In silico Analysis of HIV-1 Env-gp120 Reveals Structural Bases for Viral Adaptation in Growth-Restrictive Cells

Yokoyama, Masahiro; Nomaguchi, Masako; Doi, Naoya; Kanda, Tadahito; Adachi, Akio; Sato, Hironori

doi:10.3389/fmicb.2016.00110

Cited by 31 publications

(36 citation statements)

References 76 publications

(176 reference statements)

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“…(32,33), closed BG505 trimer (PDB ID code 5FYJ) (10,19), and molecular dynamics model of repositioned V1V2 in full-length CD4-bound gp120 (21). β-strand nomenclature in V1V2 is the same as in ref.…”

Section: Discussionmentioning

confidence: 99%

“…The details of V1V2 rearrangements in the open structure of HIV-1 Env trimer have not been addressed: The V1V2 loops were not localized in the Env trimer used in a cryo-EM single particle structure of an open KNH1144 SOSIP bound to the coreceptormimicking antibody 17b (7) or in lower-resolution cryoelectron tomography structures of CD4-bound open Env trimers on virions (4,7). However, computational modeling suggested displacement of V1V2 toward CD4 in CD4-bound Env structures (20,21), consistent with earlier studies demonstrating involvement of V1V2 in the induction of the epitopes of coreceptor mimic/CD4-induced antibodies such as 17b (22).…”

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confidence: 99%

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Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop

Wang

Cohen

Galimidi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

140

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The HIV-1 envelope (Env) glycoprotein, a trimer of gp120-gp41 heterodimers, relies on conformational flexibility to function in fusing the viral and host membranes. Fusion is achieved after gp120 binds to CD4, the HIV-1 receptor, and a coreceptor, capturing an open conformational state in which the fusion machinery on gp41 gains access to the target cell membrane. In the well-characterized closed Env conformation, the gp120 V1V2 loops interact at the apex of the Env trimer. Less is known about the structure of the open CD4-bound state, in which the V1V2 loops must rearrange and separate to allow access to the coreceptor binding site. We identified two anti-HIV-1 antibodies, the coreceptor mimicking antibody 17b and the gp120-gp41 interface-spanning antibody 8ANC195, that can be added as Fabs to a soluble native-like Env trimer to stabilize it in a CD4-bound conformation. Here, we present an 8.9-Å cryo-electron microscopy structure of a BG505 Env-sCD4-17b-8ANC195 complex, which reveals large structural rearrangements in gp120, but small changes in gp41, compared with closed Env structures. The gp120 protomers are rotated and separated in the CD4-bound structure, and the three V1V2 loops are displaced by ∼40 Å from their positions at the trimer apex in closed Env to the sides of the trimer in positions adjacent to, and interacting with, the three bound CD4s. These results are relevant to understanding CD4-induced conformational changes leading to coreceptor binding and fusion, and HIV-1 Env conformational dynamics, and describe a target structure relevant to drug design and vaccine efforts.T he HIV-1 envelope (Env) glycoprotein, a trimer of gp120-gp41 heterodimers, mediates recognition of host receptors and fusion of the viral and target cell membranes (1). Structural flexibility of HIV-1 Env is required for its function in membrane fusion; thus, Env exists in multiple conformational states on the surface of virions (2). Fusion involves several steps: The gp120 portion of Env trimer first binds to the host receptor CD4 to capture a conformational state of Env that exposes the binding site for an HIV-1 coreceptor (CCR5 or CXCR4), which, in turn, leads to gp41-mediated fusion of the viral and host cell membranes. CD4-induced conformational changes within the Env trimer are incompletely understood. The binding of soluble CD4 (sCD4) produces little to no changes in the structures of gp120 cores (gp120 monomers with truncations in the N and C termini and variable V1V2 and V3 loops) (3), but results in rotation of the gp120 protomers within virion-bound Env trimers to create an open conformation distinct from the closed conformation of unliganded virion-bound trimers (4). Single-particle electron microscopy (EM) structures of recombinant native-like soluble Env gp140 trimers (SOSIPs) confirmed that they can adopt the same closed and open architectures as virion-bound Env trimers (5-7), thus the SOSIP substitutions (introduction of a disulfide bond linking gp120 to gp41 and an Ile→Pro mutation in gp41; ref. The closed co...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop

Wang

Cohen

Galimidi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

140

200

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“…Glycosylated HA trimer models in a ligand-free state were subjected to MD simulation essentially as described for simulations of HIV-1 gp120 (Yokoyama et al, 2016). MD simulations were performed by the PMEMD (Particle Mesh Ewald Molecular Dynamics) module in the AMBER 14 program package (Case et al, 2014), employing the Amber ff99SB-ILDN force field, a protein force field with improved side-chain torsion potentials (Lindorff-Larsen et al, 2010), the GLYCAM06 force field, a biomolecular force field for glycans (Kirschner et al, 2008), and the TIP3P water model for simulations of aqueous solutions (Jorgensen et al, 1983).…”

Section: Methodsmentioning

confidence: 99%

“…The MD simulations have been used to disclose the structural basis of the adaptation and evolution of the highly mutable human immunodeficiency virus (HIV). This includes elucidation of the HIV structural changes associated with the phenotypic changes in viral neutralization sensitivity and receptor tropism (Naganawa et al, 2008; Yokoyama et al, 2012, 2016; Kuwata et al, 2013), viral sensitivity to antiviral protein (Miyamoto et al, 2012), viral drug sensitivity (Yuan et al, 2013), viral growth in non-natural host cells (Yokoyama et al, 2016), and viral sensitivities to antibodies by drug-resistance mutations (Alam et al, 2016; Hikichi et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulation of the Influenza A(H3N2) Hemagglutinin Trimer Reveals the Structural Basis for Adaptive Evolution of the Recent Epidemic Clade 3C.2a

et al. 2017

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Influenza A(H3N2) has been a major cause of seasonal influenza in humans since 1968, and has evolved by antigenic drift under the constantly changing human herd immunity. Increasing evidence suggests that the antigenic change occasionally occurred concomitant with the alterations of the N-glycosylation site profile and hemagglutination activity of the virion surface protein hemagglutinin (HA). However, the structural basis of these changes remains largely unclear. To address this issue, we performed molecular dynamics simulations of the glycosylated HA trimers of the A(H3N2), which has a novel pattern of Asn-X-Ser/Thr sequons unique in the new A(H3N2) epidemic clade 3C.2a and is characterized by attenuated ability to agglutinate nonhuman erythrocytes. Comparison of the equilibrated structures of the glycosylated HA trimers with and without the 3C.2a-specific mutations reveals that the mutations could induce a drastic reduction in the apical space for the ligand binding via glycan-shield rearrangement. The results suggest that the 3C.2a strain has evolved an HA structure that is advantageous for evading pre-existing antibodies, while also increasing the ligand binding specificity. These findings have structural implications for our understanding of the phenotypic changes, evolution, and fate of influenza A(H3N2).

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“…1). We recently showed that a mutant virus carrying a growth-enhancing mutation G310R exhibited distinct sensitivity to CCR5 antagonist TAK-779 from that of a mutant virus bearing S304G (19). Fig.…”

Section: Virological Characterization Of Hiv-1rmt Clonesmentioning

confidence: 96%

Generation and characterization of new CCR5-tropic HIV-1rmt clones

et al. 2017

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: To develop effective non -human primate models for coping with numerous HIV-1/AIDS studies, rhesus macaque-tropic HIV-1 (HIV-1rmt) clones with a variety of biological properties are required. Such clones, if available, are powerful tools to experimentally elucidate HIV-1 replication and pathogenicity in host individuals, and also to develop anti-HIV-1 drugs/vaccines. However, only limited numbers of HIV-1rmt clones have been currently reported. In the present study, we generated new HIV-1rmt clones carrying various CCR5-tropic env (envelope) genes by standard recombinant DNA and intracellular homologous recombination techniques. Resultant virus clones contain the env sequences derived from an AIDS-inducible laboratory or two clinically isolated viral strains. We further constructed their variant clones bearing N160K, S304G, or G310R mutation in Env that potentially can change the viruses to better grow. Newly generated clones were analyzed for their virological properties such as Env expression, single-cycle infectivity, and multi -cycle replication ability. Out of a number of new clones examined, two were found to grow better in macaque cells than the previously constructed clone used for comparison. Our study described here constitutes the initial and essential step towards obtaining CCR5-tropic HIV-1rmt clones useful for various basic and clinical research projects on infected individuals.

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In silico Analysis of HIV-1 Env-gp120 Reveals Structural Bases for Viral Adaptation in Growth-Restrictive Cells

Cited by 31 publications

References 76 publications

Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop

Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop

Molecular Dynamics Simulation of the Influenza A(H3N2) Hemagglutinin Trimer Reveals the Structural Basis for Adaptive Evolution of the Recent Epidemic Clade 3C.2a

Generation and characterization of new CCR5-tropic HIV-1rmt clones

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