MPER-specific antibodies induce gp120 shedding and irreversibly neutralize HIV-1

Ruprecht, Claudia R.; Krarup, Anders; Reynell, Lucy; Mann, Axel; Brandenberg, Oliver F.; Berlinger, Livia; Abela, Irene A.; Regoes, Roland R.; Günthard, Huldrych F.; Rusert, Peter; Trkola, Alexandra

doi:10.1084/jem.20101907

Cited by 98 publications

(129 citation statements)

References 72 publications

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“…While the multiple-hit hypothesis assumes that neutralization is a reversible process (181), in some cases, antibody binding results in an irreversible change in virion infectivity that persists upon the reversal of binding. Some anti-HIV-1 MAbs, such as those that bind the MPER on gp41 and the CD4-binding site on gp120, induce the shedding of viral glycoprotein gp120 from the virion, which renders virions noninfectious even when the antibody disassociates from the virus particle (182).…”

Section: Mechanisms Of Neutralizationmentioning

confidence: 99%

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

VanBlargan

Goo

Pierson

2016

Microbiol Mol Biol Rev

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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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Section: Mechanisms Of Neutralizationmentioning

confidence: 99%

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

VanBlargan

Goo

Pierson

2016

Microbiol Mol Biol Rev

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“…1, lane 2), which should ensure robust competitions. Furthermore, the SOS disulfide bond eliminates possible sCD4-or MAb-induced gp120 shedding that could complicate data interpretation if WT-VLPs are used (84). However, in all competitions involving MAbs 7B2 and 2.2B, WT-VLPs were used, as these MAbs do not efficiently recognize SOS-VLPs (Fig.…”

Section: Fig 3 Mab Neutralization Of Wt and Sos Viruses In Various Asmentioning

confidence: 99%

Topological Analysis of HIV-1 Glycoproteins Expressed In Situ on Virus Surfaces Reveals Tighter Packing but Greater Conformational Flexibility than for Soluble gp120

Tong

Osawa

Robinson

et al. 2013

J Virol

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bIn natural infection, antibodies interact with HIV-1 primarily through nonfunctional forms of envelope glycoproteins (Env), including uncleaved (UNC) gp160 and gp41 stumps. These antigens are important to fully characterize, as they may be decoys that promote nonneutralizing responses and may also be targets for nonneutralizing effector responses. In this study, we compared the antigenic properties of Env expressed in situ on pseudovirion virus-like particle (VLP) surfaces and soluble gp120 using harmonized enzyme-linked immunosorbent assays (ELISAs) and a panel of 51 monoclonal antibodies (MAbs). Only 32 of 46 soluble gp120-reactive MAbs recognized the primary UNC gp160 antigen of VLPs. Indeed, many epitopes were poorly exposed (C1, V2, C1-C4, C4, C4-V3, CD4 induced [CD4i], and PGT group 3) or obscured (C2, C5, and C1-C5) on VLPs. In further studies, VLP Env exhibited an increased degree of inter-MAb competition, the epicenter of which was the base of the V3 loop, where PGT, 2G12, V3, and CD4 binding site specificities competed. UNC gp160 also underwent more drastic soluble CD4 (sCD4)-induced conformational changes than soluble gp120, exposing CD4i, C1-C4, and V2 epitopes. A greater propensity of UNC gp160 to undergo conformational changes was also suggested by the induction of CD4i MAb binding to VLPs by a V3 MAb as well as by soluble CD4. The same effect was not observed for soluble gp120. Taken together, our data suggest that membrane-expressed UNC gp160 exists in a less "triggered" conformational state than soluble gp120 and that MAb binding to UNC gp160 tends to have greater conformational consequences.

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“…25), glycan-dependent epitopes in the V3 loop (PGT series of NAbs), the membrane proximal external region of the gp41 subunit (NAbs 2F5, 4E10, and 10E8), and a cleavage-dependent epitope at the gp41-gp120 interface of the Env trimer (PGT151 and PGT152) (11)(12)(13)(14). The neutralizing epitopes on gp41 are less accessible to bNAbs in the context of native HIV-1 Env (15,16). Thus, designing immunogens that efficiently display the more accessible neutralizing epitopes present on gp120 in its native trimeric conformation may elicit bNAb responses.…”

mentioning

confidence: 99%

Structure-based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies

Kesavardhana

Das

Citron

et al. 2017

Journal of Biological Chemistry

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A major goal for HIV-1 vaccine development is an ability to elicit strong and durable broadly neutralizing antibody (bNAb) responses. The trimeric envelope glycoprotein (Env) spikes on HIV-1 are known to contain multiple epitopes that are susceptible to bNAbs isolated from infected individuals. Nonetheless, all trimeric and monomeric Env immunogens designed to date have failed to elicit such antibodies. We report the structure-guided design of HIV-1 cyclically permuted gp120 that forms homogeneous, stable trimers, and displays enhanced binding to multiple bNAbs, including VRC01, VRC03, VRC-PG04, PGT128, and the quaternary epitope-specific bNAbs PGT145 and PGDM1400. Constructs that were cyclically permuted in the V1 loop region and contained an N-terminal trimerization domain to stabilize V1V2-mediated quaternary interactions, showed the highest homogeneity and the best antigenic characteristics. In guinea pigs, a DNA prime-protein boost regimen with these new gp120 trimer immunogens elicited potent neutralizing antibody responses against highly sensitive Tier 1A isolates and weaker neutralizing antibody responses with an average titer of about 115 against a panel of heterologous Tier 2 isolates. A modest fraction of the Tier 2 virus neutralizing activity appeared to target the CD4 binding site on gp120. These results suggest that cyclically permuted HIV-1 gp120 trimers represent a viable platform in which further modifications may be made to eventually achieve protective bNAb responses.The HIV-1 Env displayed on the virion surface mediates entry of the virion into target CD4 ϩ T cells to establish infection. Due to its surface accessibility, Env is the predominant target for neutralizing antibody responses (1, 2). Env is synthesized as a gp160 precursor protein, which is further cleaved into surface proximal gp120 and membrane anchored gp41 subunits. A functional HIV-1 Env spike consists of a trimer of gp120 and gp41 heterodimers. The base of the trimer is proximal to the viral membrane (3) and is held together by trimerization motifs within the N-heptad repeat of gp41 (4 -6). The trimer apex is stabilized by interactions between the V1V2 loops of adjacent gp120 monomers (3). Binding of Env to the CD4 receptor on T cells causes extensive conformational changes in the Env trimer and leads to the formation of an open CD4-bound conformation in which the cryptic, co-receptor binding site becomes accessible. This facilitates interaction of the co-receptor (CCR5 or CXCR4) with Env, further driving the fusion of viral and host cell membranes (3, 7).In natural HIV-1 infection, most of the B cell response is elicited against the Env protein, due to its location on the virion surface and relatively high immunogenicity. The antibody response induced during natural HIV-1 infection is predominantly non-neutralizing and strain specific, due to the shed gp120 (immunodominant decoys) and various other immune evasive mechanisms (8). However, ϳ20% of HIV-1-infected patients develop bNAbs during the course of 1-3 years of infectio...

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MPER-specific antibodies induce gp120 shedding and irreversibly neutralize HIV-1

Abstract: Antibody-mediated gp120 shedding and HIV neutralization exhibit similar kinetics and thermodynamic requirements.

Cited by 98 publications

References 72 publications

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

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

Topological Analysis of HIV-1 Glycoproteins Expressed In Situ on Virus Surfaces Reveals Tighter Packing but Greater Conformational Flexibility than for Soluble gp120

Structure-based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies

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