Summary of the probe development effort to identify small molecules that bind to the HIV-1-gp120 binding antibody, PG9
Name: Summary of the probe development effort to identify small molecules that bind to the HIV-1-gp120 binding antibody, PG9. ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Michael J. Caulfield , International Aids Vaccine Initiative
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: DA033177-01
Grant Proposal PI: Michael J. Caulfield , International Aids Vaccine Initiative
External Assay ID: HIV-PG9-GP120_INH_SUMMARY
Name: Summary of the probe development effort to identify small molecules that bind to the HIV-1-gp120 binding antibody, PG9.
Development of a vaccine to prevent AIDS is the best hope for controlling the epidemic that has led to infection of more than 30 million people with the HIV-1 virus worldwide (1). A vaccine approach that reduces viral load would certainly be beneficial, but one that elicits sterilizing immunity would be preferred (2). The HIV envelope glycoprotein (Env) is key to vaccine development since it is the only target for neutralizing antibodies (3-5). The Env consists of the gp120 surface glycoprotein and gp41 transmembrane protein associated in a trimer of gp120-gp41 heterodimers. The presence of broadly neutralizing sera from some HIV-1 infected individuals (3, 6-9) and the protection in monkeys by passive transfer of several neutralizing monoclonal antibodies (mAbs) (10) suggest that if a suitable antibody response to Env can be obtained, then protection from infection will be possible.
Conventional vaccine approaches based on delivery of HIV-1 envelope (Env) proteins or peptides derived from Env sequences have failed to generate broadly neutralizing antibodies (bNAbs) to the virus, which mutates rapidly to escape from the immune response (11). Recently, new potent and broad neutralizing antibodies against the CD4 binding site (CD4Bs) (VRC01 and VRCPG04) and a novel site on HIV-1 Env trimer consisting of conserved elements on the variable loops V1/2 stem, V2 and V3 on the Env (PG9, PG16) have been defined (12, 13) . These new bNAbs neutralize a broad panel of HIV-1 viruses at concentrations that are an order of magnitude lower than the neutralizing concentrations of "first generation" bNAbs (b12, 2G12, 2F5 and 4E10). The availability of these new bNAb reagents enhances the prospect of designing the corresponding immunogens to evaluate as vaccine candidates. Recently published results (14) document that antibody-binding small molecules could be selected by probing a large chemical library with D5, a human mAb that binds to a pre-hairpin fusion intermediate on gp41 of HIV-1. The importance of this finding is that such molecules can be rendered immunogenic by conjugation with a carrier protein thereby forming the basis for development of AIDS vaccine candidates. Since the D5 mAb used in published studies is not very potent and lacks sufficient breadth, we propose to utilize the new more potent bNAbs to test the hypothesis that individual bNAbs can bind specifically to diverse chemical entities that can be selected in a high throughput screen of a large chemical collection. The objective of this proposal is to develop and implement screening assays to utilize existing human mAbs with broad neutralizing activity (bNAbs) to screen a large and diverse small molecule library to identify haptens that bind specifically to the antibody combining site of the bNAb. These small molecule mimetics of the HIV-1 envelope protein could be useful in development of an AIDS vaccine.
This project will exploit the antigen-binding property of newly discovered broad and potent neutralizing antibodies to select complementary small molecule leads that can be used as building blocks for the development of a vaccine to prevent infection with the HIV-1 virus.
Summary of Probe Development Effort:
This probe development effort is focused on the identification of small molecules that bind to the HIV-1-gp120 binding antibody, PG9. All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
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2. Karlsson Hedestam, G.B., R.A. Fouchier, S. Phogat, D.R. Burton, J. Sodroski, and R.T. Wyatt, The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus. Nat Rev Microbiol, 2008. 6(2): p. 143-55.
3. Stamatatos, L., L. Morris, D.R. Burton, and J.R. Mascola, Neutralizing antibodies generated during natural HIV-1 infection: good news for an HIV-1 vaccine? Nat Med, 2009. 15(8): p. 866-70.
4. Haynes, B.F. and D.C. Montefiori, Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates. Expert Rev Vaccines, 2006. 5(4): p. 579-95.
5. Srivastava, I.K., J.B. Ulmer, and S.W. Barnett, Role of neutralizing antibodies in protective immunity against HIV. Hum Vaccin, 2005. 1(2): p. 45-60.
6. Binley, J.M., E.A. Lybarger, E.T. Crooks, M.S. Seaman, E. Gray, K.L. Davis, J.M. Decker, D. Wycuff, L. Harris, N. Hawkins, B. Wood, C. Nathe, D. Richman, G.D. Tomaras, F. Bibollet-Ruche, J.E. Robinson, L. Morris, G.M. Shaw, D.C. Montefiori, and J.R. Mascola, Profiling the specificity of neutralizing antibodies in a large panel of plasmas from patients chronically infected with human immunodeficiency virus type 1 subtypes B and C. J Virol, 2008. 82(23): p. 11651-68.
7. Sather, D.N., J. Armann, L.K. Ching, A. Mavrantoni, G. Sellhorn, Z. Caldwell, X. Yu, B. Wood, S. Self, S. Kalams, and L. Stamatatos, Factors associated with the development of cross-reactive neutralizing antibodies during human immunodeficiency virus type 1 infection. J Virol, 2009. 83(2): p. 757-69.
8. Carotenuto, P., D. Looij, L. Keldermans, F. de Wolf, and J. Goudsmit, Neutralizing antibodies are positively associated with CD4+ T-cell counts and T-cell function in long-term AIDS-free infection. AIDS, 1998. 12(13): p. 1591-600.
9. Li, Y., S.A. Migueles, B. Welcher, K. Svehla, A. Phogat, M.K. Louder, X. Wu, G.M. Shaw, M. Connors, R.T. Wyatt, and J.R. Mascola, Broad HIV-1 neutralization mediated by CD4-binding site antibodies. Nat Med, 2007. 13(9): p. 1032-4.
10. Hart, M.K., T.J. Palker, T.J. Matthews, A.J. Langlois, N.W. Lerche, M.E. Martin, R.M. Scearce, C. McDanal, D.P. Bolognesi, and B.F. Haynes, Synthetic peptides containing T and B cell epitopes from human immunodeficiency virus envelope gp120 induce anti-HIV proliferative responses and high titers of neutralizing antibodies in rhesus monkeys. J Immunol, 1990. 145(8): p. 2677-85.
11. Emiliani, S., C. Van Lint, W. Fischle, P. Paras, Jr., M. Ott, J. Brady, and E. Verdin, A point mutation in the HIV-1 Tat responsive element is associated with postintegration latency. Proc Natl Acad Sci U S A, 1996. 93(13): p. 6377-81.
12. Euler, Z., E.M. Bunnik, J.A. Burger, B.D. Boeser-Nunnink, M.L. Grijsen, J.M. Prins, and H. Schuitemaker, Activity of Broadly Neutralizing Antibodies, Including PG9, PG16, and VRC01, against Recently Transmitted Subtype B HIV-1 Variants from Early and Late in the Epidemic. J Virol, 2011. 85(14): p. 7236-45.
13. Doores, K.J. and D.R. Burton, Variable loop glycan dependency of the broad and potent HIV-1-neutralizing antibodies PG9 and PG16. J Virol, 2010. 84(20): p. 10510-21.
14. Caulfield, M.J., V.Y. Dudkin, E.A. Ottinger, K.L. Getty, P.D. Zuck, R.M. Kaufhold, R.W. Hepler, G.B. McGaughey, M. Citron, R.C. Hrin, Y.J. Wang, M.D. Miller, and J.G. Joyce, Small molecule mimetics of an HIV-1 gp41 fusion intermediate as vaccine leads. J Biol Chem, 2010. 285(52): p. 40604-11.
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