Topological Layers in the HIV-1 gp120 Inner Domain Regulate gp41 Interaction and CD4-Triggered Conformational Transitions

Finzi, Andrés; Xiang, Shi Hua; Pacheco, Beatriz; Wang, Liping; Haight, Jessica; Kassa, Aemro; Danek, Brenda L.; Pancera, Marie; Kwong, Peter D.; Sodroski, Joseph

doi:10.1016/j.molcel.2010.02.012

Cited by 203 publications

(369 citation statements)

References 60 publications

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“…S4). These observations are consistent with previous studies suggesting that layered movement occurs within the gp120 inner domain upon CD4 binding (17,25,28).…”

Section: Resultssupporting

confidence: 93%

“…The full-length unliganded gp120 subunit shown in our cryo-EM map exhibits a conformation different from that observed in the CD4-bound gp120 core (16). The improved resolution of the current map allows positioning of the secondary structure elements in gp120 and a detailed assessment of the conformational changes collectively associated with Env cleavage and CD4 binding (25)(26)(27)(28).…”

Section: Resultsmentioning

confidence: 85%

See 1 more Smart Citation

Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer

Mao

Wang

et al. 2013

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

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104

120

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The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer, a membrane-fusing machine, mediates virus entry into host cells and is the sole virus-specific target for neutralizing antibodies. Binding the receptors, CD4 and CCR5/CXCR4, triggers Env conformational changes from the metastable unliganded state to the fusion-active state. We used cryo-electron microscopy to obtain a 6-Å structure of the membrane-bound, heavily glycosylated HIV-1 Env trimer in its uncleaved and unliganded state. The spatial organization of secondary structure elements reveals that the unliganded conformations of both glycoprotein (gp)120 and gp41 subunits differ from those induced by receptor binding. The gp120 trimer association domains, which contribute to interprotomer contacts in the unliganded Env trimer, undergo rearrangement upon CD4 binding. In the unliganded Env, intersubunit interactions maintain the gp41 ectodomain helical bundles in a "spring-loaded" conformation distinct from the extended helical coils of the fusion-active state. Quaternary structure regulates the virus-neutralizing potency of antibodies targeting the conserved CD4-binding site on gp120. The Env trimer architecture provides mechanistic insights into the metastability of the unliganded state, receptor-induced conformational changes, and quaternary structure-based strategies for immune evasion.H uman immunodeficiency virus type 1 (HIV-1) is an enveloped retrovirus that causes AIDS (1, 2). To enter host cells, HIV-1 uses a metastable, trimeric envelope glycoprotein (Env) spike to engage cellular receptors and to fuse the viral and target cell membranes (3-5). During synthesis and folding in the endoplasmic reticulum of the virus-producing cell, the Env precursor [glycoprotein (gp)160] is heavily modified by N-linked glycosylation and assembles into trimers (6). In most HIV-1 strains, more than 27 potential N-linked glycosylation sites are present in each gp160 protomer. After further glycan processing in the Golgi apparatus, the gp160 Env trimer precursors are proteolytically cleaved and transported to the cell surface for incorporation into virions (7). Each protomer composing the trimeric Env spike thus consists of a gp120 exterior subunit and a gp41 transmembrane subunit. The sequential binding of gp120 to the target cell receptors, CD4 and chemokine receptor (either CCR5 or CXCR4), allows the metastable Env complex to transit into fusion-active conformations (3,(8)(9)(10)(11). These conformational transitions expose the hydrophobic gp41 N-terminal fusion peptide, promoting its insertion into the target cell membrane, and further permit the formation of a highly stable gp41 six-helix bundle that mediates viral-cell membrane fusion (12)(13)(14). The Env spike is the only virus-specific component potentially accessible to neutralizing antibodies and thus has evolved a protective "glycan shield" and a high degree of interstrain variability.High-resolution structures are available for monomeric HIV-1 gp120 core fragments in the CD4-boun...

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“…S4). These observations are consistent with previous studies suggesting that layered movement occurs within the gp120 inner domain upon CD4 binding (17,25,28).…”

Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 85%

Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer

Mao

Wang

et al. 2013

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

Self Cite

104

120

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“…CD4 Mimetics. sCD4 and the miniprotein M48U1 were produced and purified as previously described (26,52). The CD4-mimetic small molecules JP-III-48 and DMJ-I-228 were synthesized as described previously (20,21).…”

Section: Methodsmentioning

confidence: 99%

CD4 mimetics sensitize HIV-1-infected cells to ADCC

Richard

Veillette

Brassard

et al. 2015

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

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128

291

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HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.

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“…These subunits are linked by noncovalent bonds, allowing conformational changes of the Env trimer during the entry process (1)(2)(3). The gp120 exterior subunit mediates the initial interaction with the CD4 receptor.…”

mentioning

confidence: 99%

“…gp120 residue 375 is located in what is known as the Phe 43 cavity, where Phe 43 of CD4 makes numerous contacts with conserved gp120 residues critical for CD4 binding (4). Some gp120 residues that line this cavity contribute to an aromatic array that helps stabilize the CD4-bound conformation (1,4,5). Upon CD4 binding, major conformational changes expose the binding site for coreceptor (i.e., CCR5 and CXCR4) interaction (6).…”

mentioning

confidence: 99%

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

Prévost

Zoubchenok

Richard

et al. 2017

J Virol

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HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibodydependent cellular-mediated cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to avoid the exposure of Env ADCC epitopes by downregulating CD4 and by limiting the overall amount of Env on the cell surface. In HIV-1, substitution of large residues such as histidine or tryptophan for serine 375 (S375H/W) in the gp120 Phe 43 cavity, where Phe 43 of CD4 contacts gp120, results in the spontaneous sampling of an Env conformation closer to the CD4-bound state. While residue S375 is well conserved in the majority of group M HIV-1 isolates, CRF01_ AE strains have a naturally occurring histidine at this position (H375). Interestingly, CRF01_AE is the predominant circulating strain in Thailand, where the RV144 trial took place. In this trial, which resulted in a modest degree of protection, ADCC responses were identified as being part of the correlate of protection. Here we investigate the influence of the Phe 43 cavity on ADCC responses. Filling this cavity with a histidine or tryptophan residue in Env with a natural serine residue at this position (S375H/W) increased the susceptibility of HIV-1-infected cells to ADCC. Conversely, the replacement of His 375 by a serine residue (H375S) within HIV-1 CRF01_AE decreased the efficiency of the ADCC response. Our results raise the intriguing possibility that the presence of His 375 in the circulating strain where the RV144 trial was held contributed to the observed vaccine efficacy.

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Topological Layers in the HIV-1 gp120 Inner Domain Regulate gp41 Interaction and CD4-Triggered Conformational Transitions

Cited by 203 publications

References 60 publications

Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer

Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer

CD4 mimetics sensitize HIV-1-infected cells to ADCC

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

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