Functional Anatomy of the Trimer Apex Reveals Key Hydrophobic Constraints That Maintain the HIV-1 Envelope Spike in a Closed State

mBio. 2021 Mar 30;12(2):e00090-21. doi: 10.1128/mBio.00090-21.


The human immunodeficiency virus type 1 (HIV-1) envelope trimer maintains a closed, metastable configuration to protect vulnerable epitopes from neutralizing antibodies. Here, we identify key hydrophobic constraints at the trimer apex that function as global stabilizers of the HIV-1 envelope spike configuration. Mutation of individual residues within four hydrophobic clusters that fasten together the V1V2, V3, and C4 domains at the apex of gp120 dramatically increases HIV-1 sensitivity to weak and restricted neutralizing antibodies targeting epitopes that are largely concealed in the prefusion Env spike, consistent with the adoption of a partially open trimer configuration. Conversely, the same mutations decrease the sensitivity to broad and potent neutralizing antibodies that preferentially recognize the closed trimer. Sera from chronically HIV-infected patients neutralize open mutants with enhanced potency, compared to the wild-type virus, suggesting that a large fraction of host-generated antibodies target concealed epitopes. The identification of structural constraints that maintain the HIV-1 envelope in an antibody-protected state may inform the design of a protective vaccine.IMPORTANCE Elucidating the structure and function of the HIV-1 envelope proteins is critical for the design of an effective vaccine. Despite the availability of many high-resolution structures, key functional correlates in the envelope trimer remain undefined. We utilized a combination of structural analysis, in silico energy calculation, mutagenesis, and neutralization profiling to dissect the functional anatomy of the trimer apex, which acts as a global regulator of the HIV-1 spike conformation. We identify four hydrophobic clusters that stabilize the spike in a tightly closed configuration and, thereby, play a critical role in protecting it from the reach of neutralizing antibodies.

Keywords: HIV-1; envelope; envelope glycoprotein; immune evasion; neutralizing antibodies; prefusion state; protein structure-function; trimer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Antibodies, Neutralizing / immunology
  • HIV Antibodies
  • HIV Infections / virology
  • HIV-1 / chemistry
  • HIV-1 / genetics*
  • HIV-1 / immunology
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Mutation
  • env Gene Products, Human Immunodeficiency Virus / chemistry*
  • env Gene Products, Human Immunodeficiency Virus / genetics
  • env Gene Products, Human Immunodeficiency Virus / immunology*


  • Antibodies, Neutralizing
  • HIV Antibodies
  • env Gene Products, Human Immunodeficiency Virus