Immunity. 2017 May 16; 46(5):804-817.e7.

PubMed ID: 28514687

Particulate array of well-ordered HIV Clade C Env trimers elicits neutralizing antibodies that display a unique V2 cap approach

Martinez-Murillo P, Tran K, Guenaga J, Lindgren G, Adori M, Feng Y, Phad GE, Vazquez Bernat N, Bale S, Ingale J, Dubrovskaya V, O'Dell S, Pramanik L, Spangberg M, Corcoran M, Lore K, Mascola JR, Wyatt RT, Karlsson Hedestam GB

The development of soluble envelope glycoprotein (Env) mimetics displaying ordered trimeric symmetry has ushered in a new era in HIV-1 vaccination. The recently reported native, flexibly linked (NFL) design allows the generation of native-like trimers from clinical isolates at high yields and homogeneity. As the majority of infections world-wide are of the clade C subtype, we examined responses in non-human primates to well-ordered subtype C 16055 trimers administered in soluble or high-density liposomal formats. We detected superior germinal center formation and enhanced autologous neutralizing antibodies against the neutralization-resistant (tier 2) 16055 virus following inoculation of liposome-arrayed trimers. Epitope mapping of the neutralizing monoclonal antibodies (mAbs) indicated major contacts with the V2 apex, and 3D electron microscopy reconstructions of Fab-trimer complexes revealed a horizontal binding angle to the Env spike. These vaccine-elicited mAbs target the V2 cap, demonstrating a means to accomplish tier 2 virus neutralization by penetrating the dense N-glycan shield.