Exposing HIV-1 Env: Implications for therapeutic strategies

The human immunodeficiency virus (HIV-1) envelope glycoprotein trimer (Env) is exposed on the surfaces of both virions and infected cells. Thus, Env is the principal target for neutralizing antibodies and antibodies able to mediate antibody-dependent cellular cytotoxicity (ADCC). The HIV-1 Env is a flexible molecule known to exist in at least three different conformational states: states 1, 2 and 3. Before interacting with the primary receptor, CD4, Env preferentially adopts a compact, closed conformation (state 1) that is largely antibody-resistant. The CD4 binding opens Env increasing the vulnerability of infected cells to ADCC mediated by non-neutralizing antibodies, as these easily-elicited antibodies preferentially recognize epitopes exposed in the open conformational states (states 2/3). These antibodies include the anti-coreceptor binding site and the anti-cluster A families of antibodies that, in combination with small CD4-mimetic compounds, stabilize a new asymmetric Env conformation (state 2A) that is vulnerable to ADCC. Approaches aimed at stabilizing this open conformation represent new interventional approaches to fight HIV-1 infection.