期刊
AIDS
卷 25, 期 18, 页码 2209-2216出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0b013e32834bab68
关键词
envelope; HIV-1; KD-247; neutralization; steady-state conformation
资金
- Japan Health Science Foundation
- Japanese Ministry of Health, Labor and Welfare [H18-AIDS-W-003, H20-AIDS-G-008]
- Japanese Ministry of Education, Culture, Sports, Science and Technology [18689014, 18659136]
Objective: A humanized neutralizing antibody, KD-247, targets the V3 loop of HIV-1 Env. HIV-1 bearing the GPGR sequence at the V3 loop is potentially susceptible to KD-247. However, not all GPGR-positive HIV-1 isolates are neutralized by KD-247. We examined the potential mechanism by which the susceptibility of HIV-1 to KD-247-mediated neutralization is regulated. Design: We searched for nonepitope neutralization regulatory (NNR) mutations that sensitize GPGR-bearing HIV-1(AD8) to KD-247 and mapped the locations of such mutations relative to the V3 loop. Methods: We generated a functional HIV-1AD8 Env library, and evaluated the viral susceptibility to KD-247 by measuring the half-inhibitory concentration (IC(50)) to KD-247 on TZM-bl cell assay. Results: We identified nine KD-247-sensitizing NNR mutations from 30 mutations in various regions of gp120, including the V1/V2 loop, C2, V3 loop, C4, and C5. They specifically affected KD-247-mediated neutralization, as they did not affect the b12-mediated neutralization. When combined, the KD-247-sensitizing NNR mutations additively sensitized the virus to KD-247 by up to 10 000 folds. The KD-247-sensitizing NNR mutations increased KD-247 binding to the virion. Notably, the NNR mutation in C4 coincides with the CD4-binding site of gp120. Conclusion: Given that most of the KD-247-sensitizing NNR mutations are remote from V3 loop, it is reasonable to hypothesize that the steady-state, local conformation of the V3 loop is regulated by the interdomain contact of gp120. Our mutational analysis complements crystallographic studies by helping provide a better understanding of the steady-state conformation and the functional geometry of Env. (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
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