Functional and Highly Cross-Linkable HIV-1 Envelope Glycoproteins Enriched in a Pretriggered Conformation

Nguyen, Hanh T.; Qualizza, Alessandra; Anang, Saumya; Zhao, Mengxia; Zou, Shitao; Zhou, Rong; Wang, Qian; Zhang, Shijian; Deshpande, Ashlesha; Ding, Haitao; Chiu, Ta-Jung; Smith, Amos B.; Kappes, John C.; Sodroski, Joseph

doi:10.1128/jvi.01668-21

Cited by 20 publications

(58 citation statements)

References 184 publications

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“…BMS-806 binds HIV-1 gp120 by occupying the Phe-43 cavity and adjacent water- filled channel (near Thr 424) (Fig. 3C) (34, 79). The alterations in the shape of these gp120 structures resulting from the S375N and I424T changes likely explain the observed decreases in BMS-806 potency.…”

Section: Resultsmentioning

confidence: 99%

“…The sensitivity of HIV-1 infection to inhibition by specific Env ligands or by exposure to cold can provide an indication of global changes in Env conformation (26, 78, 79, 92, 93). Therefore, we examined the susceptibility of the virus variants to inhibition by conformation-sensitive broadly neutralizing antibodies and poorly neutralizing antibodies, the T20 peptide corresponding to the gp41 heptad repeat (HR2) region (94, 95) and cold incubation.…”

Section: Resultsmentioning

confidence: 99%

“…These conformational changes ultimately contribute to the binding affinity of the CD4mcs. Thus, resistance to CD4mcs can involve changes in HIV-1 Env near the binding site or changes outside the binding site that decrease the ability of Env to undergo the appropriate conformational changes (35, 67–69, 76, 79).…”

Section: Discussionmentioning

confidence: 99%

“…To evaluate the cold sensitivity of the Env variants, pseudotyped recombinant viruses were incubated on ice for various lengths of time prior to measuring their infectivity, as described previously (26,27,79,93). gp120 shedding.…”

Section: Virus Infectivity Neutralization and Cold Sensitivity Single...mentioning

confidence: 99%

“…Primary HIV-1 strains exhibit a continuous range of "triggerability," a property that is inversely related to the height of the activation barrier separating State 1 and State 2 (13,26,27). Viruses with Envs that have stable State-1 conformations and therefore are less prone to make transitions from State 1 are expected to exhibit greater resistance to CD4mcs (26,(78)(79)(80)(81). This second mechanism of resistance is more common than alterations within the Phe-43 cavity and reflects the different levels of responsiveness to CD4 that are advantageous to HIV-1 in different natural circumstances.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of human immunodeficiency virus (HIV-1) envelope glycoprotein variants selected for resistance to a CD4-mimetic compound

Anang

Richard

Bourassa

et al. 2022

Preprint

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Binding to host cell receptors, CD4 and CCR5/CXCR4, triggers conformational changes in the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer that promote virus entry. CD4 binding allows the gp120 exterior Env to bind CCR5/CXCR4 and induces a pre-hairpin intermediate conformation in the gp41 transmembrane Env. Small-molecule CD4-mimetic compounds (CD4mcs) bind within the conserved Phe-43 cavity of gp120, near the binding site for CD4. CD4mcs inhibit HIV-1 infection by competing with CD4 and by prematurely activating Env, leading to irreversible inactivation. BNM-III-170 is a CD4mc that inhibits the infection of approximately 70% of HIV-1 strains at micromolar concentrations. We selected and analyzed variants of the primary HIV-1AD8 strain resistant to BNM-III-170. Two changes (S375N and I424T) in gp120 residues that flank the Phe-43 cavity each conferred ∼5-fold resistance to BNM- III-170 with minimal fitness cost. A third change (E64G) in Layer 1 of the gp120 inner domain resulted in ∼100-fold resistance to BNM-III-170, ∼2-3-fold resistance to soluble CD4-Ig, and a moderate decrease in viral fitness. The gp120 changes additively or synergistically contributed to BNM-III-170 resistance. The sensitivity of the Env variants to BNM-III-170 inhibition of virus entry correlated with their sensitivity to BNM-III-170- induced Env activation and shedding of gp120. The S375N and I424T changes, but not the E64G change, conferred resistance to BMS-806, a potent HIV-1 entry inhibitor that blocks Env conformational transitions. These studies identify pathways whereby HIV-1 can develop resistance to CD4mcs and BMS-806 conformational blockers, two classes of entry inhibitors that target the conserved gp120 Phe-43 cavity.IMPORTANCECD4-mimetic compounds (CD4mcs) and BMS-806 are small-molecule inhibitors of human immunodeficiency virus (HIV-1) entry into host cells. Although CD4mcs and BMS-806 inhibit HIV-1 entry by different mechanisms, they both target a pocket on the viral envelope glycoprotein (Env) spike that is used for binding to the receptor, CD4, and is highly conserved among HIV-1 strains. Our study identifies changes near this pocket that can confer various levels of resistance to the antiviral effects of both a CD4mc and BMS-806. We relate the antiviral potency of a CD4mc against this panel of HIV-1 variants to the ability of the CD4mc to activate changes in Env conformation and to induce the shedding of the gp120 exterior Env from the spike. These findings will guide efforts to improve the potency and breadth of small-molecule HIV-1 entry inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Virus Infectivity Neutralization and Cold Sensitivity Single...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Characterization of human immunodeficiency virus (HIV-1) envelope glycoprotein variants selected for resistance to a CD4-mimetic compound

Anang

Richard

Bourassa

et al. 2022

Preprint

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Membrane HIV-1 envelope glycoproteins stabilized more strongly in a pretriggered conformation than natural virus Envs

Zhang,

Anang,

Nguyen

et al. 2024

iScience

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Asymmetric conformations of cleaved HIV-1 envelope glycoprotein trimers in styrene-maleic acid lipid nanoparticles

Wang

Zhang

et al. 2023

Commun Biol

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During virus entry, the pretriggered human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer initially transits into a default intermediate state (DIS) that remains structurally uncharacterized. Here, we present cryo-EM structures at near-atomic resolution of two cleaved full-length HIV-1 Env trimers purified from cell membranes in styrene-maleic acid lipid nanoparticles without antibodies or receptors. The cleaved Env trimers exhibited tighter subunit packing than uncleaved trimers. Cleaved and uncleaved Env trimers assumed remarkably consistent yet distinct asymmetric conformations, with one smaller and two larger opening angles. Breaking conformational symmetry is allosterically coupled with dynamic helical transformations of the gp41 N-terminal heptad repeat (HR1N) regions in two protomers and with trimer tilting in the membrane. The broken symmetry of the DIS potentially assists Env binding to two CD4 receptors—while resisting antibody binding—and promotes extension of the gp41 HR1 helical coiled-coil, which relocates the fusion peptide closer to the target cell membrane.

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Functional and Highly Cross-Linkable HIV-1 Envelope Glycoproteins Enriched in a Pretriggered Conformation

Abstract: The development of an efficient vaccine is critical for combating HIV-1 infection worldwide. However, the instability of the pretriggered shape (state 1) of the viral envelope glycoprotein (Env) makes it difficult to raise neutralizing antibodies against HIV-1.

Cited by 20 publications

References 184 publications

Characterization of human immunodeficiency virus (HIV-1) envelope glycoprotein variants selected for resistance to a CD4-mimetic compound

Characterization of human immunodeficiency virus (HIV-1) envelope glycoprotein variants selected for resistance to a CD4-mimetic compound

Membrane HIV-1 envelope glycoproteins stabilized more strongly in a pretriggered conformation than natural virus Envs

Asymmetric conformations of cleaved HIV-1 envelope glycoprotein trimers in styrene-maleic acid lipid nanoparticles

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