Trimeric HIV Env provides epitope occlusion mediated by hypervariable loops.
Hypervariable loops of HIV-1 Env protein gp120 are speculated to play roles in the conformational transition of Env to the receptor binding-induced metastable state. Structural analysis of full-length Env-based immunogens, containing the entire V2 loop, displayed tighter association between gp120 subunits, resulting in a smaller trimeric diameter than constructs lacking V2. A prominent basal quaternary location of V2 and V3' that challenges previous reports would facilitate gp41-independent gp120-gp120 interactions and suggests a quaternary mechanism of epitope occlusion facilitated by hypervariable loops. Deletion of V2 resulted in dramatic exposure of basal, membrane-proximal gp41 epitopes, consistent with its predicted basal location. The structural features of HIV-1 Env characterized here provide grounds for a paradigm shift in loop exposure and epitope occlusion, while providing substantive rationale for epitope display required for elicitation of broadly neutralizing antibodies, as well as substantiating previous pertinent literature disregarded in recent reports.
Department of Molecular and Cellular Biology, University of California, Davis, CA 95616.
Carlos G
CG
Moscoso
Department of Molecular and Cellular Biology, University of California, Davis, CA 95616.
Li
L
Xing
Department of Molecular and Cellular Biology, University of California, Davis, CA 95616.
Jinwen
J
Hui
Department of Molecular and Cellular Biology, University of California, Davis, CA 95616.
Jeffrey
J
Hu
Department of Molecular and Cellular Biology, University of California, Davis, CA 95616.
Mohammad Baikoghli
MB
Kalkhoran
Department of Molecular and Cellular Biology, University of California, Davis, CA 95616.
Onur M
OM
Yenigun
Novartis Vaccines and Diagnostics Inc., 45 Sydney Street, Cambridge, MA 02139.
Yide
Y
Sun
Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, FI-40351 Jyväskylä, Finland.
Lassi
L
Paavolainen
Commissariat à l'énergie atomique et aux énergies alternatives, Institut de Biologie et Technologies de Saclay, Service d'Ingénierie Moléculaire des Protéines, Gif-sur-Yvette F-91191, France.
Loïc
L
Martin
Karolinska Institutet, Structural Virology, Clinical Microbiology/University Hospital, 171 77 Stockholm, Sweden.
Anders
A
Vahlne
Novartis Vaccines and Diagnostics Inc., 45 Sydney Street, Cambridge, MA 02139.
Carlo
C
Zambonelli
Novartis Vaccines and Diagnostics Inc., 45 Sydney Street, Cambridge, MA 02139.
Susan W
SW
Barnett
Novartis Vaccines and Diagnostics Inc., 45 Sydney Street, Cambridge, MA 02139.
Indresh K
IK
Srivastava
1] Department of Molecular and Cellular Biology, University of California, Davis, CA 95616 [2] Karolinska Institutet, Structural Virology, Clinical Microbiology/University Hospital, 171 77 Stockholm, Sweden.
R Holland
RH
Cheng
D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry* / Q000235:genetics; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017384:Sequence Deletion; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D015704:CD4 Antigens; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D054299:env Gene Products, Human Immunodeficiency Virus