Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies

被引：202

作者：

Briney, Bryan ^{[1
,2
,3
]}

Sok, Devin ^{[1
,2
,3
]}

Jardine, Joseph G. ^{[1
,2
,3
]}

Kulp, Daniel W. ^{[1
,2
,3
]}

Skog, Patrick ^{[1
]}

Menis, Sergey ^{[1
,2
,3
]}

Jacak, Ronald ^{[2
,7
]}

Kalyuzhniy, Oleksandr ^{[1
,2
,3
]}

de Val, Natalia ^{[2
,3
,4
]}

Sesterhenn, Fabian ^{[1
,2
,3
,8
]}

Le, Khoa M. ^{[1
,2
,3
]}

Ramos, Alejandra ^{[1
,2
,3
]}

Jones, Meaghan ^{[1
,2
,3
]}

Saye-Francisco, Karen L. ^{[1
,2
,3
]}

Blane, Tanya R. ^{[1
]}

Spencer, Skye ^{[1
,2
,3
]}

Georgeson, Erik ^{[1
,2
,3
]}

Hu, Xiaozhen ^{[1
,2
,3
]}

Ozorowski, Gabriel ^{[2
,3
,4
]}

Adachi, Yumiko ^{[1
,2
,3
]}

Kubitz, Michael ^{[1
,2
,3
]}

Sarkar, Anita ^{[2
,3
,4
]}

Wilson, Ian A. ^{[2
,3
,4
,5
]}

Ward, Andrew B. ^{[2
,3
,4
]}

Nemazee, David ^{[1
]}

Burton, Dennis R. ^{[1
,2
,3
,6
]}

Schief, William R. ^{[1
,2
,3
]}

机构：

[1] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA

[2] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA

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

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

[5] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[6] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02129 USA

[7] Johns Hopkins Univ, Appl Phys Lab, Baltimore, MD 21218 USA

[8] Ecole Polytech Fed Lausanne, Inst Bioengn, CH-1015 Lausanne, Switzerland

来源：

CELL | 2016年 / 166卷 / 06期

关键词：

MONOCLONAL-ANTIBODIES; CRYSTAL-STRUCTURE; CD4-BINDING SITE; STRUCTURAL BASIS; B-CELLS; BROAD; POTENCY; DESIGN; CLADE; GENERATION;

D O I：

10.1016/j.cell.2016.08.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Induction of broadly neutralizing antibodies (bnAbs) is a primary goal of HIV vaccine development. VRC01-class bnAbs are important vaccine leads because their precursor B cells targeted by an engineered priming immunogen are relatively common among humans. This priming immunogen has demonstrated the ability to initiate a bnAb response in animal models, but recall and maturation toward bnAb development has not been shown. Here, we report the development of boosting immunogens designed to guide the genetic and functional maturation of previously primed VRC01-class precursors. Boosting a transgenic mouse model expressing germline VRC01 heavy chains produced broad neutralization of near-native isolates (N276A) and weak neutralization of fully native HIV. Functional and genetic characteristics indicate that the boosted mAbs are consistent with partially mature VRC01-class antibodies and place them on a maturation trajectory that leads toward mature VRC01-class bnAbs. The results show how reductionist sequential immunization can guide maturation of HIV bnAb responses.

引用

页码：1459 / +

页数：23

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