Structure of FIV capsid C-terminal domain demonstrates lentiviral evasion of genetic fragility by coevolved substitutions

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.

The ABCE1 capsid assembly pathway is conserved between primate lentiviruses and the non-primate lentivirus feline immunodeficiency virus

“…5A). For CA-CTD, we aligned the published FIV CA-CTD structure (PDB accession number 5DCK; (18)) with the HIV-1 CA-CTD domains from a published structure of HIV-1 CA (PDB accession number 5L93; (46)). However, because a high-resolution structure of FIV CA-NTD has not been reported, we generated a model of the FIV CA-NTD structure, using SWISS-MODEL, with the published RELIK CA-NTD structure as a template (PDB accession number 2XGU; (19)).…”

“…This observation raises the possibility that the E-R salt bridge could form in FIV Gag isolates from lion, cougar, bobcat, or Pallas’ cat and that the immature FIV capsids formed by those isolates may be more stable than those from isolates found in domestic cats. Additionally, this might be an example of coevolved substitutions (18), since helix 1 contains an arginine when helix 4 contains a glutamic acid (e.g. in HIV-1 and FIV isolates from species besides domestic cat), while helix 1 contains a lysine when helix 4 contains a glutamine (e.g.…”

“…Local quality estimates of the model were largely > 0.6. The FIV CA-NTD model obtained from SWISS-MODEL and FIV CA-CTD crystal structure (PDB accession number 5DCK;(18)) were separately aligned with HIV-1 CA structure (PDB accession number 5L93; (46)) using FATCAT (70, 71), resulting in optimized RMSD of 2.75 Å for the NTD domains and 1.94 Å for the CTD domains. The sequence alignments from FATCAT are shown in Fig.…”

“…At the level of overall amino acid sequence, conservation among different retroviral Gag proteins is low, with the major homology region of Gag being a notable exception (14–16). However, known atomic structures of CA subdomains from different retroviruses display a high degree of conservation (17–19). Thus, conservation of overall CA structure between different retroviruses argues for shared mechanisms for immature capsid assembly.…”

The Preserved HTH-Docking Cleft of HIV-1 Integrase Is Functionally Critical

“…Reciprocal NTD and CTD domain swapping and contacts with CCDs of flanking dimers are indispensable for the stabilization of functional IN assemblies, which consists of multiple dimeric CCD units (2 in prototype foamy virus (PFV) (Maertens et al, 2010) and 4 in Rous sarcoma virus (RSV) (Yin et al, 2016) and mouse mammary tumor virus (MMTV) (Ballandras-Colas et al, 2016)). Amino acid compositions of interacting interfaces must therefore coevolve to complement each other by accumulating compensatory substitutions buffering deleterious effects of mutations and preserving functional interactions during multimeric complex assembly (Khwaja et al, 2016). Compensatory IN mutations have been shown to coevolve in response to variations in IN cellular partners such as with the IN-binding-domain (IBD) of the host cofactor lens epithelium–derived growth factor (LEDGF) (Wang et al, 2014).…”