It is widely acknowledged that an important component of effective HIV-1 vaccination will be the ability to induce broadly neutralizing antibodies (Abs) to the virus. Such Abs are made only rarely in infected individuals or following immunization with viral envelope proteins because of various immune evasion mechanisms deployed by HIV. Conventional HIV-1 neutralizing Abs depend on steric hindrance as the mechanism by which they interfere with virus binding to host cell receptors. Moreover, the Abs must possess high affinity to form long-lasting complexes with the virus. Recently, Abs that catalyze the cleavage of the env protein gp120 have emerged as a novel means to neutralize HIV. These Abs inactivate antigens permanently due to the cleavage reaction, they are more potent than ordinary Abs because of their ability to cleave multiple antigen molecules, and their epitope specificity requirements are less strict than ordinary Abs, as inactivation of gp120 can occur even when cleavage occurs at sites remote from the receptor binding sites of the protein. Induction of the synthesis of catalytic Abs to gp120 has become feasible with the development of electrophilic analogs of gp120 and synthetic gp120 peptides. Abs to these analogs combine noncovalent gp120 recognition with a serine protease-like activity, resulting in specific cleavage of gp120. We propose to study as immunogens the analogs of full-length gp120, whole virus particles and a synthetic gp120 peptide. The elicited Abs will be studied in polyclonal and monoclonal form for their catalytic efficiency, cleavage specificity, ability to recognize native gp120 expressed on the viral surface and neutralization of diverse HIV-1 isolates. Novel vaccination strategies and HIV-1 neutralizing Abs will emerge from these studies if the physiological barriers to catalytic Ab synthesis can be bypassed. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058865-03
Application #
6999761
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Li, Yen
Project Start
2004-01-01
Project End
2008-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
3
Fiscal Year
2006
Total Cost
$335,444
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Pathology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Planque, Stephanie A; Mitsuda, Yukie; Chitsazzadeh, Vida et al. (2014) Deficient synthesis of class-switched, HIV-neutralizing antibodies to the CD4 binding site and correction by electrophilic gp120 immunogen. AIDS 28:2201-11
Planque, Stephanie A; Mitsuda, Yukie; Nishiyama, Yasuhiro et al. (2012) Antibodies to a superantigenic glycoprotein 120 epitope as the basis for developing an HIV vaccine. J Immunol 189:5367-81
Sapparapu, Gopal; Planque, Stephanie; Mitsuda, Yukie et al. (2012) Constant domain-regulated antibody catalysis. J Biol Chem 287:36096-104
Hanson, Carl V (2011) Vaccinogenicity. AIDS 25:581-4
Planque, Stephanie; Salas, Maria; Mitsuda, Yukie et al. (2010) Neutralization of genetically diverse HIV-1 strains by IgA antibodies to the gp120-CD4-binding site from long-term survivors of HIV infection. AIDS 24:875-84
Paul, Sudhir; Planque, Stephanie; Nishiyama, Yasuhiro et al. (2010) Back to the future: covalent epitope-based HIV vaccine development. Expert Rev Vaccines 9:1027-43
Nishiyama, Yasuhiro; Planque, Stephanie; Mitsuda, Yukie et al. (2009) Toward effective HIV vaccination: induction of binary epitope reactive antibodies with broad HIV neutralizing activity. J Biol Chem 284:30627-42
Paul, Sudhir; Planque, Stephanie A; Nishiyama, Yasuhiro et al. (2009) A covalent HIV vaccine: is there hope for the future? Future Virol 4:7-10
Planque, Stephanie; Nishiyama, Yasuhiro; Taguchi, Hiroaki et al. (2008) Catalytic antibodies to HIV: physiological role and potential clinical utility. Autoimmun Rev 7:473-9
Mitsuda, Yukie; Planque, Stephanie; Hara, Mariko et al. (2007) Naturally occurring catalytic antibodies: evidence for preferred development of the catalytic function in IgA class antibodies. Mol Biotechnol 36:113-22

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