Env Exceptionalism: Why Are HIV-1 Env Glycoproteins Atypical Immunogens?

Abstract

Recombinant HIV-1 envelope (Env) glycoproteins of ever-increasing sophistication have been evaluated as vaccine candidates for over 30 years. Structurally defined mimics of native trimeric Env glycoproteins (e.g., SOSIP trimers) present multiple epitopes for broadly neutralizing antibodies (bNAbs) and their germline precursors, but elicitation of bNAbs remains elusive. Here, we argue that the interactions between Env and the immune system render it exceptional among viral vaccine antigens and hinder its immunogenicity in absolute and comparative terms. In other words, Env binds to CD4 on key immune cells and transduces signals that can compromise their function. Moreover, the extensive array of oligomannose glycans on Env shields peptidic B cell epitopes, impedes the presentation of T helper cell epitopes, and attracts mannose binding proteins, which could affect the antibody response. We suggest lines of research for assessing how to overcome obstacles that the exceptional features of Env impose on the creation of a successful HIV-1 vaccine.

Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth

“…All are key features to be considered in vaccine design. Our findings add substantially to earlier reports of sporadic or low-titer neutralization of heterologous tier 2 viruses elicited in RMs by SHIVs bearing lab-adapted or animal passaged HIV-1Envs(61)(62)(63)(64) or Env immunogens(65)(66)(67)(68)(69)(70)(71)(72). Unlike previous reports, the current results show how closely neutralizing antibody responses in RMs can mirror responses in humans and indicate the extent to which protective responses elicited by reverse engineered or lineage-based vaccines in RMs might be expected to predict human responses to candidate vaccines(10,11,73,74).A surprising observation was the extent to which Env evolution in multiple rhesus animals recapitulated evolution of homologous Envs in human infections.…”

Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike

“…The protein surface of Env is almost completely shielded by glycans, which contributes to its poor immunogenicity 13 . Env and Env-based vaccines, including nativelike SOSIP trimers and SOSIP-based clinical candidates, have holes in their glycan shield from two different sources.…”

Conjugation of Native-Like HIV-1 Envelope Trimers onto Liposomes Using EDC/Sulfo-NHS Chemistry: Requirements and Limitations

“…It has been repeatedly reported that the charge of liposome-based vaccines determines their fate (i.e., retention at the point of injection, cellular uptake, and lymph-node trafficking) and the type of immune response they may elicit [ 80 ]. The objectives of particulate display of Env trimers are, inter alia, increased lymph-node trafficking and enhanced B cell engagement [ 2 , 4 , 5 , 6 , 7 , 8 , 9 ]. Although several studies have shown that positively charged liposomes can indeed be delivered to lymph nodes, further research is required to assess whether their use within the context of nanoparticle-based HIV-1 vaccines is indicated/useful at all [ 81 , 82 ].…”

“…Despite the introduction of these well-conceived immunogen constructs and the use of new and elaborate immunisation strategies, inducing the desired type of immune response remains a major challenge. The reasons for this are multifaceted and have recently been discussed elsewhere [ 2 , 3 ]. The nanoparticulate display of native-like Env trimers and other state-of-the-art HIV immunogens has long been regarded as a promising strategy to improve and shape immune responses [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ].…”

“…Liposomes, in particular, have gained wide attention over the last years. However, recent studies have dampened the expectations with regard to the potential of liposomal display to significantly improve the immune response against the envelope protein of HIV-1 [ 2 , 7 , 8 ].…”