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

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.

Human DNA-PK activates a STING-independent DNA sensing pathway

Detection of intracellular DNA by the cGAS-STING pathway activates a type I interferon-mediated innate immune response that protects from virus infection. Whether there are additional DNA sensing pathways, and how such pathways might function, remains controversial. We show here that humans—but not laboratory mice—have a second, potent, STING-independent DNA sensing pathway (SIDSP). We identify human DNA-dependent protein kinase (DNA-PK) as the sensor of this pathway and demonstrate that DNA-PK activity drives a robust and broad antiviral response. We show that the E1A oncoprotein of human adenovirus 5 and the ICP0 protein of herpes simplex virus 1 block this response. We found heat shock protein HSPA8/HSC70 as a target for inducible phosphorylation in the DNA-PK antiviral pathway. Last, we demonstrate that DNA damage and detection of foreign DNA trigger distinct modalities of DNA-PK activity. These findings reveal the existence, sensor, a specific downstream target, and viral antagonists of a SIDSP in human cells.

Human DNA-PK activates a STING-independent DNA sensing pathway

SummaryDetection of intracellular DNA by the cGAS-STING pathway activates a type I interferon-mediated innate immune response that protects from virus infection and can be harnessed to promote anti-tumor immunity. Whether there are additional DNA sensing pathways, and how such pathways might function, remains controversial. We show here that humans – but not mice – have a second, potent, STING-independent DNA sensing pathway that is blocked by the E1A viral oncogene of human adenovirus 5. We identify human DNA-PK as the sensor of this pathway and demonstrate that DNA-PK kinase activity drives a robust and broad antiviral response. We discover that the heat shock protein HSPA8/HSC70 is a unique target of DNA-PK. Finally, we demonstrate that detection of foreign DNA and DNA damage trigger distinct modalities of DNA-PK activity. These findings reveal the existence, sensor, unique target, and viral antagonists of a STING-independent DNA sensing pathway (SIDSP) in human cells.

A Biological "Arms Race": APOBEC3F Diversity and its Influence on Lentiviral Resistance

Restriction factors are implemented in long-term evolutionary "arms races," in which viral antagonists drive the evolution of host proteins, and vice versa. Consequently, restriction factors are remarkably variable, displaying polymorphism within species and divergence between species as a result of positive selection. This paper investigates diversity in the APOBEC3F (A3F) restriction factors of Old World primates in order to determine whether they display evidence of involvement in an evolutionary "arms race." We speculated that genetic variability in A3F could reflect evolutionary conflict with the VIF proteins of primate lentiviruses, which are known to enhance viral replication by binding and degrading host A3 proteins. A3Fs of several Old World primate species were genotyped, and the sequences revealed both intra-spcies diversity and inter-species divergence. Representative rhesus macaque (<em>macaca mulatta</em>) sequences were cloned and tested for sensitivity to VIFs from various simin immunodeficiency viruses (SIVs). Evolution of A3F in the rhesus lineage is not due to selection by SIVs, but may reflect antagonism by another retrovirus.