Mapping the immunogenic landscape of near-native HIV-1 envelope trimers in non-human primates

Abstract

The induction of broad and potent immunity by vaccines is the key focus of research efforts aimed at protecting against HIV-1 infection. Soluble native-like HIV-1 envelope glycoproteins have shown promise as vaccine candidates as they can induce potent autologous neutralizing responses in rabbits and non-human primates. In this study, monoclonal antibodies were isolated and characterized from rhesus macaques immunized with the BG505 SOSIP.664 trimer to better understand vaccine-induced antibody responses. Our studies reveal a diverse landscape of antibodies recognizing immunodominant strain-specific epitopes and non-neutralizing neo-epitopes. Additionally, we isolated a subset of mAbs against an epitope cluster at the gp120-gp41 interface that recognize the highly conserved fusion peptide and the glycan at position 88 and have characteristics akin to several humanderived broadly neutralizing antibodies.

Disassembly of HIV envelope glycoprotein trimer immunogens is driven by antibodies elicited via immunization

“…S13). RM20C does not neutralize BG505 virus as an immunoglobulin G (IgG) but can weakly neutralize as a Fab, consistent with the hypothesis that the disposition of the second Fab arm and Fc can sterically inhibit access to the base epitope on intact virions ( 26 ). Therefore, although the base epitope shared by two known bnAbs and one autologous neutralizing Fab is a bona fide site of vulnerability, access is highly constrained.…”

Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles

“…We also generated B cells expressing the base-specific non-NAb RM19R that was isolated from a BG505 SOSIP trimer-immunized macaque 36 . The exposed base of SOSIP trimers contains immunodominant non-NAb epitopes that may distract the immune response away from sites more favored to NAb induction 37 .…”

Modulating the quantity of HIV Env-specific CD4 T cell help promotes rare B cell responses in germinal centers

“…It has been suggested that glycans on gp41 are underoccupied compared with glycans on gp120 when expressed as recombinant protein on both native-like SOSIP trimers ( Guttman et al, 2014 ; Depetris et al, 2012 ; Cao et al, 2018 ; Behrens et al, 2016 ) and uncleaved recombinant gp140 ( Pabst et al, 2012 ; Go et al, 2011 ). The N611 glycosylation site, which falls within region 5, has been directly shown to be underglycosylated depending on the Env isolate ( Cottrell et al, 2020 ; Cao et al, 2018 ).…”

“…Hence, at least some of the Env-specific CD4 T cell responses are likely a result of suboptimal glycosylation on specific N-linked glycosylation sites. For example, N611 is thought to be underglycosylated in BG505 SOSIP Env trimers ( Cottrell et al, 2020 ), and N197 was directly shown to be underglycosylated in BG505 SOSIP ( Cao et al, 2018 ), although these results have yet to been shown in BG505 SOSIP trimer containing the MD39 trimer stabilizing mutations. The large CD4 T cell response to the underglycosylated gp41 region 5 trimer variants might not be recapitulated when immunizing with other Env constructs that have a much higher glycan occupancy at N611.…”