Structure and thermodynamics of surface recognition

This is the final report of a three-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). Interactions of the surface glycoprotein, gp120, with the receptors of host cells define the pathogenesis of HIV-1, the virus that causes AIDS. gp120 is made of several disulfide-bridged loops--the amino acid sequences of some of these loops are fairly conserved whereas the rest are variable. The third variable (V3) loop has been the target of vaccine design for quite some time since this loop is involved in various steps of viral pathogenesis. However, this loop also happens to be the most variable one. The authors have carried out structural and immunological studies to determine the sequence-structure-antigenicity correlations of the HIV-1 V3 loops. This resulted in the identification of a secondary structure at the tip of the V3 loop that remains invariant in spite of the sequence variation. The authors designed a multi-valent V3-based antigen that presents multiple copies of the same tip element several times in the same structure. During the course of this project, they realized that the protective epitopes of gp120 should be judged in the context of the native structure. Therefore, the authors developed a method to obtain a model of gp120 that is consistent with all the immunology and virology data. This model is useful in choosing or designing gp120 subdomains for vaccine development