The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Richard Jonathan, Grunst Michael W, Niu Ling, Díaz-Salinas Marco A, Zhu Li, Tolbert William D, Marchitto Lorie, Zhou Fei, Bourassa Catherine, Kim Hongil, Boodapati Sri Lakshmi Tejaswi, Yang Derek, Chiu Ta Jung, Chen Hung-Ching, Benlarbi Mehdi, Beaudoin-Bussières Guillaume, Gottumukkala Suneetha, Li Wenwei, Dionne Katrina, Bélanger Étienne, Chatterjee Debashree, Medjahed Halima, Hendrickson Wayne A, Sodroski Joseph, Lang Zabrina C, Morton Abraham J, Huang Rick K, Matthies Doreen, Smith Amos B, Kumar Priti, Mothes Walther, Munro James B, Pazgier Marzena, Finzi Andrés
Аннотация
HIV-1 envelope glycoproteins (Env) from primary HIV-1 isolates typically adopt a pretriggered "closed" conformation that resists to CD4-induced (CD4i) non-neutralizing antibodies (nnAbs) mediating antibody-dependent cellular cytotoxicity (ADCC). CD4-mimetic compounds (CD4mcs) "open-up" Env allowing binding of CD4i nnAbs, thereby sensitizing HIV-1-infected cells to ADCC. Two families of CD4i nnAbs, the anti-cluster A and anti-coreceptor binding site (CoRBS) Abs, are required to mediate ADCC in combination with the indane CD4mc BNM-III-170. Recently, new indoline CD4mcs with improved potency and breadth have been described. Here, we show that the lead indoline CD4mc, CJF-III-288, sensitizes HIV-1-infected cells to ADCC mediated by anti-CoRBS Abs alone, contributing to improved ADCC activity. When administrated along with the anti-CoRBS 17b, CJF-III-288 delayed viral rebound after ART interruption in HIV-1-infected humanized mice, demonstrating potential for eliciting ADCC in vivo. Structural and conformational analyses reveal that CJF-III-288, in combination with this anti-CoRBS Abs, potently stabilizes an asymmetric "open" State-3 Env conformation. This Env conformation orients the anti-CoRBS Ab to improve ADCC activity and therapeutic potential.