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Alanine scanning mutagenesis, with subsequent characterization of the mutagenic effects on folding, association with gp120, and membrane fusion were performed to systematically examine the functional significance of each amino acid residue in heptad repeat 1 of HIV gp41 (HR1). The sensitivity of gp41 HR1 to alanine substitutions indicated that even subtle changes in the local environment might severely affect envelope function, and hence HR1 is an attractive site for therapeutic intervention.

The importance of the HIV gp120 conserved domain 5 (gp120-C5) to envelope function is examined by alanine scanning mutagenesis and subsequent characterization of the mutagenic effects on viral entry and envelope expression, processing and incorporation, as well as gp120 association with gp41. The extreme sensitivity of the gp120-C5 hydrophobic elbow to alanine substitutions has shown that this region is a novel target for drug discovery efforts.