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- Planque, S., Nishiyama, Y., Mitsuda, Y., Taniguchi, R., Watanabe, K., Morris, M.K., Hanson, C.V., Massey, R.J., and Paul, S. Broad HIV neutralization by constitutive antibodies and their amplification by covalent HIV vaccination. AIDS 2012 XIX International AIDS Conference, July 22-27, 2012, Washington D.C. AIDS conference 2012 poster
- Mitsuda, Y., Planque, S., Nishiyama, Y., Hanson, C.V., Hunter, R., Massey, R.J., and Paul, S. Induction of neutralizing antibodies to the HIV CD4 binding site in macaques by covalent immunization. Nonhuman Primate Models for AIDS, October 25-28, 2011, Seattle, Washington. Nonhuman Primate Models conference 2011 poster
- Mitsuda, Y., Planque, S., Ghosh, D., Nishiyama, Y., Hanson, C.V., and Paul. S. Correction of deficient class-switched antibody response to the CD4 binding site by covalent immunization. AIDS 2010 - XVIII International AIDS Conference, July 18-23, 2010, Vienna Austria.
IAS conference 2010 poster antibody class-switching
- Planque, S., Mitsuda, Y., Ghosh, D., Nishiyama, Y., Hanson, C.V., and Paul, S. Prototype covalent HIV vaccine for inducing antibodies that neutralize genetically divergent virus strains. AIDS 2010 - XVIII International AIDS Conference, July 18-23, 2010, Vienna Austria. (Stephanie Planque, HIV researcher, receives IAS/ANRS Young Investigator Award at this conference).
IAS conference 2010 slides prototype HIV vaccine and IAS conference 2010 live presentation prototype HIV vaccine
Synposis of basic science publications supporting abzyme therapy for HIV
Our research on HIV therapy and vaccination has received considerable community support. We are committed to bring our studies to clinical translation. Following are links to recent technical presentations that provide the foundation for further therapeutic and preventative vaccination developments.
We are thankful for all of the support from the HIV community, particularly patients who have volunteered for clinical trials. We are working hard to obtain funds and set up the infrastructure to rapidly implement the clinical trials.
Sudhir Paul and the Chemical Immunology Research Center
gp120 covalent analogs as candidate HIV vaccines
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. (PI: Sudhir Paul)
Neutralizing HIV antibodies raised by covalent immunization
We propose to study the irreversible gp120 binding as a new mechanism of HIV neutralization by antibodies. Preliminary studies suggest that the monoclonal antibodies (MAbs) raised to a covalently reactive analog of gp120 (gp120-CRA) express nucleophilic reactivity leading to binding activity with covalent character; neutralization of primary HIV isolates; and, a unusual epitope specificity. The proposal is composed of two specific aims: (1) characterization of epitopes and irreversible MAb binding to gp120 on the native viral surface and (2) study of the breadth and potency of neutralizing activity. Intact virions from diverse primary HIV isolates will be studied. Immunochemical endpoints and assays of viral infection in cultured peripheral blood mononuclear cells will be applied to objectively differentiate conventional reversible binding from irreversible virion binding and to assess the functional consequences of MAb–virus interactions. The studies are likely to strengthen the foundation for further development of neutralizing antibodies capable of permanent virus inactivation. (PI: Yasuhiro Nishiyama)
Covalently reactive CD4 mimetics for inhibition of HIV
Therapeutic administration of soluble CD4 is theoretically an attractive means of competitively inhibiting the binding of HIV to its primary cellular receptor, but was a failure in clinical trials more than a decade ago. We propose the creation of novel CD4 analogs to overcome the stoichiometric and affinity limitations of that initial approach. Using electrophilic phosphonate ester probes, we recently discovered that HIV gp120 contains activated nucleophilic amino acids. In the proposed studies, CD4 (and CD4 peptide mimetic, s) will be modified by the addition of activated electrophilic phosphonates, which will result in specific covalent bonding of these constructs to nucleophilic sites on gp120 on the surface of HIV virions. Such an "infinite" affinity interaction will result in irreversible blocking of HIV infectivity. The concept is based on our successful analogous work on catalytic antibodies, in which nucleophilic immunoglobulin sites bind to electrophiles in the substrate ligand. Thus the Specific Aims of this proposed Innovation Grant are (1) to create covalently reactive CD4 and CD4 peptide mimetics; (2) to determine the potency, intra- and intersubtype breadth and irreversibility of HIV neutralization and inhibition of cell-to-cell spread of HIV infection via cell fusion by these covalently reactive CD4 analogues; (3) to demonstrate the irreversibility of binding of the constructs to gp120 and to intact virions; and (4) to determine the role in the virus neutralization that isplayed by the covalency (vs. conventional noncovalent antibody binding). Successful results should lead tofollow-up testing in primate models and human clinical trials. The proposed studies may also help to definecovalent and pseudocovalent forces as a novel mechanism of protein-ligand interactions. (PI: Carl Hanson)
Covalent gp120 assembly for induction of prophylactic catalytic antibodies to HIV
Antibodies (Abs) that catalyze the cleavage of the human immunodeficiency virus (HIV) envelope protein gp120 may prove useful in developing long−needed prophylactic and immunotherapeutic strategies against HIV. This is supported by progress in inducing the synthesis of proteolytic Abs by immunization of experimental animals with a covalently reactive analog (CRA) of gp120. However, the conformation and antigenicity of the native gp120 trimer on the virus are distinct from that of monomer gp120, which can result in Abs with incorrect specificity. Recently, we discovered that it may be possible to self−assembly of gp120 to mimic the native structure of the envelope protein and induce the synthesis of proteolytic Abs with efficient HIV neutralizing activity. We will study self−assembly of CRA derivatives of gp120 under conditions that favor correct apposition of the monomers. In addition, we will analyze the assembly of a gp120 analog containing the partial sequence of another protein (gp41) thought to facilitate oligomerization. A second goal is to improve the rate of gp120 cleavage by the Abs. To this end, novel CRAs will be prepared. Immunization with these compounds is hypothesized to induce the synthesis of Abs that catalyze multiple transition states en route to peptide bond hydrolysis. The antigenic reactivity of the trimers will be studied using available neutralizing Abs to HIV. Transgenic mice expressing the human Ab repertoire (provided by Abgenix Inc) will be immunized. The catalytic activity, specificity and neutralizing activity of polyclonals and monoclonal Abs from these mice will be studied to establish whether the novel immunogens offer advantages over current ways to raise anti−HIV Abs. (PI: Sudhir Paul)