This leads to a lower rate of non-synonymous mutations (dN) than of synonymous mutations (dS) in the host gene, and the dN/dS ratio is predicted to be less than one. In the presence of a genetic conflict, such as that caused by a viral antagonist, the host gene will rapidly accumulate non-synonymous mutations, and the dN/dS ratio is predicted to be greater than one. Grey boxes represent synonymous changes, and orange boxes represent non-synonymous changes.

Figure 3. Identifying paleoviruses using positive selection.

a | Phylogeny of a restriction factor. Lineages under positive selection (shown in red) are identified using likelihood methods to calculate the ratio of the rate of non-synonymous mutations (dN) to the rate of synonymous mutations (dS) of the restriction factor for each branch. b | Infectivity assays. Restriction factor orthologues from extant species are tested for antiviral activity against a panel of viral targets, with the goal of finding species-specific antiviral activity. c | Inference of a paleovirus. In lineages that are under positive selection, a paleovirus similar to the virus against which the restriction factor has gained species-specific activity is predicted to have existed during the time of selection.