The trimeric human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) spike is a molecular machine that mediates virus entry into host cells and is the sole target for virus-neutralizing antibodies. The mature Env spike results from cleavage of a trimeric glycoprotein precursor, gp160, into three gp120 and three gp41 subunits. Here, we describe an ∼11-Å cryo-EM structure of the trimeric HIV-1 Env precursor in its unliganded state. The three gp120 and three gp41 subunits form a cage-like structure with an interior void surrounding the trimer axis. Interprotomer contacts are limited to the gp41 transmembrane region, the torus-like gp41 ectodomain and a trimer-association domain of gp120 composed of the V1, V2 and V3 variable regions. The cage-like architecture, which is unique among characterized viral envelope proteins, restricts antibody access, reflecting requirements imposed by HIV-1 persistence in the host.
Bibliographical noteFunding Information:
The authors thank J. Mascola and P. Kwong (NIH Vaccine Research Center, Bethesda, Maryland, USA) and D. Burton (Scripps Institute, La Jolla, California, USA) for kindly providing antibodies; M. Ericsson, L. Trakimas and E. Benecchi for help in initial sample screening by conventional electron microscopy; D. Bell, E. Hodges and D. Wei for assistance and coordination in data collection; J. Faltskog, S. Doktor and B. Battle for laboratory coordination and assistance in building a high-performance computing system; and Y. McLaughlin and E. Carpelan for assistance in manuscript preparation. The experiments and data processing were performed in part at the Center for Nanoscale Systems at Harvard University, a member of National Nanotechnology Infrastructure Network (NNIN), which is supported by the US National Science Foundation under NSF award no. ECS-0335765. This work was funded by the US National Institutes of Health (NIH) (AI93256, AI67854 and AI24755 to J.S.), by an Innovation Award (J.S.) and a Fellowship Award (Y.M.) from the Ragon Institute of MGH, MIT and Harvard, by the International AIDS Vaccine Initiative, and by a gift from the late William F. McCarty-Cooper (J.S.).