Search bioRxiv⌕ Search

Biology subjects

Newby, M.

Publications and source records attributed to Newby, M..

2 recordsLinked to original sources
bioRxiv2022

Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimers as HIV-1 vaccine candidates

Uncleaved prefusion-optimized (UFO) design can stabilize diverse HIV-1 envelope glycoproteins (Envs). Single-component, self-assembling protein nanoparticles (1c-SApNP) can display 8 or 20 trimeric antigens as multivalent vaccines. Here, we characterized the biophysical, structural, and antigenic properties of 1c-SApNPs that present the BG505 UFO trimer with wildtype and modified glycans. Trimming the glycan shield improved Env recognition by broadly neutralizing antibodies (bNAbs) to the CD4 binding site and other major glycan-containing epitopes. In mice, rabbits, and nonhuman primates, glycan trimming increased the frequency of vaccine responders (FVR) and steered antibody responses away from immunodominant glycan holes and glycan epitopes. The mechanism of vaccine-induced immunity was examined in mice. Compared with the soluble trimer, two large 1c-SApNPs showed 420 times longer retention, 20-32 times greater presentation on follicular dendritic cell dendrites, and up-to-4 times stronger germinal center reactions in lymph node follicles. These findings will inform the next phase of HIV-1 vaccine development. ONE-SENTENCE SUMMARYGlycan trimming of HIV-1 Env immunogens improves the vaccine-induced neutralizing antibody responses in small animals and primates

microbiology↗
bioRxiv2021

Structure of the hepatitis C virus E1E2 glycoprotein complex

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma in humans, and afflicts more than 58 million people worldwide. The HCV envelope E1 and E2 glycoproteins are essential for viral entry and infection, and comprise the primary antigenic target for neutralizing antibody responses. The molecular mechanisms of E1E2 assembly, as well as how the E1E2 heterodimer binds broadly neutralizing antibodies, remains elusive. We present the cryo-electron microscopy (cryoEM) structure of the membrane-extracted full-length E1E2 heterodimer in complex with broadly neutralizing antibodies (bNAbs) AR4A, AT12009 and IGH505 at [~]3.5 [A] resolution. We resolve the long sought-after interface between the E1 and E2 ectodomains and reveal how it is stabilized by hydrophobic interactions and glycans. This structure deepens our understanding of the HCV fusion glycoprotein and delivers a blueprint for the rational design of novel vaccine immunogens and anti-viral drugs.

immunology↗