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.

Keywords: restriction factors; retroviruses; viral antagonists; viral evolution.

Figure 1

Restriction factors block specific stages of the retroviral life cycle.

Figure 2

Structure and functional features of the HIV-1 and MLV cell surface receptors. (A) Schematic diagrams of the receptors for HIV-1 (CD4 and CCR5) and for different MLV subtypes (XPR1 and CAT1). Red bars indicate regions that bind virus envelope [7,16,17]. (B) XPR1 and CD4 receptor proteins. Blocks identify the transmembrane domain of CD4 and the extracellular loops (ECLs) in XPR1. Positively selected residues are marked with red arrows [13,17,18,19]. Receptor critical sites are marked with blue arrows and black arrows identify polymorphic sites in chimpanzee CD4 that influence SIV binding. Green bars identify CD4 sites susceptible to downregulation by Nef and Vpu [8,9,11,12].

Figure 3

Domain organization of retroviral post-entry restriction factors. Schematic representation identifies positively selected residues (down arrows) found through analyses of Fv1 in rodents and primate genes for TRIM5α, APOBEC3G, SAMHD1 and MX2 [64,65,66,67,68]. The red bars indicate the binding regions for Vif in APOBEC3G, Vpx in SAMHDI and capsid in TRIM5α, TRIMCyp and MX2 [69,70,71,72,73,74]. MHR, major homology region; CypA, cyclophilin A; BSE, bundle signaling element; NLS, nuclear localization signal; N, unstructured amino terminal domain.

Figure 4

BST2 domain organization and membrane association. (A) Schematic diagram of the domain organization of BST2. Positively selected residues are identified by down arrows [345,346]. Regions of HIV-1 Vpu and Nef interaction are indicated with red bars [347,348]. (B) Structural representation of BST2 as a transmembrane protein with a GPI anchor. TM, transmembrane domain; GPI, glycosylphosphatidylinositol anchor.

Figure 5

Retroviral targets and virus-encoded antagonists of restriction factors. Viral antagonists and the restriction factors they target are indicated above each schematically represented MLV and HIV-1 genome. Restriction factors and their known viral protein targets are shown below each genome. LTR: long terminal repeat, MA: matrix, CA: capsid, NC: nucleocapsid, PR: protease, RT: reverse transcriptase, IN: integrase, RBD: receptor binding domain, SU: surface protein, TM: transmembrane protein. Vif, Vpu, Vpx/r and Nef are lentiviral accessory proteins.