Enhanced Potency of a Broadly Neutralizing HIV-1 Antibody In Vitro Improves Protection against Lentiviral Infection In Vivo

被引:244
作者
Rudicell, Rebecca S. [1 ]
Do Kwon, Young [1 ]
Ko, Sung-Youl [1 ]
Pegu, Amarendra [1 ]
Louder, Mark K. [1 ]
Georgiev, Ivelin S. [1 ]
Wu, Xueling [1 ]
Zhu, Jiang [1 ]
Boyington, Jeffrey C. [1 ]
Chen, Xuejun [1 ]
Shi, Wei [1 ]
Yang, Zhi-Yong [1 ]
Doria-Rose, Nicole A. [1 ]
McKee, Krisha [1 ]
O'Dell, Sijy [1 ]
Schmidt, Stephen D. [1 ]
Chuang, Gwo-Yu [1 ]
Druz, Aliaksandr [1 ]
Soto, Cinque [1 ]
Yang, Yongping [1 ]
Zhang, Baoshan [1 ]
Zhou, Tongqing [1 ]
Todd, John-Paul [1 ]
Lloyd, Krissey E. [2 ]
Eudailey, Joshua [2 ]
Roberts, Kyle E. [3 ]
Donald, Bruce R. [3 ,4 ]
Bailer, Robert T. [1 ]
Ledgerwood, Julie [1 ]
Mullikin, James C. [5 ]
Shapiro, Lawrence [1 ,6 ]
Koup, Richard A. [1 ]
Graham, Barney S. [1 ]
Nason, Martha C. [7 ]
Connors, Mark [8 ]
Haynes, Barton F. [2 ]
Rao, Srinivas S. [1 ]
Roederer, Mario [1 ]
Kwong, Peter D. [1 ]
Mascola, John R. [1 ]
Nabel, Gary J. [1 ]
机构
[1] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA
[2] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA
[3] Duke Univ, Dept Comp Sci, Durham, NC 27706 USA
[4] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA
[5] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA
[6] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA
[7] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA
[8] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA
基金
美国国家卫生研究院; 比尔及梅琳达.盖茨基金会;
关键词
IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODIES; MUCOSAL SHIV CHALLENGE; N-GLYCAN RECOGNITION; ENVELOPE GLYCOPROTEIN; STRUCTURAL BASIS; DEPENDENT EPITOPE; VAGINAL CHALLENGE; CD4-BINDING SITE; PASSIVE TRANSFER;
D O I
10.1128/JVI.02213-14
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Over the past 5 years, a new generation of highly potent and broadly neutralizing HIV-1 antibodies has been identified. These antibodies can protect against lentiviral infection in nonhuman primates (NHPs), suggesting that passive antibody transfer would prevent HIV-1 transmission in humans. To increase the protective efficacy of such monoclonal antibodies, we employed next-generation sequencing, computational bioinformatics, and structure-guided design to enhance the neutralization potency and breadth of VRC01, an antibody that targets the CD4 binding site of the HIV-1 envelope. One variant, VRC07-523, was 5- to 8-fold more potent than VRC01, neutralized 96% of viruses tested, and displayed minimal autoreactivity. To compare its protective efficacy to that of VRC01 in vivo, we performed a series of simian-human immunodeficiency virus (SHIV) challenge experiments in nonhuman primates and calculated the doses of VRC07-523 and VRC01 that provide 50% protection (EC50). VRC07-523 prevented infection in NHPs at a 5-fold lower concentration than VRC01. These results suggest that increased neutralization potency in vitro correlates with improved protection against infection in vivo, documenting the improved functional efficacy of VRC07-523 and its potential clinical relevance for protecting against HIV-1 infection in humans. IMPORTANCE In the absence of an effective HIV-1 vaccine, alternative strategies are needed to block HIV-1 transmission. Direct administration of HIV-1-neutralizing antibodies may be able to prevent HIV-1 infections in humans. This approach could be especially useful in individuals at high risk for contracting HIV-1 and could be used together with antiretroviral drugs to prevent infection. To optimize the chance of success, such antibodies can be modified to improve their potency, breadth, and in vivo half-life. Here, knowledge of the structure of a potent neutralizing antibody, VRC01, that targets the CD4-binding site of the HIV-1 envelope protein was used to engineer a next-generation antibody with 5- to 8-fold increased potency in vitro. When administered to nonhuman primates, this antibody conferred protection at a 5-fold lower concentration than the original antibody. Our studies demonstrate an important correlation between in vitro assays used to evaluate the therapeutic potential of antibodies and their in vivo effectiveness.
引用
收藏
页码:12669 / 12682
页数:14
相关论文
共 87 条
[1]   PHENIX: a comprehensive Python']Python-based system for macromolecular structure solution [J].
Adams, Paul D. ;
Afonine, Pavel V. ;
Bunkoczi, Gabor ;
Chen, Vincent B. ;
Davis, Ian W. ;
Echols, Nathaniel ;
Headd, Jeffrey J. ;
Hung, Li-Wei ;
Kapral, Gary J. ;
Grosse-Kunstleve, Ralf W. ;
McCoy, Airlie J. ;
Moriarty, Nigel W. ;
Oeffner, Robert ;
Read, Randy J. ;
Richardson, David C. ;
Richardson, Jane S. ;
Terwilliger, Thomas C. ;
Zwart, Peter H. .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2010, 66 :213-221
[2]   ASAView: Database and tool for solvent accessibility representation in proteins [J].
Ahmad, S ;
Gromiha, M ;
Fawareh, H ;
Sarai, A .
BMC BIOINFORMATICS, 2004, 5 (1)
[3]   Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission [J].
Balazs, Alejandro B. ;
Ouyang, Yong ;
Hong, Christin M. ;
Chen, Joyce ;
Nguyen, Steven M. ;
Rao, Dinesh S. ;
An, Dong Sung ;
Baltimore, David .
NATURE MEDICINE, 2014, 20 (03) :296-300
[4]   Antibody-based protection against HIV infection by vectored immunoprophylaxis [J].
Balazs, Alejandro B. ;
Chen, Joyce ;
Hong, Christin M. ;
Rao, Dinesh S. ;
Yang, Lili ;
Baltimore, David .
NATURE, 2012, 481 (7379) :81-U88
[5]   Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys [J].
Barouch, Dan H. ;
Whitney, James B. ;
Moldt, Brian ;
Klein, Florian ;
Oliveira, Thiago Y. ;
Liu, Jinyan ;
Stephenson, Kathryn E. ;
Chang, Hui-Wen ;
Shekhar, Karthik ;
Gupta, Sanjana ;
Nkolola, Joseph P. ;
Seaman, Michael S. ;
Smith, Kaitlin M. ;
Borducchi, Erica N. ;
Cabral, Crystal ;
Smith, Jeffrey Y. ;
Blackmore, Stephen ;
Sanisetty, Srisowmya ;
Perry, James R. ;
Beck, Matthew ;
Lewis, Mark G. ;
Rinaldi, William ;
Chakraborty, Arup K. ;
Poignard, Pascal ;
Nussenzweig, Michel C. ;
Burton, Dennis R. .
NATURE, 2013, 503 (7475) :224-+
[6]   Structural Delineation of a Quaternary, Cleavage-Dependent Epitope at the gp41-gp120 Interface on Intact HIV-1 Env Trimers [J].
Blattner, Claudia ;
Lee, Jeong Hyun ;
Sliepen, Kwinten ;
Derking, Ronald ;
Falkowska, Emilia ;
de la Pena, Alba Torrents ;
Cupo, Albert ;
Julien, Jean-Philippe ;
van Gils, Marit ;
Lee, Peter S. ;
Peng, Wenjie ;
Paulson, James C. ;
Poignard, Pascal ;
Burton, Dennis R. ;
Moore, John P. ;
Sanders, Rogier W. ;
Wilson, Ian A. ;
Ward, Andrew B. .
IMMUNITY, 2014, 40 (05) :669-680
[7]   Analysis of a Clonal Lineage of HIV-1 Envelope V2/V3 Conformational Epitope-Specific Broadly Neutralizing Antibodies and Their Inferred Unmutated Common Ancestors [J].
Bonsignori, Mattia ;
Hwang, Kwan-Ki ;
Chen, Xi ;
Tsao, Chun-Yen ;
Morris, Lynn ;
Gray, Elin ;
Marshall, Dawn J. ;
Crump, John A. ;
Kapiga, Saidi H. ;
Sam, Noel E. ;
Sinangil, Faruk ;
Pancera, Marie ;
Yang Yongping ;
Zhang, Baoshan ;
Zhu, Jiang ;
Kwong, Peter D. ;
O'Dell, Sijy ;
Mascola, John R. ;
Wu, Lan ;
Nabel, Gary J. ;
Phogat, Sanjay ;
Seaman, Michael S. ;
Whitesides, John F. ;
Moody, M. Anthony ;
Kelsoe, Garnett ;
Yang, Xinzhen ;
Sodroski, Joseph ;
Shaw, George M. ;
Montefiori, David C. ;
Kepler, Thomas B. ;
Tomaras, Georgia D. ;
Alam, S. Munir ;
Liao, Hua-Xin ;
Haynes, Barton F. .
JOURNAL OF VIROLOGY, 2011, 85 (19) :9998-10009
[8]   A Blueprint for HIV Vaccine Discovery [J].
Burton, Dennis R. ;
Ahmed, Rafi ;
Barouch, Dan H. ;
Butera, Salvatore T. ;
Crotty, Shane ;
Godzik, Adam ;
Kaufmann, Daniel E. ;
McElrath, M. Juliana ;
Nussenzweig, Michel C. ;
Pulendran, Bali ;
Scanlan, Chris N. ;
Schief, William R. ;
Silvestri, Guido ;
Streeck, Hendrik ;
Walker, Bruce D. ;
Walker, Laura M. ;
Ward, Andrew B. ;
Wilson, Ian A. ;
Wyatt, Richard .
CELL HOST & MICROBE, 2012, 12 (04) :396-407
[9]   Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody [J].
Burton, Dennis R. ;
Hessell, Ann J. ;
Keele, Brandon F. ;
Klasse, Per Johan ;
Ketas, Thomas A. ;
Moldt, Brian ;
Dunlop, D. Cameron ;
Poignard, Pascal ;
Doyle, Lara A. ;
Cavacini, Lisa ;
Veazey, Ronald S. ;
Moore, John P. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (27) :11181-11186
[10]   Computational structure-based redesign of enzyme activity [J].
Chen, Cheng-Yu ;
Georgiev, Ivelin ;
Anderson, Amy C. ;
Donald, Bruce R. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (10) :3764-3769