Author: Carlos G. Moscoso

Publisher:

Published: 2014

Total Pages:

ISBN-13: 9781321609516

Advancements in the field of HIV rational vaccine design are greatly complemented by detailed understanding of the quaternary arrangement of the Env trimer, which is the principal target of neutralizing antibodies and the initial point of contact between virus and cell. The development of Env-based soluble trimeric immunogens has thus met with limited success in elicitation of an antibody response capable of protection against acquisition of infection. Recent immunogen candidates have had limited success in preclinical immunogenicity studies, but this success has not been replicated in clinical trials. Different strategies of immunogen design have led to distinct classes of Env trimers with similar antigenicity, though cleavage-defective trimers have thus far proven superior at eliciting broadly neutralizing antibodies. Structure characterization by cryoelectron microscopy and single particle reconstruction has allowed for structure-based immunogen design, by which determinants of immunogenicity can be identified, enhanced and tested. Novel mechanisms of epitope exposure were identified, as were distinct quaternary conformational rearrangements elicited by ligand binding. The Tat protein has recently been identified as a suitable vaccine component in conjunction with Env trimeric immunogens. We propose a novel mechanism for Tat-assisted, integrin-mediated and CD4-independent viral entry, by virtue of Tat-Env association. Significant aggregation induced by Tat may constitute a mechanism for decreased viral infectivity observed at high Tat concentrations. Finally, the use of hepatitis E virus-like particles (HEV VLPs) as scaffolds of HIV Env epitope insertion provide a new vehicle for epitope presentation and induction of mucosal antibody responses. The potential for these HEV VLPs to both carry foreign epitope and encapsulate small molecules or genetic material bode well for targeted delivery of therapeutics to infected cells displaying receptors recognizing the Env epitope. These advances in our understanding of Env structural transitions, Tat-assisted viral internalization and epitope presentation of HIV-1 epitopes on chimeric VLPs present opportunities for design of Env trimers with high immunogenicity to use as efficacious vaccine components.