In order to better understand morphogenesis, infectivity, and cytopathogenicity of the human immunodeficiency virus (HIV), it is necessary to accurately define the structures and interactions of viral proteins in intimate molecular and atomic detail. In this project we address the important question: how is variability in the amino acid sequence of the principal neutralizing domain (PND) of the HIV manifested in its three-dimensional (3D) structures and specificity towards its antibodies? To answer this question, we propose combining molecular modeling, physico-chemical and two-dimensional magnetic resonance (2D NMR). We will examine global and local changes in the 3D structures of the PNDs in response to changes in amino acid sequence as well as possible consequences of such changes for the specificity of PND-antibody complexes, a major focus in vaccine development. These results will also explain various other functional aspects of the PND or gp120, including the effect of sequence on the structure of proteolytic cleavage site located inside the PND (proteolysis is an important step in HIV infection), and the effect of sequence on the glycosylation site. Our unique, rigorous approach will help us to classify PNDs into different families of folding motifs. This will enable us to quantify structural variations of PNDs belonging to the same family of folding motif, as well as between two families of different folding motifs. Our approach is not limited to PNDs (V3 loops) of HIVs; it can easily be applied to the V3 loop of SIV, to the V4 loop, and to the gp41 of HIV.
| Catasti, P; Bradbury, E M; Gupta, G (1996) Structure and polymorphism of HIV-1 third variable loops. J Biol Chem 271:8236-42 |
| Fontenot, J D; Gatewood, J M; Mariappan, S V et al. (1995) Human immunodeficiency virus (HIV) antigens: structure and serology of multivalent human mucin MUC1-HIV V3 chimeric proteins. Proc Natl Acad Sci U S A 92:315-9 |
| Catasti, P; Fontenot, J D; Bradbury, E M et al. (1995) Local and global structural properties of the HIV-MN V3 loop. J Biol Chem 270:2224-32 |
| Fontenot, J D; VanCott, T C; Parekh, B S et al. (1995) Presentation of HIV V3 loop epitopes for enhanced antigenicity, immunogenicity and diagnostic potential. AIDS 9:1121-9 |
| Gupta, G; Anantharamaiah, G M; Scott, D R et al. (1993) Solution structure of the V3 loop of a Thailand HIV isolate. J Biomol Struct Dyn 11:345-66 |
