Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens

Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):11947-52. doi: 10.1073/pnas.1507793112. Epub 2015 Sep 8.


A key challenge in the quest toward an HIV-1 vaccine is design of immunogens that can generate a broadly neutralizing antibody (bnAb) response against the enormous sequence diversity of the HIV-1 envelope glycoprotein (Env). We previously demonstrated that a recombinant, soluble, fully cleaved SOSIP.664 trimer based on the clade A BG505 sequence is a faithful antigenic and structural mimic of the native trimer in its prefusion conformation. Here, we sought clade C native-like trimers with comparable properties. We identified DU422 and ZM197M SOSIP.664 trimers as being appropriately thermostable (Tm of 63.4 °C and 62.7 °C, respectively) and predominantly native-like, as determined by negative-stain electron microscopy (EM). Size exclusion chromatography, ELISA, and surface plasmon resonance further showed that these trimers properly display epitopes for all of the major bnAb classes, including quaternary-dependent, trimer-apex (e.g., PGT145) and gp120/gp41 interface (e.g., PGT151) epitopes. A cryo-EM reconstruction of the ZM197M SOSIP.664 trimer complexed with VRC01 Fab against the CD4 binding site at subnanometer resolution revealed a striking overall similarity to its BG505 counterpart with expected local conformational differences in the gp120 V1, V2, and V4 loops. These stable clade C trimers contribute additional diversity to the pool of native-like Env immunogens as key components of strategies to induce bnAbs to HIV-1.

Keywords: HIV immunogens; HIV-1 envelope; antigenic diversity; clade C trimers; neutralizing antibodies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cryoelectron Microscopy
  • Drug Design*
  • HIV Antigens / chemistry
  • HIV Antigens / immunology
  • HIV-1 / immunology*
  • Humans
  • Immunoglobulin Fab Fragments / chemistry
  • Immunoglobulin Fab Fragments / immunology
  • Models, Molecular
  • Negative Staining
  • Protein Multimerization*
  • Protein Stability
  • Solubility
  • Temperature
  • env Gene Products, Human Immunodeficiency Virus / chemistry*
  • env Gene Products, Human Immunodeficiency Virus / immunology*


  • HIV Antigens
  • Immunoglobulin Fab Fragments
  • env Gene Products, Human Immunodeficiency Virus