Featured Article - January 2015
Short description: A crystal structure of the pre-fusion HIV-1 Env captures gp41 and provides insights into immune recognition.
The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike is a type-1 fusion machine that mediates viral entry into the host cell and an important target in HIV-1 vaccine development. Comprised of a trimer, each protomer with a gp120 and a gp41 subunit, Env undergoes a series of structural changes as it binds the CD4 receptor and CCR5/CXCR4 coreceptors on the host cell, eventually fusing the viral and cellular membranes. Several structures of the spike at different stages have been reported, including a recent structure of pre-fusion gp120 and two gp41 helices (PDB 4NCO), but a complete picture of pre-fusion gp41 has remained elusive.
Kwong and colleagues used two neutralizing antibodies, PGT122 and 35O22, to capture the pre-fusion HIV-1 Env ectodomain in a mature, closed state. They solved a 3.5-Å resolution crystal structure that provides a nearly complete view of gp41 in the trimer. This new structure (PDB 4TVP) shows that gp41 forms a hydrophobic ring that holds the C- and N-termini of gp120, sharing similarities with other type-1 fusion machines, such as those of Ebola and influenza. In HIV-1, this ring is made up of two sets of two small helices connected by a loop, a substructure that was previously unappreciated. By comparing their data to available post-fusion structures, the authors found that each of these sets of small helices aligns into a long helix at the post-fusion stage, forming the six-helical bundle that interacts with the host membrane.
Modeling high-mannose glycans onto pre-fusion Env allowed the researchers to investigate the accessibility of protein or glycan surfaces to antibodies. The results were sobering—only about 3% of the pre-fusion surface is accessible to an immunoglobulin domain, as compared to 14% in influenza virus. When combined with data on residue and glycan variability, only 2% of HIV-1 Env surface was accessible to antibodies and had a variability of less than 10%. Nevertheless, antibodies can be raised against the pre-fusion closed state of the spike, and this new structure gives us insight into HIV-1 vulnerabilities and how to direct immune defenses to combat the virus.
M. Pancera et al. Structure and immune recognition of trimeric pre-fusion HIV-1 Env.
Nature. 514, 455-461 (2014). doi:10.1038/nature13808