The envelope
glycoproteins (Envs) on the surfaces of HIV-1 particles are targeted by host
antibodies. Primary HIV-1 isolates demonstrate different global sensitivities to antibody neutralization; tier-1 isolates are sensitive, whereas tier-2 isolates are more resistant. Single-site mutations in Env can convert tier-2 into tier-1-like viruses. We hypothesized that such global change in neutralization sensitivity results from weakening of intramolecular interactions that maintain Env integrity. Three strategies commonly applied to perturb
protein structure were tested for their effects on global neutralization sensitivity: exposure to low temperature, Env-activating
ligands, and a chaotropic agent. A large panel of diverse tier-2 isolates from clades B and C was analyzed. Incubation at 0°C, which globally weakens hydrophobic interactions, causes gradual and reversible exposure of the coreceptor-binding site. In the cold-induced state, Envs progress at isolate-specific rates to unstable forms that are sensitive to antibody neutralization and then gradually lose function. Agents that mimic the effects of CD4 (CD4Ms) also induce reversible structural changes to states that exhibit isolate-specific stabilities. The chaotropic agent
urea (at low concentrations) does not affect the structure or function of native Env. However,
urea efficiently perturbs metastable states induced by cold and CD4Ms and increases their sensitivity to antibody neutralization and their inactivation rates Therefore, chemical and physical agents can guide Env from the stable native state to perturbation-sensitive forms and modulate their stability to bestow tier-1-like properties on primary tier-2 strains. These concepts can be applied to enhance the potency of vaccine-elicited
antibodies and
microbicides at mucosal sites of HIV-1 transmission.IMPORTANCE An effective
vaccine to prevent transmission of HIV-1 is a primary goal of the scientific and health care communities.
Vaccine-elicited
antibodies target the
viral envelope glycoproteins (Envs) and can potentially inhibit
infection. However, the potency of such
antibodies is generally low. Single-site mutations in Env can enhance the global sensitivity of HIV-1 to neutralization by
antibodies. We found that such a
hypersensitivity phenotype can also be induced by agents that destabilize
protein structure. Exposure to 0°C or low concentrations of Env-activating
ligands gradually guides Env to metastable forms that expose cryptic
epitopes and that are highly sensitive to neutralization. Low concentrations of the chaotropic agent
urea do not affect native Env but destabilize perturbed states induced by cold or CD4Ms and increase their neutralization. The concept of enhancing antibody sensitivity by chemical agents that affect the structural stability of
proteins can be applied to increase the potency of
topical microbicides and
vaccine-elicited
antibodies.