Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance

被引：297

作者：

Cirelli, Kimberly M. ^{[1
,2
]}

Carnathan, Diane G. ^{[2
,3
,4
]}

Nogal, Bartek ^{[2
,5
]}

Martin, Jacob T. ^{[2
,6
]}

Rodriguez, Oscar L. ^{[7
]}

Upadhyay, Amit A. ^{[3
]}

Enemuo, Chiamaka A. ^{[3
,4
]}

Gebru, Etse H. ^{[3
,4
]}

Choe, Yury ^{[3
,4
]}

Viviano, Federico ^{[3
,4
]}

Nakao, Catherine ^{[1
]}

Pauthner, Matthias G. ^{[2
,8
]}

Reiss, Samantha ^{[1
,2
]}

Cottrell, Christopher A. ^{[2
,5
]}

Smith, Melissa L. ^{[7
]}

Bastidas, Raiza ^{[2
,8
]}

Gibson, William ^{[9
]}

Wolabaugh, Amber N. ^{[3
]}

Melo, Mariane B. ^{[2
,6
]}

Cossette, Benjamin ^{[6
]}

Kumar, Venkatesh ^{[10
]}

Patel, Nirav B. ^{[11
]}

Tokatlian, Talar ^{[2
,6
]}

Menis, Sergey ^{[2
,8
]}

Kulp, Daniel W. ^{[2
,8
,12
]}

Burton, Dennis R. ^{[2
,8
,13
]}

Murrell, Ben ^{[10
,14
]}

Schief, William R. ^{[2
,8
,13
]}

Bosinger, Steven E. ^{[3
,11
]}

Ward, Andrew B. ^{[2
,5
]}

Watson, Corey T. ^{[9
]}

Silvestri, Guido ^{[2
,3
,4
]}

Irvine, Darrell J. ^{[2
,6
,13
,15
,16
]}

Crotty, Shane ^{[1
,2
,10
]}

机构：

[1] La Jolla Inst Immunol LJI, Div Vaccine Discovery, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA

[3] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA

[4] Emory Univ, Emory Vaccine Ctr, Sch Med, Atlanta, GA 30322 USA

[5] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA

[6] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[7] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[8] Scripps Res Inst, Dept Immunol & Microbiol, La Jolla, CA 92037 USA

[9] Univ Louisville, Dept Biochem & Mol Genet, Sch Med, Louisville, KY 40202 USA

[10] Univ Calif San Diego, Dept Med, La Jolla, CA 92037 USA

[11] Yerkes Natl Primate Res Ctr, Yerkes NHP Genom Core Lab, Atlanta, GA 30329 USA

[12] Wistar Inst Anat & Biol, Vaccine & Immunotherapy Ctr, Philadelphia, PA 19104 USA

[13] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA

[14] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden

[15] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[16] MIT, Dept Mat Sci & Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

CELL | 2019年 / 177卷 / 05期

关键词：

MULTIPLE SEQUENCE ALIGNMENT; FOLLICULAR HELPER-CELLS; CRYO-EM STRUCTURE; RNA-SEQ; NONHUMAN-PRIMATES; VACCINE; ANTIGEN; MICRONEEDLES; PERFORMANCE; MICROSCOPY;

D O I：

10.1016/j.cell.2019.04.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (T-FH) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identified differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes.

引用

页码：1153 / +

页数：47

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