Bonsignori Mattia, Kreider Edward F, Fera Daniela, Meyerhoff R Ryan, Bradley Todd, Wiehe Kevin, Alam S Munir, Aussedat Baptiste, Walkowicz William E, Hwang Kwan-Ki, Saunders Kevin O, Zhang Ruijun, Gladden Morgan A, Monroe Anthony, Kumar Amit, Xia Shi-Mao, Cooper Melissa, Louder Mark K, McKee Krisha, Bailer Robert T, Pier Brendan W, Jette Claudia A, Kelsoe Garnett, Williams Wilton B, Morris Lynn, Kappes John, Wagh Kshitij, Kamanga Gift, Cohen Myron S, Hraber Peter T, Montefiori David C, Trama Ashley, Liao Hua-Xin, Kepler Thomas B, Moody M Anthony, Gao Feng, Danishefsky Samuel J, Mascola John R, Shaw George M, Hahn Beatrice H, Harrison Stephen C, Korber Bette T, Haynes Barton F
Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Duke Human Vaccine Institute, Durham, NC 27710, USA.
Sci Transl Med. 2017 Mar 15;9(381). doi: 10.1126/scitranslmed.aai7514.
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.
预防性HIV-1疫苗应诱导产生HIV-1特异性的广泛中和抗体（bnAbs）。然而，bnAbs通常需要高水平的体细胞超突变（SHM）才能获得广泛的中和活性，而目前的疫苗策略在诱导bnAbs方面尚未取得成功。由于针对HIV-1包膜蛋白第三个可变环（V3）附近糖基化位点的bnAbs只需要有限的SHM，因此V3-聚糖表位是一个有吸引力的疫苗靶点。通过研究多个V3-聚糖B细胞谱系之间的协同作用以及它们在5年感染过程中与自体病毒的共同进化，我们确定了一种V3-聚糖bnAb个体发生过程中的关键事件。两个自体中和抗体谱系因病毒逃逸突变而被选择，从而启动并促进了一个V3-聚糖bnAb谱系的亲和力成熟。启动bnAb谱系所需的核苷酸替换发生在激活诱导的胞苷脱氨酶活性的低概率位点。B细胞谱系的协同作用以及对bnAb活性至关重要的罕见突变定义了导致该V3-聚糖bnAb谱系产生广泛中和活性的必要事件。这些发现可能部分解释了为何V3-聚糖bnAbs的产生很少见，并提示了一种诱导产生类似V3-聚糖bnAbs的免疫策略。
