Abstract
Viruses use a strategy of high mutational rates to adapt to environmental and therapeutic pressures, circumventing the deleterious effects of random single-point mutations by coevolved compensatory mutations, which restore protein fold, function or interactions damaged by initial ones. This mechanism has been identified as contributing to drug resistance in the HIV-1 Gag polyprotein and especially its capsid proteolytic product, which forms the viral capsid core and plays multifaceted roles in the viral life cycle. Here, we determined the X-ray crystal structure of C-terminal domain of the feline immunodeficiency virus (FIV) capsid and through interspecies analysis elucidate the structural basis of co-evolutionarily and spatially correlated substitutions in capsid sequences, which when otherwise uncoupled and individually substituted into HIV-1 capsid impair virion assembly and infectivity. The ability to circumvent the deleterious effects of single amino acid substitutions by cooperative secondary substitutions allows mutational flexibility that may afford viruses an important survival advantage. The potential of such interspecies structural analysis for preempting viral resistance by identifying such alternative but functionally equivalent patterns is discussed.
Highlights
Viruses use a strategy of high mutational rates to adapt to environmental and therapeutic pressures, circumventing the deleterious effects of random single-point mutations by coevolved compensatory mutations, which restore protein fold, function or interactions damaged by initial ones
The α -helical fold of the CA protein and capsid-core assemblies are highly conserved across the various retroviruses including human immunodeficiency virus (HIV)-1, equine infectious anemia virus (EIAV), human T-cell leukemia virus type I (HTLV) and Rous sarcoma virus (RSV)
A simple sequence analysis immediately highlights that the Y164 mentioned above forms part of a conserved amino acid pair F/Y in primate viruses (HIV-1 F161/Y164) that is switched to Y/F in non-primate viruses (Fig. 1A)
Summary
Capsid (CA) proteins from different retroviruses have remarkably low sequence identity[23,24]. This suggests that the deleterious action of the single Y164F mutation in HIV-1 CA might be rescued by the acquisition of a second-site mutation, F161Y, which would restore the conserved amino acid set To probe for such structurally essential and potentially correlated pairs in the lentiviral CA, we determined the structure of the C-terminal domain (CTD) of FIV CA (CACTD), which naturally evolved to cope with substitutions individually shown deleterious to HIV-1 CA, and compared it to other non-primate and primate lentiviral CA structures available in the Protein Data Bank. Walling the groove are FIV F161 (HIV-1 Y169) and L203 (HIV-1 L211) that appear essential for packing the α -11 from the adjacent monomer (Fig. 2, inset) These residues are conserved in most retroviruses and while the overall intrinsic structures of HIV-1 Y169A and L211A/S CACTD mutants were not altered, cone-shaped cores and virus infectivity were completely lost, suggesting that these positions are critical for CA reorganization and assembly of mature-like particles[33]. This mechanism provides the virus with flexibility to exploit alternative but functionally equivalent patterns when the default ones are impaired by mutations, especially during the acquisition of resistance to antiviral therapeutics and
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