An entry-competent intermediate state of the HIV-1 envelope glycoproteins.

The human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) mediate viral entry and are the sole target of neutralizing antibodies. Recent studies show that the metastable HIV-1 Env trimer can transit among three conformational states: State 1, State 3, and State 2, corresponding to the "closed", "open" and intermediate conformations, respectively. During virus entry, binding to the CD4 receptor drives Env from state 1 to state 3. In the unliganded Env, transitions from the closed (State 1) conformation are restrained by intramolecular interactions among different Env residues, which regulate HIV-1 Env conformation. Releasing the specific restraints on State 1 Env leads to increased occupancy of State 2, which is a functional conformation on the entry pathway and an obligate intermediate between State 1 and State 3. Frequent sampling of intermediate State 2 allows HIV-1 to infect cells expressing low levels of CD4, and leads to resistance to several broadly neutralizing antibodies as well as small-molecule inhibitors. Recent findings provide new mechanistic insights into the function and inhibition of HIV-1 Env and will contribute to the development of new therapeutic and prophylactic interventions to combat HIV-1.