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29 results on '"Torrents de la Peña, Alba"'

1. Triple tandem trimer immunogens for HIV-1 and influenza nucleic acid-based vaccines

Author

del Moral-Sánchez, Iván, Wee, Edmund G., Xian, Yuejiao, Lee, Wen-Hsin, Allen, Joel D., Torrents de la Peña, Alba, Fróes Rocha, Rebeca, Ferguson, James, León, André N., Koekkoek, Sylvie, Schermer, Edith E., Burger, Judith A., Kumar, Sanjeev, Zwolsman, Robby, Brinkkemper, Mitch, Aartse, Aafke, Eggink, Dirk, Han, Julianna, Yuan, Meng, Crispin, Max, Ozorowski, Gabriel, Ward, Andrew B., Wilson, Ian A., Hanke, Tomáš, Sliepen, Kwinten, and Sanders, Rogier W.

Published
2024
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5. Complementary antibody lineages achieve neutralization breadth in an HIV-1 infected elite neutralizer

Author

van Schooten, Jelle, primary, Schorcht, Anna, additional, Farokhi, Elinaz, additional, Umotoy, Jeffrey C., additional, Gao, Hongmei, additional, van den Kerkhof, Tom L. G. M., additional, Dorning, Jessica, additional, Rijkhold Meesters, Tim G., additional, van der Woude, Patricia, additional, Burger, Judith A., additional, Bijl, Tom, additional, Ghalaiyini, Riham, additional, Torrents de la Peña, Alba, additional, Turner, Hannah L., additional, Labranche, Celia C., additional, Stanfield, Robyn L., additional, Sok, Devin, additional, Schuitemaker, Hanneke, additional, Montefiori, David C., additional, Burton, Dennis R., additional, Ozorowski, Gabriel, additional, Seaman, Michael S., additional, Wilson, Ian A., additional, Sanders, Rogier W., additional, Ward, Andrew B., additional, and van Gils, Marit J., additional

Published
2022
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6. Structure of the hepatitis C virus E1E2 glycoprotein complex

Author

Torrents de la Peña, Alba, primary, Sliepen, Kwinten, additional, Eshun-Wilson, Lisa, additional, Newby, Maddy L., additional, Allen, Joel D., additional, Zon, Ian, additional, Koekkoek, Sylvie, additional, Chumbe, Ana, additional, Crispin, Max, additional, Schinkel, Janke, additional, Lander, Gabriel C., additional, Sanders, Rogier W., additional, and Ward, Andrew B., additional

Published
2022
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7. Allelic polymorphism controls autoreactivity and vaccine elicitation of human broadly neutralizing antibodies against influenza virus

Author

Sangesland, Maya, primary, Torrents de la Peña, Alba, additional, Boyoglu-Barnum, Seyhan, additional, Ronsard, Larance, additional, Mohamed, Faez Amokrane Nait, additional, Moreno, Thalia Bracamonte, additional, Barnes, Ralston M., additional, Rohrer, Daniel, additional, Lonberg, Nils, additional, Ghebremichael, Musie, additional, Kanekiyo, Masaru, additional, Ward, Andrew, additional, and Lingwood, Daniel, additional

Published
2022
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9. Structural mapping of antibody landscapes to human betacoronavirus spike proteins

Author

Bangaru, Sandhya, primary, Antanasijevic, Aleksandar, additional, Kose, Nurgun, additional, Sewall, Leigh M., additional, Jackson, Abigail M., additional, Suryadevara, Naveenchandra, additional, Zhan, Xiaoyan, additional, Torres, Jonathan L., additional, Copps, Jeffrey, additional, Torrents de la Peña, Alba, additional, Crowe, James E., additional, and Ward, Andrew B., additional

Published
2021
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11. Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers

Author

Schorcht, Anna, primary, van den Kerkhof, Tom L. G. M., additional, Cottrell, Christopher A., additional, Allen, Joel D., additional, Torres, Jonathan L., additional, Behrens, Anna-Janina, additional, Schermer, Edith E., additional, Burger, Judith A., additional, de Taeye, Steven W., additional, Torrents de la Peña, Alba, additional, Bontjer, Ilja, additional, Gumbs, Stephanie, additional, Ozorowski, Gabriel, additional, LaBranche, Celia C., additional, de Val, Natalia, additional, Yasmeen, Anila, additional, Klasse, Per Johan, additional, Montefiori, David C., additional, Moore, John P., additional, Schuitemaker, Hanneke, additional, Crispin, Max, additional, van Gils, Marit J., additional, Ward, Andrew B., additional, and Sanders, Rogier W., additional

Published
2020
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12. Immunogenicity in Rabbits of HIV-1 SOSIP Trimers from Clades A, B, and C, Given Individually, Sequentially, or in Combination

Author

Torrents de la Peña, Alba, de Taeye, Steven W., Sliepen, Kwinten, LaBranche, Celia C., Burger, Judith A., Schermer, Edith E., Montefiori, David C., Moore, John P., Klasse, Per Johan, and Sanders, Rogier W.

Subjects
AIDS Vaccines, Immunogenicity, Vaccine, vaccine, Vaccines and Antiviral Agents, HIV-1, env Gene Products, Human Immunodeficiency Virus, HIV, Animals, Humans, Rabbits, immunogenicity, Protein Multimerization
Abstract

Recombinant soluble HIV-1 envelope glycoprotein (Env) SOSIP trimers are a design platform for inducing broadly neutralizing antibodies (bNAbs) by vaccination. To date, these and alternative designs of native-like trimers, given singly or in pairs, have not induced bNAbs in test animals such as rabbits or macaques. Here, we have evaluated whether trivalent and tetravalent combinations of SOSIP trimers from clades A, B, and C, delivered simultaneously or sequentially, induce better neutralizing antibody responses in rabbits than when given alone. None of the tested formulations led to the induction of bNAbs. We found that BG505 clade A trimers dominated the autologous NAb responses induced by combinations, which probably relates to the presence of immunodominant glycan holes on the BG505 trimer. Furthermore, autologous NAb responses to all individual trimers were reduced when they were delivered in combinations compared with when delivered alone, suggesting that immunogen interference had occurred. Finally, in a sequential regimen, a heterologous clade C trimer cross-boosted NAb responses that were primed by earlier immunizations with clade A and B trimers. Taken together, these findings should allow us to improve the design of immunization regimens based on native-like HIV-1 Env trimers. IMPORTANCE A successful HIV-1 vaccine most probably requires a trimeric envelope glycoprotein (Env) component, as Env is the only viral protein on the surface of the virus and therefore the only target for neutralizing antibodies. Native-like Env trimers can induce strain-specific neutralizing antibodies but not yet broadly neutralizing antibodies. To try to broaden the antibody response, we immunized rabbits with soluble native-like Env trimers from three different clades using monovalent, multivalent, and sequential regimens. We found that the neutralizing antibody response against each immunogen was reduced when the immunogens were delivered in combination or sequentially compared to the monovalent regimen. In contrast, when the Env trimers from different clades were delivered sequentially, the neutralizing antibody response could be cross-boosted. Although the combination of native-like Env trimers from different clades did not induce broadly neutralizing antibodies, the results provide clues on how to use native-like trimers in vaccination experiments.

Published
2018

13. Stabilization of the gp120 V3 loop through hydrophobic interactions reduces the immunodominant V3-directed non-neutralizing response to HIV-1 envelope trimers

Author

de Taeye, Steven W., Torrents de la Peña, Alba, Vecchione, Andrea, Scutigliani, Enzo, Sliepen, Kwinten, Burger, Judith A., van der Woude, Patricia, Schorcht, Anna, Schermer, Edith E., van Gils, Marit J., LaBranche, Celia C., Montefiori, David C., Wilson, Ian A., Moore, John P., Ward, Andrew B., Sanders, Rogier W., Graduate School, AII - Infectious diseases, Medical Microbiology and Infection Prevention, AII - Amsterdam institute for Infection and Immunity, and Other departments

Abstract

To provide protective immunity against circulating primary HIV-1 strains, a vaccine most likely has to induce broadly neutralizing antibodies to the HIV-1 envelope glycoprotein (Env) spike. Recombinant Env trimers such as the prototype BG505 SOSIP.664 that closely mimic the native Env spike can induce autologous neutralizing antibodies (NAbs) against relatively resistant (tier 2) primary viruses. Ideally, Env immunogens should present broadly neutralizing antibody epitopes but limit the presentation of immunodominant non-NAb epitopes that might induce off-target and potentially interfering responses. The V3 loop in gp120 is such a non-NAb epitope that can effectively elicit non-NAbs when animals are immunized with SOSIP.664 trimers. V3 immunogenicity can be diminished, but not abolished, by reducing the conformational flexibility of trimers via targeted sequence changes, including an A316W substitution in V3, that create the SOSIP.v4.1 and SOSIP.v5.2 variants. Here, we further modified these trimer designs by introducing leucine residues at V3 positions 306 and 308 to create hydrophobic interactions with the tryptophan residue at position 316 and with other topologically proximal sites in the V1V2 domain. Together, these modifications further stabilized the resulting SOSIP.v5.2 S306L/R308L trimers in the prefusion state in which V3 is sequestered. When we tested these trimers as immunogens in rabbits, the induction of V3 non-NAbs was significantly reduced compared with the SOSIP.v5.2 trimers and even more so compared with the SOSIP.664 prototype, without affecting the autologous NAb response. Hence, these additional trimer sequence modifications may be beneficial for immunization strategies that seek to minimize off-target non-NAb responses

Published
2018

14. Immunogenicity in rabbits of SOSIP trimers from clades A, B and C, given individually, sequentially or in combinations

Author

Torrents de la Peña, Alba, de Taeye, Steven W., Sliepen, Kwinten, LaBranche, Celia C., Burger, Judith A., Schermer, Edith E., Montefiori, David C., Moore, John P., Klasse, Per Johan, Sanders, Rogier W., AII - Infectious diseases, Graduate School, Medical Microbiology and Infection Prevention, Other departments, and Amsterdam institute for Infection and Immunity

Abstract

Recombinant soluble HIV-1 envelope glycoprotein (Env) SOSIP trimers are a design platform for inducing broadly neutralizing antibodies (bNAbs) by vaccination. To date, these and alternative designs of native-like trimers given singly or in pairs, have not induced bNAbs in test animals such as rabbits or macaques. Here, we have evaluated whether trivalent and tetravalent combinations of SOSIP trimers from clades A, B and C, delivered simultaneously or sequentially, induce better neutralizing antibody responses in rabbits than when given alone. None of the tested formulations led to the induction of bNAbs. We found that BG505 clade A trimers dominated the autologous NAb responses induced by combinations, which probably relates to the presence of immunodominant glycan holes on the BG505 trimer. Furthermore, autologous NAb responses to all individual trimers were reduced when they were delivered in combinations compared with when delivered alone, suggesting that immunogen interference had occurred. Finally, in a sequential regimen, a heterologous clade C trimer cross-boosted NAb responses that were primed by earlier immunizations with clade A and B trimers. Taken together, these findings should allow us to improve the design of immunization regimens based on native-like HIV-1 Env trimers.IMPORTANCE A successful HIV-1 vaccine most probably requires a trimeric envelope glycoprotein (Env) component, as Env is the only viral protein on the surface of the virus and therefore the only target for neutralizing antibodies. Native-like Env trimers can induce strain-specific neutralizing antibodies, but not yet broadly neutralizing antibodies. To try to broaden the antibody response, we immunized rabbits with soluble native-like Env trimers from three different clades using monovalent, multivalent and sequential regimens. We found that the neutralizing antibody response against each immunogen was reduced when the immunogens were delivered in combination or sequentially compared to the monovalent regimen. In contrast, when the Env trimers from different clades were delivered sequentially, the neutralizing antibody response could be cross-boosted. Although the combination of native-like Env trimers from different clades did not induce broadly neutralizing antibodies, the results provide clues on how to use native-like trimers in vaccination experiments

Published
2018

17. Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization

Author

Torrents de la Peña, Alba, primary, Julien, Jean-Philippe, additional, de Taeye, Steven W., additional, Garces, Fernando, additional, Guttman, Miklos, additional, Ozorowski, Gabriel, additional, Pritchard, Laura K., additional, Behrens, Anna-Janina, additional, Go, Eden P., additional, Burger, Judith A., additional, Schermer, Edith E., additional, Sliepen, Kwinten, additional, Ketas, Thomas J., additional, Pugach, Pavel, additional, Yasmeen, Anila, additional, Cottrell, Christopher A., additional, Torres, Jonathan L., additional, Vavourakis, Charlotte D., additional, van Gils, Marit J., additional, LaBranche, Celia, additional, Montefiori, David C., additional, Desaire, Heather, additional, Crispin, Max, additional, Klasse, Per Johan, additional, Lee, Kelly K., additional, Moore, John P., additional, Ward, Andrew B., additional, Wilson, Ian A., additional, and Sanders, Rogier W., additional

Published
2017
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18. Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches

Author

Pauthner, Matthias, primary, Havenar-Daughton, Colin, additional, Sok, Devin, additional, Nkolola, Joseph P., additional, Bastidas, Raiza, additional, Boopathy, Archana V., additional, Carnathan, Diane G., additional, Chandrashekar, Abishek, additional, Cirelli, Kimberly M., additional, Cottrell, Christopher A., additional, Eroshkin, Alexey M., additional, Guenaga, Javier, additional, Kaushik, Kirti, additional, Kulp, Daniel W., additional, Liu, Jinyan, additional, McCoy, Laura E., additional, Oom, Aaron L., additional, Ozorowski, Gabriel, additional, Post, Kai W., additional, Sharma, Shailendra K., additional, Steichen, Jon M., additional, de Taeye, Steven W., additional, Tokatlian, Talar, additional, Torrents de la Peña, Alba, additional, Butera, Salvatore T., additional, LaBranche, Celia C., additional, Montefiori, David C., additional, Silvestri, Guido, additional, Wilson, Ian A., additional, Irvine, Darrell J., additional, Sanders, Rogier W., additional, Schief, William R., additional, Ward, Andrew B., additional, Wyatt, Richard T., additional, Barouch, Dan H., additional, Crotty, Shane, additional, and Burton, Dennis R., additional

Published
2017
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19. Direct Probing of Germinal Center Responses Reveals Immunological Features and Bottlenecks for Neutralizing Antibody Responses to HIV Env Trimer

Author

Havenar-Daughton, Colin, primary, Carnathan, Diane G., additional, Torrents de la Peña, Alba, additional, Pauthner, Matthias, additional, Briney, Bryan, additional, Reiss, Samantha M., additional, Wood, Jennifer S., additional, Kaushik, Kirti, additional, van Gils, Marit J., additional, Rosales, Sandy L., additional, van der Woude, Patricia, additional, Locci, Michela, additional, Le, Khoa M., additional, de Taeye, Steven W., additional, Sok, Devin, additional, Mohammed, Ata Ur Rasheed, additional, Huang, Jessica, additional, Gumber, Sanjeev, additional, Garcia, AnaPatricia, additional, Kasturi, Sudhir P., additional, Pulendran, Bali, additional, Moore, John P., additional, Ahmed, Rafi, additional, Seumois, Grégory, additional, Burton, Dennis R., additional, Sanders, Rogier W., additional, Silvestri, Guido, additional, and Crotty, Shane, additional

Published
2016
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20. Cytokine-Independent Detection of Antigen-Specific Germinal Center T Follicular Helper Cells in Immunized Nonhuman Primates Using a Live Cell Activation-Induced Marker Technique

Author

Havenar-Daughton, Colin, primary, Reiss, Samantha M., additional, Carnathan, Diane G., additional, Wu, Jennifer E., additional, Kendric, Kayla, additional, Torrents de la Peña, Alba, additional, Kasturi, Sudhir Pai, additional, Dan, Jennifer M., additional, Bothwell, Marcella, additional, Sanders, Rogier W., additional, Pulendran, Bali, additional, Silvestri, Guido, additional, and Crotty, Shane, additional

Published
2016
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21. Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes

Author

de Taeye, Steven W., primary, Ozorowski, Gabriel, additional, Torrents de la Peña, Alba, additional, Guttman, Miklos, additional, Julien, Jean-Philippe, additional, van den Kerkhof, Tom L.G.M., additional, Burger, Judith A., additional, Pritchard, Laura K., additional, Pugach, Pavel, additional, Yasmeen, Anila, additional, Crampton, Jordan, additional, Hu, Joyce, additional, Bontjer, Ilja, additional, Torres, Jonathan L., additional, Arendt, Heather, additional, DeStefano, Joanne, additional, Koff, Wayne C., additional, Schuitemaker, Hanneke, additional, Eggink, Dirk, additional, Berkhout, Ben, additional, Dean, Hansi, additional, LaBranche, Celia, additional, Crotty, Shane, additional, Crispin, Max, additional, Montefiori, David C., additional, Klasse, P.J., additional, Lee, Kelly K., additional, Moore, John P., additional, Wilson, Ian A., additional, Ward, Andrew B., additional, and Sanders, Rogier W., additional

Published
2015
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23. Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike

Author

Lee, Jeong Hyun, primary, Leaman, Daniel P., additional, Kim, Arthur S., additional, Torrents de la Peña, Alba, additional, Sliepen, Kwinten, additional, Yasmeen, Anila, additional, Derking, Ronald, additional, Ramos, Alejandra, additional, de Taeye, Steven W., additional, Ozorowski, Gabriel, additional, Klein, Florian, additional, Burton, Dennis R., additional, Nussenzweig, Michel C., additional, Poignard, Pascal, additional, Moore, John P., additional, Klasse, Per Johan, additional, Sanders, Rogier W., additional, Zwick, Michael B., additional, Wilson, Ian A., additional, and Ward, Andrew B., additional

Published
2015
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24. Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens

Author

Julien, Jean-Philippe, primary, Lee, Jeong Hyun, additional, Ozorowski, Gabriel, additional, Hua, Yuanzi, additional, Torrents de la Peña, Alba, additional, de Taeye, Steven W., additional, Nieusma, Travis, additional, Cupo, Albert, additional, Yasmeen, Anila, additional, Golabek, Michael, additional, Pugach, Pavel, additional, Klasse, P. J., additional, Moore, John P., additional, Sanders, Rogier W., additional, Ward, Andrew B., additional, and Wilson, Ian A., additional

Published
2015
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26. Differences in tetracycline resistance determinant carriage among Shigella flexneriand Shigella sonneiare not related to different plasmid Inc-type carriage

Author

Pons, María J., Torrents de la Peña, Alba, Mensa, Laura, Martón, Pilar, Ruiz-Roldán, Lidia, Martínez-Puchol, Sandra, Vila, Jordi, Gascón, Joaquim, and Ruiz, Joaquim

Abstract

•tet(B) was the most frequently detected tetracycline resistance determinant in Shigellaisolates.•The tet(A) gene was more frequent in Shigella sonnei.•The tet(B) gene was more frequent in Shigella flexneri.•Plasmid incompatibility (Inc) groups showed a species-specific distribution.•No relationship between plasmid Inc groups and tetgenes was found.

Published
2018
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27. Development and analysis of furazolidone-resistant Escherichia coli mutants.

Author

Martínez‐Puchol, Sandra, Gomes, Cláudia, Pons, Maria J., Ruiz‐Roldán, Lidia, Torrents de la Peña, Alba, Ochoa, Theresa J., and Ruiz, Joaquim

Subjects
ESCHERICHIA coli, FURAZOLIDONE, DRUG resistance in bacteria, GENETIC mutation, DIARRHEA, ENTEROBACTERIACEAE
Abstract

Furazolidone-resistant mutants were obtained from four clinical isolates of diarrhoeagenic Escherichia coli. The stability of the resistance and the frequency of mutation were established. The minimal inhibitory concentration of furazolidone, nitrofurantoin, nalidixic acid, ampicillin, chloramphenicol and tetracycline was established both in the presence and absence of the efflux pump inhibitor Phe-Arg-β-Naphtylamyde. The presence of mutations in the nitroreductase genes nfsA and nfsB was analysed by PCR; sequencing and their enzymatic activity was assessed by a spectrophotometric assay. Alterations in outer membrane proteins were studied by SDS- PAGE. The frequency of mutation ranged from <9.6 × 10−10 to 9.59 × 10−7. Neither an effect on efflux pumps inhibited by Phe-Arg-β-Naphtylamyde nor cross-resistance with the antibiotics studied was observed. Nineteen mutants (52.94%) presented mutations in the nitroreductase-encoding genes: 17 in the nfsA gene (15 mutants with an internal stop codon, 2 with amino acid changes), 2 in the nfsB (all amino acid changes). Alterations in the outer membrane proteins OmpA and OmpW were also observed. Although more studies are necessary to find other resistance mechanisms, present data showed the low potential of selecting furazolidone-resistant mutants, together with the lack of cross-resistance with unrelated antimicrobial agents. [ABSTRACT FROM AUTHOR]

Published
2015
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28. Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches

Author

Pauthner, Matthias, Havenar-Daughton, Colin, Sok, Devin, Nkolola, Joseph P., Bastidas, Raiza, Boopathy, Archana V., Carnathan, Diane G., Chandrashekar, Abishek, Cirelli, Kimberly M., Cottrell, Christopher A., Eroshkin, Alexey M., Guenaga, Javier, Kaushik, Kirti, Kulp, Daniel W., Liu, Jinyan, McCoy, Laura E., Oom, Aaron L., Ozorowski, Gabriel, Post, Kai W., Sharma, Shailendra K., Steichen, Jon M., de Taeye, Steven W., Tokatlian, Talar, Torrents de la Peña, Alba, Butera, Salvatore T., LaBranche, Celia C., Montefiori, David C., Silvestri, Guido, Wilson, Ian A., Irvine, Darrell J., Sanders, Rogier W., Schief, William R., Ward, Andrew B., Wyatt, Richard T., Barouch, Dan H., Crotty, Shane, and Burton, Dennis R.

Subjects
HIV vaccine, nonhuman primates, rhesus macaques, BG505, SOSIP, NFL, GC B cells, protein design, Tfh cells, germinal centers
Abstract

Summary The development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. Here, we tested multiple immunogens and immunization strategies head-to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer. We identified immunogens that minimized non-neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation.

Published
2017
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29. Convergent HIV-1 Evolution upon Targeted Destabilization of the gp120-gp41 Interface.

Author

Torrents de la Peña A, Del Moral Sánchez I, Burger JA, Bontjer I, Isik G, Eggink D, van Gils MJ, and Sanders RW

Subjects
Antibodies, Neutralizing, HEK293 Cells, HIV Envelope Protein gp120 genetics, HIV Envelope Protein gp41 genetics, Humans, Mutagenesis, Mutation, Protein Conformation, Protein Multimerization, Evolution, Molecular, HIV Envelope Protein gp120 metabolism, HIV Envelope Protein gp41 metabolism, HIV-1 genetics
Abstract

The HIV-1 envelope glycoprotein (Env) trimer is responsible for viral entry into target cells and is the sole target of neutralizing antibodies. The Env protein is therefore the focus of HIV-1 vaccine design. Env consists of two noncovalently linked subunits (gp120 and gp41) that form a trimer of heterodimers and this 6-subunit complex is metastable and conformationally flexible. Several approaches have been pursued to stabilize the Env trimer for vaccine purposes, which include structure-based design, high-throughput screening, and selection by mammalian cell display. Here, we employed directed virus evolution to improve Env trimer stability. Accordingly, we deliberately destabilized the Env gp120-gp41 interface by mutagenesis in the context of replicating HIV-1 LAI virus and virus evolution over time. We identified compensatory changes that pointed at convergent evolution, as they were largely restricted to specific Env regions, namely, the V1V2 domain of gp120 and the HR1 and HR2 domain of gp41. Specifically, S614G in V1V2 and Q567R in HR1 were frequently identified. Interestingly, the majority of the compensatory mutations were at distant locations from the original mutations and most likely strengthen intersubunit interactions. These results show how the virus can overcome Env instability and illuminate the regions that play a dominant role in Env stability. IMPORTANCE A successful HIV-1 vaccine most likely requires an envelope glycoprotein (Env) component, as Env is the only viral protein on the surface of the virus and the target for neutralizing antibodies. However, HIV Env is metastable and flexible because of the weak interactions between the Env subunits, complicating the generation of recombinant mimics of native Env. Here, we used directed viral evolution to study Env stability. We deliberately destabilized the interface between Env subunits and explored the capacity of the virus to repair trimer instability by evolution. We identified compensatory mutations that converged in specific Env locations: the apex and the trimer interface. Selected mutations enhanced the stability of recombinant soluble Env trimer proteins. These results provided clues on understanding the structural mechanisms involved in Env trimer stability, which can guide future immunogen design.

Published
2021
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