HIV-1 Envelope Conformation, Allostery, and Dynamics

Abstract

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution.

Keywords: HIV-1; allostery; envelope; molecular dynamics; structure.

Figure 1

Structure and allosteric elements of the HIV-1 Env trimer. (A) Linear depiction of the HIV-1 Env structural elements highlighting the position of the SOSIP mutations and the soluble ectodomain region (to dashed line). (B) (upper left) Side view of the closed state trimer. The protomer to the left is colored according to the gp120 and gp41 domains, while the protomer to the right is colored according to allosteric elements, including the β20–β21 loop (yellow), V1/V2 (lime), V3 (red), layer-1 (dark blue), and layer-2 (purple). (lower left) Top view of the closed state trimer depicting the apex gp120 contacts. (middle left) Closed state allosteric elements. (middle right) Open state allosteric elements. (top right) Side view of the open state trimer colored as the closed state trimer. (lower right) Top view of the open state trimer depicting the broken apex contacts. (C) Closed and open state surfaces highlighting the epitopes of HIV-1 Env-targeting antibodies.