Binding of Anti-Membrane-Proximal gp41 Monoclonal Antibodies to CD4-Liganded and -Unliganded Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus Virions

Rathinakumar, Ramesh; Dutta, Moumita; Zhu, Ping; Johnson, Welkin E.; Roux, Kenneth H.

doi:10.1128/jvi.05489-11

Cited by 23 publications

(22 citation statements)

References 89 publications

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“…A recent study that compared capture assay formats suggested that anti-MPER MAbs bind misfolded envelope structures trapped on virions and neutralize via interactions with fusion intermediates formed postattachment (45). Our findings are consistent with a postattachment neutralization mechanism, although the FCS analyses failed to show sCD4-induced changes in MAb 2F5-virion binding in contrast with previous observations (79,92). At the same time, the reported impact of CD4 on MPER epitope exposure has been variable (15,(92)(93)(94)(95).…”

Section: Discussionsupporting

confidence: 62%

“…Data from virus capture assays may be biased by mechanical forces (e.g., via centrifuga- tion) applied to virions, avidity effects, and/or indirect detection of antibody-virion complexes (40,45). Solution-based antibody binding was previously used to explore virion-associated envelope antigens (79); however, the method involved washing and fixation steps followed by negative-stain electron microscopy to image virion-bound antibody. Thus, data from this approach are derived from visual surveys of a limited range of selected particles.…”

Section: Discussionmentioning

confidence: 99%

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Antigenic Properties of the HIV Envelope on Virions in Solution

Ray

Mengistu

Lewis

et al. 2014

J Virol

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The structural flexibility found in human immunodeficiency virus (HIV) envelope glycoproteins creates a complex relationship between antigenicity and sensitivity to antiviral antibodies. The study of this issue in the context of viral particles is particularly problematic as conventional virus capture approaches can perturb antigenicity profiles. Here, we employed a unique analytical system based on fluorescence correlation spectroscopy (FCS), which measures antibody-virion binding with all reactants continuously in solution. Panels of nine anti-envelope monoclonal antibodies (MAbs) and five virus types were used to connect antibody binding profiles with neutralizing activities. Anti-gp120 MAbs against the 2G12 or b12 epitope, which marks functional envelope structures, neutralized viruses expressing CCR5-tropic envelopes and exhibited efficient virion binding in solution. MAbs against CD4-induced (CD4i) epitopes considered hidden on functional envelope structures poorly bound these viruses and were not neutralizing. Anti-gp41 MAb 2F5 was neutralizing despite limited virion binding. Similar antigenicity patterns occurred on CXCR4-tropic viruses, except that anti-CD4i MAbs 17b and 19e were neutralizing despite little or no virion binding. Notably, anti-gp120 MAb PG9 and anti-gp41 MAb F240 bound to both CCR5-tropic and CXCR4-tropic viruses without exerting neutralizing activity. Differences in the virus production system altered the binding efficiencies of some antibodies but did not enhance antigenicity of aberrant gp120 structures. Of all viruses tested, only JRFL pseudoviruses showed a direct relationship between MAb binding efficiency and neutralizing potency. Collectively, these data indicate that the antigenic profiles of free HIV particles generally favor the exposure of functional over aberrant gp120 structures. However, the efficiency of virion-antibody interactions in solution inconsistently predicts neutralizing activity in vitro.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Antigenic Properties of the HIV Envelope on Virions in Solution

Ray

Mengistu

Lewis

et al. 2014

J Virol

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“…S6). In control experiments, treatment of either HXB2pp or JRFLpp with soluble CD4 (sCD4) enhanced the relative 2G12 binding, in agreement with a previous report (37). Our results suggest that the MPER is more accessible on SER5ϩ JRFLpp, in line with a more efficient 4E10-mediated neutralization of this virus as compared with control JRFLpp (Fig.…”

Section: Ser5 Enhances Hiv-1 Sensitivity To Neutralizing Antibodies Asupporting

confidence: 92%

SERINC5 protein inhibits HIV-1 fusion pore formation by promoting functional inactivation of envelope glycoproteins

Sood

Marin

Chande

et al. 2017

Journal of Biological Chemistry

118

189

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Edited by Charles E. SamuelThe host proteins, SERINC3 and SERINC5, have been recently shown to incorporate into HIV-1 particles and compromise their ability to fuse with target cells, an effect that is antagonized by the viral Nef protein. Envelope (Env) glycoproteins from different HIV-1 isolates exhibit a broad range of sensitivity to SERINC-mediated restriction, and the mechanism by which SERINCs interfere with HIV-1 fusion remains unclear. Here, we show that incorporation of SERINC5 into virions in the absence of Nef inhibits the formation of small fusion pores between viruses and cells. Strikingly, we found that SERINC5 promotes spontaneous functional inactivation of sensitive but not resistant Env glycoproteins. Although SERINC5-Env interaction was not detected by co-immunoprecipitation, incorporation of this protein enhanced the exposure of the conserved gp41 domains and sensitized the virus to neutralizing antibodies and gp41-derived inhibitory peptides. These results imply that SERINC5 restricts HIV-1 fusion at a step prior to small pore formation by selectively inactivating sensitive Env glycoproteins, likely through altering their conformation. The increased HIV-1 sensitivity to anti-gp41 antibodies and peptides suggests that SER5 also delays refolding of the remaining fusion-competent Env trimers.

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“…Another implication of these findings is that the MPER region is accessible to Z13e1 in the activated state and not in the unliganded state. Our results are consistent with those of a number of studies that have suggested that binding of MPER site antibodies to virion and cell surface Env is enhanced by the presence of soluble CD4 (11,15,16). Taken together, all of these findings lead to a model for binding of MPER antibodies at a late stage in the HIV entry process, following CD4 binding and possibly after gp120 has bound cellular receptors such as CCR5 or CXCR4.…”

Section: Figsupporting

confidence: 91%

“…appear to block entry by virtue of their location at the apex of the spike, interfering with virus-cell contact. The action of MPER antibodies is at a distance from the site of virus-cell contact, but it has been shown (11,(16)(17)(18) that at least some antibodies, such as 2F5, 4E10, and Z13e1, are capable of binding membrane surfaces even in the absence of Env. While it is formally possible that Z13e1 may work by binding to the closed conformation and pretriggering the open conformation of the spike or that Z13e1 captures a conformation of trimeric Env that is sampled by thermal fluctuations from the closed conformation, we favor the possibility that Z13e1 functions in HIV neutralization by binding to the viral membrane surface first prior to binding Env.…”

Section: Figmentioning

confidence: 99%

HIV-1 Envelope Glycoprotein Trimers Display Open Quaternary Conformation When Bound to the gp41 Membrane-Proximal External-Region-Directed Broadly Neutralizing Antibody Z13e1

Harris

Bartesaghi

Milne

et al. 2013

J Virol

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We describe cryo-electron microscopic studies of the interaction between the ectodomain of the trimeric HIV-1 envelope glycoprotein (Env) and Z13e1, a broadly neutralizing antibody that targets the membrane-proximal external region (MPER) of the gp41 subunit. We show that Z13e1-bound Env displays an open quaternary conformation similar to the CD4-bound conformation. Our results support the idea that MPER-directed antibodies, such as Z13e1, block viral entry by interacting with Env at a step after CD4 activation. The HIV-1 envelope glycoprotein (Env) is a key target for neutralizing antibodies that can bind to the virus and thus prevent entry into target cells (1-3). Functional Env is a trimer, with each protomer composed of a heterodimer of gp120 and gp41 (4). The three protomers associate to form a "spike" on the surface of the viral membrane (5). Cryo-electron tomographic studies have provided molecular structures of a variety of trimeric envelope glycoproteins, both as spikes displayed on intact viruses and as soluble ectodomains (5-9). These studies have shown that when trimeric HIV-1 Env is in an unliganded state or when bound to the neutralizing antibody VRC01, it exists in a "closed" conformation, with the V1/V2 loops located close to the apex of the spike. When trimeric HIV-1 Env is bound to the neutralizing antibody b12, the trimer displays a partially open conformation with only a slight rearrangement of each gp120 monomer. In contrast, when bound to soluble CD4 or to coreceptor binding site reagents, such as the monoclonal antibody 17b, both soluble and native forms of trimeric HIV-1 Env display a fully open quaternary conformation. In this open state, the three gp120 monomers display a major structural rearrangement relative to their conformation in the closed state, involving large rotations of each gp120 monomer (5, 7 Atomic-resolution structures are available for the complexes formed between the monomeric gp120 subunit of Env and a variety of antibodies that target the CD4 binding site region. Much less structural information is available for complexes formed between the gp41 subunit and gp41-targeted neutralizing antibodies. No atomic-resolution structural models are available for trimeric gp41 in the prefusion state. However, the region of the gp41 ectodomain that is closest to the viral membrane, the membraneproximal external region (MPER), has been identified as a key antigenic site that is the target of a number of neutralizing antibodies, such as 2F5, 4E10, 10E8, and Z13e1, with atomic structures available for the complexes formed between Fab fragments from each of these antibodies and the relevant peptide epitopes on gp41 (10-13). However, no structural information is available for the complex formed between MPER-binding antibodies and gp41 either as a protomer or in the context of intact trimeric HIV-1 Env.Here, we present cryo-electron microscopic studies of the complex formed between the Fab fragment of the MPER antibody Z13e1 and trimeric SOSIP gp140, which is a cleaved, solubilized ver...

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Binding of Anti-Membrane-Proximal gp41 Monoclonal Antibodies to CD4-Liganded and -Unliganded Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus Virions

Cited by 23 publications

References 89 publications

Antigenic Properties of the HIV Envelope on Virions in Solution

Antigenic Properties of the HIV Envelope on Virions in Solution

SERINC5 protein inhibits HIV-1 fusion pore formation by promoting functional inactivation of envelope glycoproteins

HIV-1 Envelope Glycoprotein Trimers Display Open Quaternary Conformation When Bound to the gp41 Membrane-Proximal External-Region-Directed Broadly Neutralizing Antibody Z13e1

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