Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions

Munro, James B.; Gorman, Jason; Ma, Xiaochu; Zhou, Zhou; Arthos, James; Burton, Dennis R.; Koff, Wayne C.; Courter, Joel R.; Smith, Amos B.; Kwong, Peter D.; Blanchard, Scott C.; Mothes, Walther

doi:10.1126/science.1254426

Cited by 445 publications

(803 citation statements)

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“…high-FRET states were discovered, with the predominating low-FRET state identified as the closed Env trimer conformation, and the intermediate-FRET state (populated almost exclusively from the high-FRET state) interpreted as a coreceptor-stabilized conformation that was stabilized by simultaneous introduction of sCD4 and 17b (2). Although the high-FRET state could not be precisely identified, the proportions of both the high-and medium-FRET states were increased by sCD4 and 17b addition, suggesting they represent distinct forms of open Env conformational states.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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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.

135

189

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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.

135

189

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“…A slowing of fusion could explain the reduced infection efficiency; alternatively, the observation of increased binding of free virus by neutralizing antibodies in the absence of receptor, suggests that SERINC5 may promote Env adopting a more "open" conformation, comparable with that seen during fusion (8), thereby increasing the sensitivity to neutralizing antibodies. This could be interpreted as SERINC5 triggering a premature activation of the fusion machinery and may explain the greater resistance of primary isolates to the effects of SERINC5; Env proteins of primary isolates have been shown to resist exposure of potentially neutralizing epitopes to a greater degree than laboratory isolates (9). The closed structure of primary isolates is presumed to play a role in concealing conserved functional motifs from neutralizing antibodies, and Nef has also been linked to this protection (10).…”

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confidence: 99%

Exposing HIV's weaknesses

Tedbury

Sarafianos

2017

Journal of Biological Chemistry

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Edited by Charles E. SamuelThe viral restriction factor SERINC5 inhibits HIV-1 infection via unknown mechanisms. Sood and co-workers now show that SERINC5 suppresses HIV-1 fusogenicity and increases sensitivity to neutralizing antibodies by perturbing the folding of the fusion machinery. This work advances our understanding of host-virus interactions and provides a compelling case for considering the host immune system in studies of restriction factor mechanisms.Despite the enormous impact of the HIV-1 pandemic on human health and the intense scrutiny to which the virus has been subjected, many facets of HIV-1 biology have eluded comprehensive explanation for many years. Among these are viral accessory proteins, which have evolved to circumvent host factors that restrict retroviral infection. Perhaps the most enigmatic of these HIV-1 accessory proteins is Nef. Nef is known to interact with and regulate a myriad of host proteins and processes and has long been known to enhance viral infectivity (1). However, unlike other HIV-1 accessory proteins, none of the well-studied functions of Nef appeared to explain the enhanced viral infectivity, suggesting that an as-yet-unidentified host factor must inhibit HIV-1 infectivity and, in turn, be countered by Nef.In 2015, back-to-back publications revealed the identities of the Nef-targeted host factors to be SERINC5 (serine incorporator 5) and SERINC3 (2, 3); the SERINC proteins are multipass membrane-spanning proteins, of which little is known beyond a role in the synthesis of serine-containing lipids. Of the five SERINC proteins, only SERINC3 and SERINC5 have activity against HIV-1, and SERINC5 is significantly more potent. These papers, and others that followed, quickly established the importance of SERINC5 as a genuine viral restriction factor. For example, where Nef is absent, retroviruses have independently evolved proteins to counter SERINC5 activity, such as glycoGag of murine leukemia virus (2, 3) and the S2 accessory protein of equine infectious anemia virus (4). Furthermore, a study of primate lentiviruses in the wild revealed a correlation between their prevalence in the susceptible population and the ability to antagonize SERINC5 (5). We have since learned that Nef counters SERINC5 by preventing its incorporation into virions. In the absence of Nef, SERINC5 packages into virions and appears to inhibit viral fusion at a post-receptorbinding step; however, the mechanism by which SERINC5 impairs fusion is not clear, and there is a significantly greater impact on viral infectivity than on fusion (2, 3). Intriguingly, it has been reported that many primary isolates of HIV-1 are resistant to this fusion-defect and that resistance is conferred by the envelope glycoprotein (Env) in the viral membrane (6). This protein binds to receptors on the target cell and mediates fusion between the virus and host membranes. Primary isolates were not entirely impervious to the effects of SERINC5, however, as they exhibited increased sensitivity to neutralizing antisera (6). Thus, ...

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“…Indeed, it has been suggested that HIV-1 has evolved to express a substantial amount of nonfunctional forms of Env on the virion surface, in addition to the functional trimer, as decoys to evade host immune responses (13). Moreover, the intrinsic, strain-dependent dynamics of Env also cause exposure of a varied range of epitopes (8). We recently reported that Envs derived from two difficult-to-neutralize HIV-1 primary isolates (92UG037.8 and C97ZA012) are antigenically homogeneous and hence conformationally restricted when expressed on cell surfaces (10).…”

mentioning

confidence: 99%

“…During the fusion process, Env has at least three distinct conformational states: a prefusion state, a fusion intermediate, and a postfusion state. The prefusion state is an ensemble of closed and open (or partly open) conformations (substates) (7)(8)(9), and the extended intermediate probably also populates a dynamically exchanging set of conformations. This conformational plasticity creates substantial difficulties for producing stable recombinant protein that mimics the structure and antigenicity of the native HIV-1 Env on the virion surface.…”

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confidence: 99%

Antigenicity-defined conformations of an extremely neutralization-resistant HIV-1 envelope spike

Cai

Karaca-Griffin

Chen

et al. 2017

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

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The extraordinary genetic diversity of the HIV-1 envelope spike [Env; trimeric (gp160) 3 , cleaved to (gp120/gp41) 3 ] poses challenges for vaccine development. Envs of different clinical isolates exhibit different sensitivities to antibody-mediated neutralization. Envs of difficult-to-neutralize viruses are thought to be more stable and conformationally homogeneous trimers than those of easyto-neutralize viruses, thereby providing more effective concealment of conserved, functionally critical sites. In this study we have characterized the antigenic properties of an Env derived from one of the most neutralization-resistant HIV-1 isolates, CH120.6. Sequence variation at neutralizing epitopes does not fully account for its exceptional resistance to antibodies. The full-length, membrane-bound CH120.6 Env is indeed stable and conformationally homogeneous. Its antigenicity correlates closely with its neutralization sensitivity, and major changes in antigenicity upon CD4 engagement appear to be restricted to the coreceptor site. The CH120.6 gp140 trimer, the soluble and uncleaved ectodomain of (gp160) 3 , retains many antigenic properties of the intact Env, consistent with a conformation close to that of Env spikes on a virion, whereas its monomeric gp120 exposes many nonneutralizing or strain-specific epitopes. Thus, trimer organization and stability are important determinants not only for occluding many epitopes but also for conferring resistance to neutralization by all but a small set of antibodies. Env preparations derived from neutralization-resistant viruses may induce irrelevant antibody responses less frequently than do other Envs and may be excellent templates for developing soluble immunogens.HIV-1 gp160 | neutralizing antibodies | vaccine design

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Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions

Cited by 445 publications

References 53 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

Exposing HIV's weaknesses

Antigenicity-defined conformations of an extremely neutralization-resistant HIV-1 envelope spike

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