Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design

Ron Diskin, Johannes F. Scheid, Paola M. Marcovecchio, Anthony P., Jr. West, Florian Klein, Han Gao, Priyanthi N. P. Gnanapragasam, Alexander Abadir, Michael S. Seaman, Michel C. Nussenzweig, Pamela J. Bjorkman

نتاج البحث: نشر في مجلةمقالةمراجعة النظراء

ملخص

Antibodies against the CD4 binding site (CD4bs) on the HIV-1 spike protein gp120 can show exceptional potency and breadth. We determined structures of NIH45-46, a more potent clonal variant of VRC01, alone and bound to gp120. Comparisons with VRC01-gp120 revealed that a four-residue insertion in heavy chain complementarity-determining region 3 (CDRH3) contributed to increased interaction between NIH45-46 and the gp120 inner domain, which correlated with enhanced neutralization. We used structure-based design to create NIH45-46(G54W), a single substitution in CDRH2 that increases contact with the gp120 bridging sheet and improves breadth and potency, critical properties for potential clinical use, by an order of magnitude. Together with the NIH45-46-gp120 structure, these results indicate that gp120 inner domain and bridging sheet residues should be included in immunogens to elicit CD4bs antibodies.
اللغة الأصليةالإنجليزيّة
الصفحات (من إلى)1289-1293
عدد الصفحات5
دوريةScience
مستوى الصوت334
رقم الإصدار6060
المعرِّفات الرقمية للأشياء
حالة النشرنُشِر - ديسمبر 2011

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