Doctor of Philosophy

thesisThe HIV entry process is a critical step in the lifecycle of the virus. Beingthe sole protein on the surface of the virus, Env is responsible for mediating entry into the host cell. Env is composed of two subunits, gp120 which is responsible for the targeting of the virus to the host cell, and gp41 which mediates membrane fusion. During the fusion process and after gp120 interacts with CD4 and the coreceptor, gp41 undergoes a large conformational change, inserting the fusion peptide in the host cell membrane and forming the prehairpin intermediate. The prehairpin intermediate represents a unique drug target with which to inhibit HIV entry, exposing the N-trimer and its hydrophobic grooves before the C-peptide region can fold back into these grooves and drive membrane fusion. Our lab has been developing entry inhibitors composed of D-peptides (PIE7 and PIE12) that target a highly conserved region of the N-trimer that is exposed during this extended intermediate. During the development process, resistance studies have been done using PIE7-dimer, PIE12-dimer, and PIE12-trimer. These studies have elucidated key mutations in the N-trimer of gp41 that allow HIV to escape inhibition by our D-peptides: E560K and Q577R. In this thesis we use N-trimer mimics to characterize the stability of the wild type and mutant proteins. Additionally, we show that Q577R interferes with the D-peptide binding through the disruption of a hydrogen bond while E560K does not affect the binding affinity