Holes in the Glycan Shield of the Native HIV Envelope Are a Target of Trimer-Elicited Neutralizing Antibodies

Abstract

SUMMARY A major advance in the search for an HIV vaccine has been the development of a near-native Envelope trimer (BG505 SOSIP.664) that can induce robust autologous Tier 2 neutralization. Here, potently neutralizing monoclonal antibodies (nAbs) from rabbits immunized with BG505 SOSIP.664 are shown to recognize an immunodominant region of gp120 centered on residue 241. Residue 241 occupies a hole in the glycan defenses of the BG505 isolate with fewer than 3% of global isolates lacking a glycan site at this position. However, at least one conserved glycan site is missing in 89% of viruses, suggesting the presence of glycan holes in a majority of HIV isolates. Indeed, serum evidence is consistent with targeting of holes in natural infection. The immunogenic nature of breaches in the glycan shield has been under-appreciated in previous attempts to understand autologous neutralizing antibody responses and has important potential consequences for HIV vaccine design.

Identification and specificity of broadly neutralizing antibodies against HIV

“…The development of native‐like stabilized trimers has greatly improved our ability to use this method to select for B cells that bind the functional Env trimers as compared with non‐functional forms of Env. However, even with stabilized near‐native trimers as FACS baits, non‐neutralizing binders and strain‐specific nAbs are captured 88, 89. Also, it is important to note that inherently a binding screen will select the best binders for the particular assay used.…”

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

“…Advances in the design of immunogens (BG505 SOSIP) that antigenically mimic the HIV envelope glycoprotein (Env) 1 have improved the elicitation of potent isolate-specific Ab responses in rabbits 2 and macaques 3 , but so far failed to induce bnAbs. One possible contributor to this failure is that the relevant antibody repertoires are poorly suited to target somewhat occluded conserved epitope regions on Env relative to exposed variable epitopes.…”

Polyvalent vaccine approaches to combat HIV‐1 diversity

“…The intentional minimization of such rare amino acids in Mosaic vaccines may help elicit greater breadth of not only T‐cell but also B‐cell responses. Indeed, a recent study showed that Env mosaic vaccines elicited both cellular and humoral responses, and that vaccine‐induced antibodies correlated with protection from acquisition in a SHIV challenge model 28. A second approach to improve induction of cross‐reactive antibodies is based on the idea of tracking B‐cell lineage development in chronically infected subjects who have generated potent and broad neutralizing antibody (bNAb) responses.…”

“…A bivalent mosaic vaccine including pairs of HIV‐1 Gag, Pol, and Env mosaics delivered in adenovirus and poxvirus vectors conferred significant protection against serial, low‐dose rectal challenges with a difficult‐to‐neutralize simian‐human immunodeficiency virus SHIV‐SF162P3 28. As noted above, the only mosaic proteins that would have been able to elicit cross‐reactive protective responses in this vaccine were the two HIV‐1 Env glycoproteins, since the HIV‐1 Gag and Pol directed responses are unlikely to cross‐protect against the SIVmac Gag and Pol proteins of the SHIV challenge virus.…”