Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies

被引：147

作者：

Bonsignori, Mattia ^{[1
,2
]}

Kreider, Edward F. ^{[3
,4
]}

Fera, Daniela ^{[5
]}

Meyerhoff, R. Ryan ^{[1
,2
]}

Bradley, Todd ^{[1
,2
]}

Wiehe, Kevin ^{[1
,2
]}

Alam, S. Munir ^{[1
,2
]}

Aussedat, Baptiste ^{[6
]}

Walkowicz, William E. ^{[6
]}

Hwang, Kwan-Ki ^{[2
]}

Saunders, Kevin O. ^{[2
,7
]}

Zhang, Ruijun ^{[2
]}

Gladden, Morgan A. ^{[2
]}

Monroe, Anthony ^{[2
]}

Kumar, Amit ^{[2
]}

Xia, Shi-Mao ^{[2
]}

Cooper, Melissa ^{[2
]}

Louder, Mark K. ^{[8
]}

McKee, Krisha ^{[8
]}

Bailer, Robert T. ^{[8
]}

Pier, Brendan W. ^{[5
]}

Jette, Claudia A. ^{[5
]}

Kelsoe, Garnett ^{[2
,9
]}

Williams, Wilton B. ^{[1
,2
]}

Morris, Lynn ^{[10
]}

Kappes, John ^{[11
]}

Wagh, Kshitij ^{[12
]}

Kamanga, Gift ^{[13
,20
]}

Cohen, Myron S. ^{[14
,15
,16
]}

Hraber, Peter T. ^{[12
]}

Montefiori, David C. ^{[2
,7
]}

Trama, Ashley ^{[2
]}

Liao, Hua-Xin ^{[1
,2
]}

Kepler, Thomas B. ^{[17
,18
]}

Moody, M. Anthony ^{[2
,9
,19
]}

Gao, Feng ^{[1
,2
]}

Danishefsky, Samuel J. ^{[6
]}

Mascola, John R. ^{[8
]}

Shaw, George M. ^{[3
,4
]}

Hahn, Beatrice H. ^{[3
,4
]}

Harrison, Stephen C. ^{[5
]}

Korber, Bette T. ^{[12
]}

Haynes, Barton F. ^{[1
,2
]}

机构：

[1] Duke Univ, Med Ctr, Sch Med, Dept Med, Durham, NC 27710 USA

[2] Duke Human Vaccine Inst, Durham, NC 27710 USA

[3] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA

[4] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA

[5] Harvard Med Sch, Boston Childrens Hosp, Mol Med Lab, Boston, MA 02115 USA

[6] Mem Sloan Kettering Canc Ctr, Dept Biol Chem, New York, NY 10065 USA

[7] Duke Univ, Med Ctr, Sch Med, Dept Surg, Durham, NC 27710 USA

[8] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA

[9] Duke Univ, Med Ctr, Sch Med, Dept Immunol, Durham, NC 27710 USA

[10] Natl Inst Communicable Dis, ZA-2131 Johannesburg, South Africa

[11] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA

[12] Los Alamos Natl Lab, Los Alamos, NM 87545 USA

[13] Kamuzu Cent Hosp, Univ North Carolina Project, Lilongwe, Malawi

[14] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA

[15] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA

[16] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA

[17] Boston Univ, Dept Microbiol, Boston, MA 02215 USA

[18] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA

[19] Duke Univ, Med Ctr, Sch Med, Dept Pediat, Durham, NC 27710 USA

[20] FHI 360, Lilongwe, Malawi

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2017年 / 9卷 / 381期

关键词：

B-CELL-LINEAGE; AFFINITY MATURATION; POTENT; RECOGNITION; EVOLUTION; RESPONSES; GERMLINE; DISTINCT; PATHWAY; COMPLEX;

D O I：

10.1126/scitranslmed.aai7514

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3-glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs.

引用

页数：12

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