Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations

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.

Patterns of Coevolutionary Adaptations across Time and Space in Mouse Gammaretroviruses and Three Restrictive Host Factors

“…Viruses 2021, 13, 1864 2 of 19 The various laboratory strains and wild mouse subspecies differ in their susceptibility to MLVs, and to virus-induced disease, due to host factors that can inhibit virus replication at different stages of the virus life cycle, including entry, reverse transcription, transport to the nucleus, transcription, and budding [8]. Some of these factors have no known function other than virus restriction, while others serve important host functions that also facilitate virus replication but can have restrictive polymorphic variants.…”

HTLV-1 Infection and Pathogenesis: New Insights from Cellular and Animal Models

“…Many RF suppress viral replication by directly targeting conserved essential steps of the viral cycle, including viral entry, uncoating, DNA integration, proviral genome transcription, and budding, thus exerting broad antiviral activity. In contrast, some RF inhibit viral pathogens more indirectly by affecting the stability, localization or activity of cellular factors or limiting the availability of cellular resources such as nucleotides needed in the viral replication cycle [ 51 , 52 ]. While each RF uses a distinct mechanism of inhibition, the virus has equally evolved complex strategies to neutralize their inhibitory effect.…”

Foamy Viruses, Bet, and APOBEC3 Restriction

“…Specific IFN-induced cellular gene products are able to restrict different retroviruses, including FVs [ 121 , 122 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 ]. Similar to other retroviruses, TRIM5α targets the core of PFV, SFV, and FFV during early post-infection events in a species-dependent manner [ 135 , 139 , 143 ].…”