The 2F5 and 2G12 human monoclonal antibodies (mABs) are two of the most effective broadly neutralizing antibodies against primary isolates of human immunodeficiency virus (HIV). The target epitopes for these antibodies have been mapped to gp41 and gpl20 respectively. Attempts to elicit broadly neutralizing antibodies by immunizing with these defined epitopes either as short peptides or in the context of larger proteins have failed. Thus it appears that the 2F5 and 2G12 antibodies recognize specific secondary and tertiary structures on the HIV envelope that are difficult to recapitulate. The applicants propose to assess the potential utility of ribonucleic acid (RNA) selection methods for the generation of RNA molecules that bind to the 2F5 and 2G12 antibodies and that mimic the structures of the HIV immunogens responsible for eliciting these antibodies. Previously, the investigators have demonstrated that RNAs can be isolated that bind to antibodies associated with insulin resistance and myasthenia gravis. These RNAs appear to mimic the structures of the antigens responsible for eliciting such antibodies (epitopes on the human insulin and acetylcholine receptors respectively). Finally, the applicants will determine if the 2F5- and 2G12-derived RNA mimotopes can be employed to vaccinate animals and elicit antibodies that can neutralize a variety of HIV isolates. Toward this end, there are three specific objectives: (1) To isolate high affinity RNA ligands that bind specifically to the 2F5 and 2G12 human monoclonal antibodies; (2) To determine if these RNA ligands can compete with the respective HIV target-peptide epitopes for binding to these antibodies; and (3) To immunize animals with these RNA mimotopes and determine if such immunization results in the generation of anti-RNA and anti-HIV antibodies in the vaccinated animals.
| Zhong, Lingwen; Wu, Chun-Hua; Lee, Wen-Hui et al. (2004) Zeta-associated protein of 70 kDa (ZAP-70), but not Syk, tyrosine kinase can mediate apoptosis of T cells through the Fas/Fas ligand, caspase-8 and caspase-3 pathways. J Immunol 172:1472-82 |
