Vaccines Bearing Engineered HIV-1 gp41 Transmembrane and Cytoplasmic-tail Domains Elicit Rare Reactivities Targeting the C-terminal Subdomain of the MPER

Abstract

Abstract Numerous vaccine strategies have failed to induce neutralizing (Nt) antibodies (Abs) against the HIV-1 gp41 MPER, the target of several broadly NtAbs. Factors contributing to this include an incomplete understanding of native MPER structure, and restricted/transient exposure of key Nt sites. Here, we describe novel MPER DNA and MPER-peptide liposome vaccines (PLVs) that best elicit Abs against N- and C-terminal (N- & C-) subdomains of the MPER; these subdomains are targeted by the 2F5 and 4E10/10E8 NtAbs, respectively. DNA-prime, PLV-boost immunization of rabbits and guinea pigs (GPs) with vaccines that optimize exposure of the N-terminal subdomain, elicited low-level 2F5-like reactivities that were moderately elevated with boosting. Co-immunization with the vaccines increased durability of these responses, with preliminary results showing moderate Nt activity from GPs (but not rabbits; however, GP pre-immune sera exhibited high Nt background). DNA and PLV vaccines were optimized to expose both the N- and C-subdomains. DNA vaccines were engineered to (i) encode an N-terminal coiled-coil to support a trimeric structure, (ii) express the native gp41 TMD, and (iii) truncate the cytoplasmic tail. Lipids and peptides for PLVs were designed to optimally expose the C-subdomain. Prime-boost and co-immunization of rabbits with the DNA vaccines and mixed N- and C-subdomain PLVs elicited Abs targeting both Nt sites of the MPER, but no Nt activity. Similar immunizations are underway in GPs. Together, our results illustrate the importance of (i) the TMD in eliciting Abs against the C-subdomain, (ii) co-immunization, and (iii) perhaps of GPs as a model, for eliciting NtAb responses.