Robust Neutralizing Antibodies Elicited by HIV-1 JRFL Envelope Glycoprotein Trimers in Non-human Primates.

TitleRobust Neutralizing Antibodies Elicited by HIV-1 JRFL Envelope Glycoprotein Trimers in Non-human Primates.
Publication TypeJournal Article
Year of Publication2013
AuthorsChakrabarti BK, Feng Y, Sharma SKumar, McKee K, Karlsson Hedestam GB, Labranche CC, Montefiore DC, Mascola JR, Wyatt RT
JournalJ Virol
Date Published12/01/2013
ISSN1098-5514
Abstract

Host cell-mediated proteolytic cleavage of the HIV-1 gp160 precursor glycoprotein into gp120 and gp41 subunits is required to generate fusion-competent envelope glycoprotein (Env) spikes. The gp120-directed broadly neutralizing monoclonal antibodies (bNabs) isolated from HIV-infected individuals efficiently recognize fully cleaved JRFL Env spikes; however, non-neutralizing gp120-directed monoclonal antibodies isolated from infected or vaccinated subjects recognize only uncleaved JRFL spikes. Therefore, as an immunogen, cleaved, spikes that selectively present desired neutralizing epitopes to B cells may elicit cross-reactive neutralizing antibodies. Accordingly, we inoculated non-human primates (NHPs) with plasmid DNA encoding transmembrane-anchored, cleaved JRFL Env or by electroporation (EP). Priming with DNA expressing soluble, uncleaved gp140 trimers was included as a comparative experimental group of NHPs. DNA inoculation was followed by boosts with soluble JRFL gp140 trimers and control NHPs were inoculated with soluble JRFL protein trimers without DNA priming. In the TZM-bl assay, elicitation of neutralizing antibodies against HIV-1 Tier 1 isolates was robust following the protein boost. Neutralization of Tier 2 isolates was detected, but only in animals primed with plasmid DNA and boosted with trimeric protein. Using the more sensitive A3R5 assay, consistent neutralization of both clade B and C Tier 2 isolates was detected from all regimens assessed in the current study, exceeding levels achieved by our previous vaccine regimens in primates. Together, these data suggest a potential advantage of B cell priming followed by a rest interval and protein boosting to present JRFL Env spikes to the immune system to better generate HIV-1 cross-clade neutralizing antibodies.

DOI10.1128/JVI.01247-13
Alternate JournalJ. Virol.
PubMed ID24067980
CHAVI-ID: 
1
Cover Picture: