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Increasing the potency and breadth of an HIV antibody by using structure-based rational design (2011)

R. Diskin ; J. F. Scheid ; P. M. Marcovecchio ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 334(6060): 1289-93. doi: 10.1126/science.1213782.

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Publication Date: 2011-10-29

Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232316/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Diskin, Ron -- Scheid, Johannes F -- Marcovecchio, Paola M -- West, Anthony P Jr -- Klein, Florian -- Gao, Han -- Gnanapragasam, Priyanthi N P -- Abadir, Alexander -- Seaman, Michael S -- Nussenzweig, Michel C -- Bjorkman, Pamela J -- P01 AI081677-01/AI/NIAID NIH HHS/ -- RR00862/RR/NCRR NIH HHS/ -- RR022220/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Dec 2;334(6060):1289-93. doi: 10.1126/science.1213782. Epub 2011 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22033520" target="_blank"〉PubMed〈/a〉

Keywords: AIDS Vaccines ; Amino Acid Sequence ; Antibodies, Neutralizing/chemistry/*immunology/metabolism ; Antibody Affinity ; Antigens, CD4/chemistry/metabolism ; Binding Sites ; Complementarity Determining Regions ; Crystallography, X-Ray ; HIV Antibodies/chemistry/*immunology/metabolism ; HIV Envelope Protein gp120/chemistry/*immunology/metabolism ; HIV-1/*immunology ; Humans ; Hydrophobic and Hydrophilic Interactions ; Immunoglobulin Fab Fragments/chemistry/immunology/metabolism ; Immunoglobulin Heavy Chains/chemistry/immunology/metabolism ; Molecular Mimicry ; Molecular Sequence Data ; Mutant Proteins/chemistry/immunology/metabolism ; Protein Conformation ; *Protein Engineering ; Protein Structure, Tertiary

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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HIV therapy by a combination of broadly neutralizing antibodies in humanized mice (2012)

F. Klein ; A. Halper-Stromberg ; J. A. Horwitz ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 492(7427): 118-22. doi: 10.1038/nature11604.

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Publication Date: 2012-10-30

Description: Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection. Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time. However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design. Here we re-examine passive antibody transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody monotherapy, combinations of broadly neutralizing antibodies can effectively control HIV-1 infection and suppress viral load to levels below detection. Moreover, in contrast to antiretroviral therapy, the longer half-life of antibodies led to control of viraemia for an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV-1-infected individuals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809838/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809838/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Klein, Florian -- Halper-Stromberg, Ariel -- Horwitz, Joshua A -- Gruell, Henning -- Scheid, Johannes F -- Bournazos, Stylianos -- Mouquet, Hugo -- Spatz, Linda A -- Diskin, Ron -- Abadir, Alexander -- Zang, Trinity -- Dorner, Marcus -- Billerbeck, Eva -- Labitt, Rachael N -- Gaebler, Christian -- Marcovecchio, Paola M -- Incesu, Reha-Baris -- Eisenreich, Thomas R -- Bieniasz, Paul D -- Seaman, Michael S -- Bjorkman, Pamela J -- Ravetch, Jeffrey V -- Ploss, Alexander -- Nussenzweig, Michel C -- 1UM1AI100663/AI/NIAID NIH HHS/ -- AI081677/AI/NIAID NIH HHS/ -- P01 AI081677/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Dec 6;492(7427):118-22. doi: 10.1038/nature11604. Epub 2012 Oct 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23103874" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; Antibodies, Monoclonal/immunology/therapeutic use ; Antibodies, Neutralizing/*immunology/*therapeutic use ; Antibody Specificity/immunology ; Disease Models, Animal ; HIV Antibodies/*immunology/*therapeutic use ; HIV Infections/*drug therapy/*immunology/virology ; HIV-1/genetics/growth & development/immunology/isolation & purification ; Half-Life ; Humans ; Immunization, Passive ; Mice ; Mice, Inbred NOD ; Time Factors ; Viral Load/drug effects

Print ISSN: 0028-0836

Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics