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HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates.
J Virol. 2017 11 01; 91(21)JV

Abstract

Elicitation of broadly neutralizing antibody (bNAb) responses is a major goal for the development of an HIV-1 vaccine. Current HIV-1 envelope glycoprotein (Env) vaccine candidates elicit predominantly tier 1 and/or autologous tier 2 virus neutralizing antibody (NAb) responses, as well as weak and/or sporadic cross-reactive tier 2 virus NAb responses with unknown specificity. To delineate the specificity of vaccine-elicited cross-reactive tier 2 virus NAb responses, we performed single memory B cell sorting from the peripheral blood of a rhesus macaque immunized with YU2gp140-F trimers in adjuvant, using JR-FL SOSIP.664, a native Env trimer mimetic, as a sorting probe to isolate monoclonal Abs (MAbs). We found striking genetic and functional convergence of the SOSIP-sorted Ig repertoire, with predominant VH4 or VH5 gene family usage and Env V3 specificity. Of these vaccine-elicited V3-specific MAbs, nearly 20% (6/33) displayed cross-reactive tier 2 virus neutralization, which recapitulated the serum neutralization capacity. Substantial similarities in binding specificity, neutralization breadth and potency, and sequence/structural homology were observed between selected macaque cross-reactive V3 NAbs elicited by vaccination and prototypic V3 NAbs derived from natural infections in humans, highlighting the convergence of this subset of primate V3-specific B cell repertories. Our study demonstrated that cross-reactive primary virus neutralizing B cell lineages could be elicited by vaccination as detected using a standardized panel of tier 2 viruses. Whether these lineages could be expanded to acquire increased breadth and potency of neutralization merits further investigation.IMPORTANCE Elicitation of antibody responses capable of neutralizing diverse HIV-1 primary virus isolates (designated broadly neutralizing antibodies [bNAbs]) remains a high priority for the vaccine field. bNAb responses were so far observed only in response to natural infection within a subset of individuals. To achieve this goal, an improved understanding of vaccine-elicited responses, including at the monoclonal Ab level, is essential. Here, we isolated and characterized a panel of vaccine-elicited cross-reactive neutralizing MAbs targeting the Env V3 loop that moderately neutralized several primary viruses and recapitulated the serum neutralizing antibody response. Striking similarities between the cross-reactive V3 NAbs elicited by vaccination in macaques and natural infections in humans illustrate commonalities between the vaccine- and infection-induced responses to V3 and support the feasibility of exploring the V3 epitope as a HIV-1 vaccine target in nonhuman primates.

Authors+Show Affiliations

Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Maryland, USA. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, USA.Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Maryland, USA.Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Maryland, USA.International AIDS Vaccine Initiative Neutralizing Antibody Center at the Scripps Research Institute, La Jolla, California, USA.International AIDS Vaccine Initiative Neutralizing Antibody Center at the Scripps Research Institute, La Jolla, California, USA.Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center at the Scripps Research Institute, La Jolla, California, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, California, USA.Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center at the Scripps Research Institute, La Jolla, California, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, California, USA.Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Maryland, USA liy@ibbr.umd.edu. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

28835491

Citation

Wang, Yimeng, et al. "HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited By Immunization in Nonhuman Primates." Journal of Virology, vol. 91, no. 21, 2017.
Wang Y, O'Dell S, Turner HL, et al. HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates. J Virol. 2017;91(21).
Wang, Y., O'Dell, S., Turner, H. L., Chiang, C. I., Lei, L., Guenaga, J., Wilson, R., Martinez-Murillo, P., Doria-Rose, N., Ward, A. B., Mascola, J. R., Wyatt, R. T., Karlsson Hedestam, G. B., & Li, Y. (2017). HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates. Journal of Virology, 91(21). https://doi.org/10.1128/JVI.00910-17
Wang Y, et al. HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited By Immunization in Nonhuman Primates. J Virol. 2017 11 1;91(21) PubMed PMID: 28835491.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates. AU - Wang,Yimeng, AU - O'Dell,Sijy, AU - Turner,Hannah L, AU - Chiang,Chi-I, AU - Lei,Lin, AU - Guenaga,Javier, AU - Wilson,Richard, AU - Martinez-Murillo,Paola, AU - Doria-Rose,Nicole, AU - Ward,Andrew B, AU - Mascola,John R, AU - Wyatt,Richard T, AU - Karlsson Hedestam,Gunilla B, AU - Li,Yuxing, Y1 - 2017/10/13/ PY - 2017/06/23/received PY - 2017/08/10/accepted PY - 2017/8/25/pubmed PY - 2017/11/10/medline PY - 2017/8/25/entrez KW - human immunodeficiency virus KW - neutralizing antibodies KW - nonhuman primate KW - vaccines JF - Journal of virology JO - J Virol VL - 91 IS - 21 N2 - Elicitation of broadly neutralizing antibody (bNAb) responses is a major goal for the development of an HIV-1 vaccine. Current HIV-1 envelope glycoprotein (Env) vaccine candidates elicit predominantly tier 1 and/or autologous tier 2 virus neutralizing antibody (NAb) responses, as well as weak and/or sporadic cross-reactive tier 2 virus NAb responses with unknown specificity. To delineate the specificity of vaccine-elicited cross-reactive tier 2 virus NAb responses, we performed single memory B cell sorting from the peripheral blood of a rhesus macaque immunized with YU2gp140-F trimers in adjuvant, using JR-FL SOSIP.664, a native Env trimer mimetic, as a sorting probe to isolate monoclonal Abs (MAbs). We found striking genetic and functional convergence of the SOSIP-sorted Ig repertoire, with predominant VH4 or VH5 gene family usage and Env V3 specificity. Of these vaccine-elicited V3-specific MAbs, nearly 20% (6/33) displayed cross-reactive tier 2 virus neutralization, which recapitulated the serum neutralization capacity. Substantial similarities in binding specificity, neutralization breadth and potency, and sequence/structural homology were observed between selected macaque cross-reactive V3 NAbs elicited by vaccination and prototypic V3 NAbs derived from natural infections in humans, highlighting the convergence of this subset of primate V3-specific B cell repertories. Our study demonstrated that cross-reactive primary virus neutralizing B cell lineages could be elicited by vaccination as detected using a standardized panel of tier 2 viruses. Whether these lineages could be expanded to acquire increased breadth and potency of neutralization merits further investigation.IMPORTANCE Elicitation of antibody responses capable of neutralizing diverse HIV-1 primary virus isolates (designated broadly neutralizing antibodies [bNAbs]) remains a high priority for the vaccine field. bNAb responses were so far observed only in response to natural infection within a subset of individuals. To achieve this goal, an improved understanding of vaccine-elicited responses, including at the monoclonal Ab level, is essential. Here, we isolated and characterized a panel of vaccine-elicited cross-reactive neutralizing MAbs targeting the Env V3 loop that moderately neutralized several primary viruses and recapitulated the serum neutralizing antibody response. Striking similarities between the cross-reactive V3 NAbs elicited by vaccination in macaques and natural infections in humans illustrate commonalities between the vaccine- and infection-induced responses to V3 and support the feasibility of exploring the V3 epitope as a HIV-1 vaccine target in nonhuman primates. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/28835491/HIV_1_Cross_Reactive_Primary_Virus_Neutralizing_Antibody_Response_Elicited_by_Immunization_in_Nonhuman_Primates_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28835491/ DB - PRIME DP - Unbound Medicine ER -