Abstract
The evolutionary conflict between retroviruses and their vertebrate hosts over millions of years has led to the emergence of cellular innate immune proteins termed restriction factors as well as their viral antagonists. Evidence accumulated in the last two decades has substantially increased our understanding of the elaborate mechanisms utilized by these restriction factors to inhibit retroviral replication, mechanisms that either directly block viral proteins or interfere with the cellular pathways hijacked by the viruses. Analyses of these complex interactions describe patterns of accelerated evolution for these restriction factors as well as the acquisition and evolution of their virus-encoded antagonists. Evidence is also mounting that many restriction factors identified for their inhibition of specific retroviruses have broader antiviral activity against additional retroviruses as well as against other viruses, and that exposure to these multiple virus challenges has shaped their adaptive evolution. In this review, we provide an overview of the restriction factors that interfere with different steps of the retroviral life cycle, describing their mechanisms of action, adaptive evolution, viral targets and the viral antagonists that evolved to counter these factors.
Highlights
Retroviruses replicate by converting their single-stranded RNA genome into double-stranded DNA through a virus-encoded reverse transcriptase
SERINC5 belongs to the serine incorporator (SERINC) gene family, a highly conserved group of genes found in all eukaryotes that encode 9-11 pass transmembrane proteins
This is in line with the high degree of conservation in the primary amino acid sequence of SERINC5 in vertebrate lineages, and this conservation is reflected in the fact that SERINC5 is under purifying rather than positive selection in primates, suggesting that preservation of its cellular function cannot tolerate alterations [56]
Summary
Retroviruses replicate by converting their single-stranded RNA genome into double-stranded DNA through a virus-encoded reverse transcriptase. The majority of these factors were discovered in primates or rodents through studies on HIV-1 which causes the acquired immune deficiency syndrome (AIDS) in humans, and on mouse leukemia viruses (MLVs) which induce lymphomas, immunodeficiencies, and neurological diseases Some of these factors are restricted to specific taxonomic lineages, while others are carried by many mammalian species, showing broad antiviral activity against multiple retroviruses and in some cases against other families of viruses (Table 1). The mouse genome contains several such resistance genes including Fv4, which blocks ecotropic MLVs, and Rmcf and Rmcf which restrict XPR1-dependent MLVs (Figure 1) These genes have all been identified as ERVs that are defective but have intact env genes capable of producing trimeric proteins comprised of extracellular surface (SU) subunits that bind virus and the transmembrane (TM) subunit responsible for fusing host and viral membranes. This use of co-opted Env genes to block exogenous infection has been described in chickens, sheep, and cats (reviewed in [33])
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