Envelope glycoproteins sampling states 2/3 are susceptible to ADCC by sera from HIV-1-infected individuals

Highlights: • HIV-1 Env can sample at least three different conformations or states (States 1–3). • Envs from primary viruses preferentially sample a "closed" State 1 conformation. • Infected cells expressing Env in State 1 are mainly resistant to ADCC by HIV+ sera. • Infected cells expressing Env in States 2/3 are highly susceptible to ADCC. • Env conformation at the surface of infected cells has a significant impact on ADCC. Recent analysis of HIV-1 envelope glycoproteins (Env) dynamics showed that the unliganded Env trimer can potentially sample three conformations: a metastable "closed" conformation (State 1), an "open" CD4-bound conformation (State 3), and an intermediate "partially open" conformation (State 2). HIV-1 evolved several mechanisms to avoid "opening" its Env in order to evade immune responses such as antibody-dependent cellular cytotoxicity (ADCC), which preferentially targets Envs in the CD4-bound conformation on the surface of infected cells. Here we took advantage of a well-characterized single-residue change in the gp120 trimer association domain to modify Env conformation and evaluate its impact on ADCC responses. We found that cells infected with viruses expressing Env stabilized in States 2/3 become highly susceptible to ADCC responses by sera from HIV-1-infected individuals. Our results indicate that the conformations spontaneously sampled by the Env trimer at the surface of infected cells has a significant impact on ADCC responses.