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Title: Antigenicity-defined conformations of an extremely neutralization-resistant HIV-1 envelope spike

Abstract

Here, the extraordinary genetic diversity of the HIV-1 envelope spike [Env; trimeric (gp160) 3, cleaved to (gp120/gp41) 3] poses challenges for vaccine development. Envs of different clinical isolates exhibit different sensitivities to antibody-mediated neutralization. Envs of difficult-to-neutralize viruses are thought to be more stable and conformationally homogeneous trimers than those of easy-to-neutralize viruses, thereby providing more effective concealment of conserved, functionally critical sites. In this study we have characterized the antigenic properties of an Env derived from one of the most neutralization-resistant HIV-1 isolates, CH120.6. Sequence variation at neutralizing epitopes does not fully account for its exceptional resistance to antibodies. The full-length, membrane-bound CH120.6 Env is indeed stable and conformationally homogeneous. Its antigenicity correlates closely with its neutralization sensitivity, and major changes in antigenicity upon CD4 engagement appear to be restricted to the coreceptor site. The CH120.6 gp140 trimer, the soluble and uncleaved ectodomain of (gp160) 3, retains many antigenic properties of the intact Env, consistent with a conformation close to that of Env spikes on a virion, whereas its monomeric gp120 exposes many nonneutralizing or strain-specific epitopes. Thus, trimer organization and stability are important determinants not only for occluding many epitopes but also for conferring resistance to neutralization bymore » all but a small set of antibodies. Env preparations derived from neutralization-resistant viruses may induce irrelevant antibody responses less frequently than do other Envs and may be excellent templates for developing soluble immunogens.« less

Authors:
 [1];  [2];  [1];  [2];  [3];  [2];  [1];  [4]; ORCiD logo [5]; ORCiD logo [5];  [5];  [3];  [1];  [6];  [1]
  1. Boston Children's Hospital, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
  2. GlaxoSmithKline Vaccines, Rockville, MD (United States)
  3. Beth Israel Deaconess Medical Center, Boston, MA (United States)
  4. Codex BioSolutions, Inc., Gaithersburg, MD (United States)
  5. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  6. GlaxoSmithKline Vaccines, Rockville, MD (United States); Valera LLC, Cambridge, MA (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
Universities/Institutions; USDOE
OSTI Identifier:
1374321
Report Number(s):
LA-UR-16-29058
Journal ID: ISSN 0027-8424
Grant/Contract Number:
AC52-06NA25396
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 114; Journal Issue: 17; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science; HIV-1 gp160; neutralizing antibodies; vaccine design

Citation Formats

Cai, Yongfei, Karaca-Griffin, Selen, Chen, Jia, Tian, Sai, Fredette, Nicholas, Linton, Christine E., Rits-Volloch, Sophia, Lu, Jianming, Wagh, Kshitij, Theiler, James Patrick, Korber, Bette Tina Marie, Seaman, Michael S., Harrison, Stephen C., Carfi, Andrea, and Chen, Bing. Antigenicity-defined conformations of an extremely neutralization-resistant HIV-1 envelope spike. United States: N. p., 2017. Web. doi:10.1073/pnas.1700634114.
Cai, Yongfei, Karaca-Griffin, Selen, Chen, Jia, Tian, Sai, Fredette, Nicholas, Linton, Christine E., Rits-Volloch, Sophia, Lu, Jianming, Wagh, Kshitij, Theiler, James Patrick, Korber, Bette Tina Marie, Seaman, Michael S., Harrison, Stephen C., Carfi, Andrea, & Chen, Bing. Antigenicity-defined conformations of an extremely neutralization-resistant HIV-1 envelope spike. United States. doi:10.1073/pnas.1700634114.
Cai, Yongfei, Karaca-Griffin, Selen, Chen, Jia, Tian, Sai, Fredette, Nicholas, Linton, Christine E., Rits-Volloch, Sophia, Lu, Jianming, Wagh, Kshitij, Theiler, James Patrick, Korber, Bette Tina Marie, Seaman, Michael S., Harrison, Stephen C., Carfi, Andrea, and Chen, Bing. Mon . "Antigenicity-defined conformations of an extremely neutralization-resistant HIV-1 envelope spike". United States. doi:10.1073/pnas.1700634114. https://www.osti.gov/servlets/purl/1374321.
@article{osti_1374321,
title = {Antigenicity-defined conformations of an extremely neutralization-resistant HIV-1 envelope spike},
author = {Cai, Yongfei and Karaca-Griffin, Selen and Chen, Jia and Tian, Sai and Fredette, Nicholas and Linton, Christine E. and Rits-Volloch, Sophia and Lu, Jianming and Wagh, Kshitij and Theiler, James Patrick and Korber, Bette Tina Marie and Seaman, Michael S. and Harrison, Stephen C. and Carfi, Andrea and Chen, Bing},
abstractNote = {Here, the extraordinary genetic diversity of the HIV-1 envelope spike [Env; trimeric (gp160)3, cleaved to (gp120/gp41)3] poses challenges for vaccine development. Envs of different clinical isolates exhibit different sensitivities to antibody-mediated neutralization. Envs of difficult-to-neutralize viruses are thought to be more stable and conformationally homogeneous trimers than those of easy-to-neutralize viruses, thereby providing more effective concealment of conserved, functionally critical sites. In this study we have characterized the antigenic properties of an Env derived from one of the most neutralization-resistant HIV-1 isolates, CH120.6. Sequence variation at neutralizing epitopes does not fully account for its exceptional resistance to antibodies. The full-length, membrane-bound CH120.6 Env is indeed stable and conformationally homogeneous. Its antigenicity correlates closely with its neutralization sensitivity, and major changes in antigenicity upon CD4 engagement appear to be restricted to the coreceptor site. The CH120.6 gp140 trimer, the soluble and uncleaved ectodomain of (gp160)3, retains many antigenic properties of the intact Env, consistent with a conformation close to that of Env spikes on a virion, whereas its monomeric gp120 exposes many nonneutralizing or strain-specific epitopes. Thus, trimer organization and stability are important determinants not only for occluding many epitopes but also for conferring resistance to neutralization by all but a small set of antibodies. Env preparations derived from neutralization-resistant viruses may induce irrelevant antibody responses less frequently than do other Envs and may be excellent templates for developing soluble immunogens.},
doi = {10.1073/pnas.1700634114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 17,
volume = 114,
place = {United States},
year = {Mon Apr 10 00:00:00 EDT 2017},
month = {Mon Apr 10 00:00:00 EDT 2017}
}

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  • 'Centralized' (ancestral and consensus) HIV-1 envelope immunogens induce broadly cross-reactive T cell responses in laboratory animals; however, their potential to elicit cross-reactive neutralizing antibodies has not been fully explored. Here, we report the construction of a panel of consensus subtype B (ConB) envelopes and compare their biologic, antigenic, and immunogenic properties to those of two wild-type Env controls from individuals with early and acute HIV-1 infection. Glycoprotein expressed from full-length (gp160), uncleaved (gp160-UNC), truncated (gp145), and N-linked glycosylation site deleted (gp160-201N/S) versions of the ConB env gene were packaged into virions and, except for the fusion defective gp160-UNC, mediated infectionmore » via the CCR5 co-receptor. Pseudovirions containing ConB Envs were sensitive to neutralization by patient plasma and monoclonal antibodies, indicating the preservation of neutralizing epitopes found in contemporary subtype B viruses. When used as DNA vaccines in guinea pigs, ConB and wild-type env immunogens induced appreciable binding, but overall only low level neutralizing antibodies. However, all four ConB immunogens were significantly more potent than one wild-type vaccine at eliciting neutralizing antibodies against a panel of tier 1 and tier 2 viruses, and ConB gp145 and gp160 were significantly more potent than both wild-type vaccines at inducing neutralizing antibodies against tier 1 viruses. Thus, consensus subtype B env immunogens appear to be at least as good as, and in some instances better than, wild-type B env immunogens at inducing a neutralizing antibody response, and are amenable to further improvement by specific gene modifications.« less
  • The external domains of the HIV-1 envelope glycoprotein (gp120 and the gp41 ectodomain, collectively known as gp140) contain all known viral neutralization epitopes. Various strategies have been used to create soluble trimers of the envelope to mimic the structure of the native viral protein, including mutation of the gp120-gp41 cleavage site, introduction of disulfide bonds, and fusion to heterologous trimerization motifs. We compared the effects on quaternary structure, antigenicity, and immunogenicity of three such motifs: T4 fibritin, a GCN4 variant, and the Escherichia coli aspartate transcarbamoylase catalytic subunit. Fusion of each motif to the C-terminus of a noncleavable JRCSF gp140(-)more » envelope protein led to enhanced trimerization but had limited effects on the antigenic profile and CD4-binding ability of the trimers. Immunization of rabbits provided no evidence that the trimerized gp140(-) constructs induced significantly improved neutralizing antibodies to several HIV-1 pseudoviruses, compared to gp140 lacking a trimerization motif. However, modest differences in both binding specificity and neutralizing antibody responses were observed among the various immunogens.« less
  • In addition to the major ectodomain, the gp41 transmembrane glycoprotein of HIV-1 is now known to have a minor ectodomain that is part of the long C-terminal tail. Both ectodomains are highly antigenic, carry neutralizing and non-neutralizing epitopes, and are involved in virus-mediated fusion activity. However, data have so far been biologically based, and derived solely from T cell line-adapted (TCLA), B clade viruses. Here we have carried out sequence and theoretically based structural analyses of 357 gp41 C-terminal sequences of mainly primary isolates of HIV-1 clades A, B, C, and D. Data show that all these viruses have themore » potential to form a tail loop structure (the minor ectodomain) supported by three, {beta}-sheet, membrane-spanning domains (MSDs). This means that the first (N-terminal) tyrosine-based sorting signal of the gp41 tail is situated outside the cell membrane and is non-functional, and that gp41 that reaches the cell surface may be recycled back into the cytoplasm through the activity of the second tyrosine-sorting signal. However, we suggest that only a minority of cell-associated gp41 molecules - those destined for incorporation into virions - has 3 MSDs and the minor ectodomain. Most intracellular gp41 has the conventional single MSD, no minor ectodomain, a functional first tyrosine-based sorting signal, and in line with current thinking is degraded intracellularly. The gp41 structural diversity suggested here can be viewed as an evolutionary strategy to minimize HIV-1 envelope glycoprotein expression on the cell surface, and hence possible cytotoxicity and immune attack on the infected cell.« less
  • The third variable (V3) loop and the CD4 binding site (CD4bs) of the viral envelope are frequently targeted by neutralizing antibodies (nAbs) in HIV-1-infected individuals. In chronic infection, virus escape mutants repopulate the plasma and V3 and CD4bs nAbs emerge that can neutralize heterologous tier 1 easy-to-neutralize, but not tier 2 difficult-to-neutralize HIV-1 isolates. However, neutralization sensitivity of autologous plasma viruses to this type of nAb response has not been studied. We describe the development and evolution in vivo of antibodies distinguished by their target specificity for V3and CD4bs epitopes on autologous tier 2 viruses but not on heterologous tiermore » 2 viruses. A surprisingly high fraction of autologous circulating viruses was sensitive to these antibodies. These findings demonstrate a role for V3 and CD4bs antibodies in constraining the native envelope trimer in vivo to a neutralization-resistant phenotype, explaining why HIV-1 transmission generally occurs by tier 2 neutralization-resistant viruses.« less