Trimeric HIV Env provides epitope occlusion mediated by hypervariable loops

Carlos G. Moscoso (1) , Li Xing (1) , Jinwen Hui (1) , Jeffrey Hu (1) , Mohammad Baikoghli Kalkhoran (1) , Onur M. Yenigun (1) , Yide Sun (2) , Lassi Paavolainen (3, 4) , Loïc M Martin (5, 6, 7) , Anders Vahlne (8) , Carlo Zambonelli (2) , Susan W. Barnett (2) , Indresh Srivastava (2) , R. Holland Cheng (1, 9)

1 UC Davis - University of California [Davis]
2 Novartis Vaccines and Diagnostics [Siena]
3 JYU - Department of Biological and Environmental Science [Jyväskylä Univ]
4 NSC@JYU - Nanoscience Center [Jyväskylä Univ]
5 DRF (CEA) - Direction de Recherche Fondamentale (CEA)
6 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
7 MTS - Médicaments et Technologies pour la Santé
8 Karolinska Institutet [Stockholm]
9 CCK - Cancer Center Karolinska [Karolinska Institutet]

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.

Domaines: Cristallographie; Chimie thérapeutique; Biochimie [q-bio.BM]; Biologie structurale [q-bio.BM]; Immunothérapie

Carlos G. Moscoso, Li Xing, Jinwen Hui, Jeffrey Hu, Mohammad Baikoghli Kalkhoran, et al.. Trimeric HIV Env provides epitope occlusion mediated by hypervariable loops. Scientific Reports, 2015, 4, pp.7025. ⟨10.1038/srep07025⟩. ⟨cea-02530807⟩