Isolate-Specific Differences in the Conformational Dynamics and Antigenicity of HIV-1 gp120

Davenport, Thaddeus M.; Guttman, Miklós; Guo, Wenjin; Cleveland, Brad; Kahn, Maria; Hu, Shiu Lok; Lee, Kelly K.

doi:10.1128/jvi.01535-13

Cited by 30 publications

(55 citation statements)

References 106 publications

(139 reference statements)

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“…The N/C-terminal regions, bridging sheet, and V1/V2 and V3 loops were largely unrestrained, as they have been shown to be highly disordered in solution (43,57). For glycans at N276, N363, N386, and N463, the clashes are similar to what was observed with the trimers (Fig.…”

Section: Resultssupporting

confidence: 69%

“…Small-angle X-ray scattering (SAXS) measurements were conducted on Beam Line 4-2 at the Stanford Synchrotron Radiation Laboratory with online size exclusion chromatography (SEC) as described previously (42,43). Fifty microliters of the BG505 trimer (2 mg/ml) was injected over a precision S200 column (GE Healthcare) and eluted with PBS (pH 7.4) with a solution containing 1 mM EDTA and 0.02% sodium azide.…”

Section: Dynamic Light Scattering (Dls)mentioning

confidence: 99%

“…Models of glycosylated BG505 SOSIP.664 trimers and gp120 monomers were generated by threading the BG505 sequence into the available crystal structure of the SOSIP.664 trimer (PDB accession number 4TVP) (61) by using MODELLER (62). In monomeric gp120, the N/C-terminal tails, the V1/V2 loop, and the V3 loop are highly dynamic (43,57). For this reason, residues 32 to 41, 495 to 511, 114 to 205, and 299 to 326 were left unrestrained, with the exception of disulfide bond connectivities during modeling.…”

Section: Dynamic Light Scattering (Dls)mentioning

confidence: 99%

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Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan

Liang

Guttman

Williams

et al. 2016

J Virol

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The envelope glycoprotein (Env) is the major target for HIV-1 broadly neutralizing antibodies (bNAbs). One of the mechanisms that HIV has evolved to escape the host's immune response is to mask conserved epitopes on Env with dense glycosylation. Previous studies have shown that the removal of a particular conserved glycan at N197 increases the neutralization sensitivity of the virus to antibodies targeting the CD4 binding site (CD4bs), making it a site of significant interest from the perspective of vaccine design. At present, the structural consequences that result from the removal of the N197 glycan have not been characterized. Using native-like SOSIP trimers, we examine the effects on antigenicity and local structural dynamics resulting from the removal of this glycan. A large increase in the binding of CD4bs and V3-targeting antibodies is observed for the N197Q mutant in trimeric Env, while no changes are observed with monomeric gp120. While the overall structure and thermostability are not altered, a subtle increase in the flexibility of the variable loops at the trimeric interface of adjacent protomers is evident in the N197Q mutant by hydrogen-deuterium exchange mass spectrometry. Structural modeling of the glycan chains suggests that the spatial occupancy of the N197 glycan leads to steric clashes with CD4bs antibodies in the Env trimer but not monomeric gp120. Our results indicate that the removal of the N197 glycan enhances the exposure of relevant bNAb epitopes on Env with a minimal impact on the overall trimeric structure. These findings present a simple modification for enhancing trimeric Env immunogens in vaccines. IMPORTANCEThe HIV-1 Env glycoprotein presents a dense patchwork of host cell-derived N-linked glycans. This so-called glycan shield is considered to be a major protective mechanism against immune recognition. While the positions of many N-linked glycans are isolate specific, some are highly conserved and are believed to play key functional roles. In this study, we examine the conserved, CD4 binding site-proximal N197 glycan and demonstrate that its removal both facilitates neutralizing antibody access to the CD4 binding site and modestly impacts the structural dynamics at the trimer crown without drastically altering global Env trimer stability. This indicates that surgical glycosylation site modification may be an effective way of sculpting epitope presentation in Env-based vaccines.T he trimeric HIV-1 envelope glycoprotein (Env), a trimer composed of gp120/gp41 heterodimers, is the primary antigenic feature on the virus and the sole target for neutralizing antibodies (1). Despite the extensive genetic diversity that exists among circulating HIV-1 variants, broadly neutralizing antibodies (bNAbs) capable of neutralizing a diverse panel of viral isolates have been identified in rare HIV-infected individuals. Elicitation of such bNAbs is thought to be a critical requirement for an effective HIV-1 vaccine (2, 3), but to date, HIV vaccine efforts have resulted in limited, narrow neu...

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Section: Resultssupporting

confidence: 69%

Section: Dynamic Light Scattering (Dls)mentioning

confidence: 99%

Section: Dynamic Light Scattering (Dls)mentioning

confidence: 99%

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Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan

Liang

Guttman

Williams

et al. 2016

J Virol

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“…In contrast, sCD4 (57) and MAbs directed against gp41 (58) do cause gp120/gp41 dissociation. These cooperative interactions probably result from the structural flexibility of this Env in its native state and the conformational alterations that have been observed to result upon CD4 or MAb binding (59)(60)(61).…”

Section: Resultsmentioning

confidence: 99%

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins

Pincus

Song

Maresh

et al. 2017

J Virol

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The envelope (Env) glycoprotein of HIV is the only intact viral protein expressed on the surface of both virions and infected cells. Env is the target of neutralizing antibodies (Abs) and has been the subject of intense study in efforts to produce HIV vaccines. Therapeutic anti-Env Abs can also exert antiviral effects via Fcmediated effector mechanisms or as cytotoxic immunoconjugates, such as immunotoxins (ITs). In the course of screening monoclonal antibodies (MAbs) for their ability to deliver cytotoxic agents to infected or Env-transfected cells, we noted disparities in their functional activities. Different MAbs showed diverse functions that did not correlate with each other. For example, MAbs against the external loop region of gp41 made the most effective ITs against infected cells but did not neutralize virus and bound only moderately to the same cells that they killed so effectively when they were used in ITs. There were also differences in IT-mediated killing among transfected and infected cell lines that were unrelated to the binding of the MAb to the target cells. Our studies of a well-characterized antigen demonstrate that MAbs against different epitopes have different functional activities and that the binding of one MAb can influence the interaction of other MAbs that bind elsewhere on the antigen. These results have implications for the use of MAbs and ITs to kill HIVinfected cells and eradicate persistent reservoirs of HIV infection.IMPORTANCE There is increased interest in using antibodies to treat and cure HIV infection. Antibodies can neutralize free virus and kill cells already carrying the virus. The virus envelope (Env) is the only HIV protein expressed on the surfaces of virions and infected cells. In this study, we examined a panel of human anti-Env antibodies for their ability to deliver cell-killing toxins to HIV-infected cells and to perform other antiviral functions. The ability of an antibody to make an effective immunotoxin could not be predicted from its other functional characteristics, such as its neutralizing activity. Anti-HIV immunotoxins could be used to eliminate virus reservoirs that persist despite effective antiretroviral therapy.

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“…The conformational dynamics of E proteins incorporated into the virion also modulate epitope accessibility. Viral "breathing" has been shown in several systems to impact neutralization sensitivity (166,(208)(209)(210)(211). Antibodies have the potential to trap transiently exposed epitopes, as flaviviruses sample an ensemble of structures at steady state.…”

Section: Conformational Masking Of Conserved Regionsmentioning

confidence: 99%

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

VanBlargan

Goo

Pierson

2016

Microbiol Mol Biol Rev

100

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SUMMARY The antibody response plays a key role in protection against viral infections. While antiviral antibodies may reduce the viral burden via several mechanisms, the ability to directly inhibit (neutralize) infection of cells has been extensively studied. Eliciting a neutralizing-antibody response is a goal of many vaccine development programs and commonly correlates with protection from disease. Considerable insights into the mechanisms of neutralization have been gained from studies of monoclonal antibodies, yet the individual contributions and dynamics of the repertoire of circulating antibody specificities elicited by infection and vaccination are poorly understood on the functional and molecular levels. Neutralizing antibodies with the most protective functionalities may be a rare component of a polyclonal, pathogen-specific antibody response, further complicating efforts to identify the elements of a protective immune response. This review discusses advances in deconstructing polyclonal antibody responses to flavivirus infection or vaccination. Our discussions draw comparisons to HIV-1, a virus with a distinct structure and replication cycle for which the antibody response has been extensively investigated. Progress toward deconstructing and understanding the components of polyclonal antibody responses identifies new targets and challenges for vaccination strategies.

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Isolate-Specific Differences in the Conformational Dynamics and Antigenicity of HIV-1 gp120

Cited by 30 publications

References 106 publications

Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan

Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

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