9dim
Q23.MD39 in Complex with Fab from antibody 35O22
Structural highlights
FunctionO55774_HV1 Envelope glycoprotein gp160: Oligomerizes in the host endoplasmic reticulum into predominantly trimers. In a second time, gp160 transits in the host Golgi, where glycosylation is completed. The precursor is then proteolytically cleaved in the trans-Golgi and thereby activated by cellular furin or furin-like proteases to produce gp120 and gp41.[HAMAP-Rule:MF_04083] Surface protein gp120: Attaches the virus to the host lymphoid cell by binding to the primary receptor CD4. This interaction induces a structural rearrangement creating a high affinity binding site for a chemokine coreceptor like CXCR4 and/or CCR5. Acts as a ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses. These interactions allow capture of viral particles at mucosal surfaces by these cells and subsequent transmission to permissive cells. HIV subverts the migration properties of dendritic cells to gain access to CD4+ T-cells in lymph nodes. Virus transmission to permissive T-cells occurs either in trans (without DCs infection, through viral capture and transmission), or in cis (following DCs productive infection, through the usual CD4-gp120 interaction), thereby inducing a robust infection. In trans infection, bound virions remain infectious over days and it is proposed that they are not degraded, but protected in non-lysosomal acidic organelles within the DCs close to the cell membrane thus contributing to the viral infectious potential during DCs' migration from the periphery to the lymphoid tissues. On arrival at lymphoid tissues, intact virions recycle back to DCs' cell surface allowing virus transmission to CD4+ T-cells.[HAMAP-Rule:MF_04083] Transmembrane protein gp41: Acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During fusion of viral and target intracellular membranes, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Complete fusion occurs in host cell endosomes and is dynamin-dependent, however some lipid transfer might occur at the plasma membrane. The virus undergoes clathrin-dependent internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. Membranes fusion leads to delivery of the nucleocapsid into the cytoplasm.[HAMAP-Rule:MF_04083] Publication Abstract from PubMedGermline targeting vaccination strategies against highly variable pathogens such as HIV aim to elicit broadly neutralizing antibodies (bnAbs) with particular immunogenetic or structural features. The V2 apex of the HIV Env protein is a promising target for a class of bnAbs that contain conserved structural motifs in the heavy chain complementarity determining region 3 (CDRH3). Here, we show that these structural motifs are targetable by vaccination by characterizing V2 apex 'axe-like' CDRH3s in the human repertoire and developing new immunogens capable of engaging them. We determined the frequency and diversity of axe-like CDHR3s in healthy human donors using a series of structural informatics approaches, finding these precursors in nearly 90% of donors. Axe-targeting immunogens based on the HIV Env Q23.17 bound axe-like precursors in cryo-EM structures, induced V2 apex-specific antibody responses in humanized mice, and induced axe-like heterologous neutralizing antibodies in rhesus macaques infected with a germline-targeted simian-human immunodeficiency virus. These results illustrate a new structure-guided immunoinformatic vaccine design paradigm that can be employed to elicit immunogenetically diverse yet structurally conserved classes of antibodies. SIGNIFICANCE STATEMENT: Many broadly neutralizing antibodies (bnAbs) utilize modes of epitope recognition dominated by the antibody complementarity determining region 3 (CDRH3). The CDRH3 is the most diverse part of the antibody, posing a challenge for germline targeting vaccine designs that aim to elicit antibodies with particular immunogenetic features. Vaccine design strategies that accommodate CDRH3 variability are therefore needed. Many HIV Env V2 apex bnAbs share "axe-like" CDRH3 microfolds that arise from diverse immunogenetic origins. Here we determined the frequency in humans of B cells with such CDRH3 topologies and designed immunogens to engage their precursors. This work opens a path toward vaccines that engage specific structural classes of B cells, thereby advancing the rational design of immunogens for HIV and other pathogens. Deep Mining of the Human Antibody Repertoire Identifies Frequent and Genetically Diverse CDRH3 Topologies Targetable by Vaccination.,Habib R, Solieva SO, Lin ZJ, Ghosh S, Bayruns K, Singh M, Agostino CJ, Tursi NJ, Sowers KJ, Huang J, Roark RS, Purwar M, Park Y, Ayyanathan K, Li H, Carey JW, Kim A, Park J, McCanna ME, Skelly AN, Chokkalingam N, Kriete S, Shupin N, Huynh A, Walker S, Sadeesh R, Laenger N, Du J, Cui J, Patel A, Escolano A, Kwong PD, Shapiro L, Bowman GR, Hahn BH, Shaw GM, Weiner DB, Pallesen J, Kulp DW bioRxiv [Preprint]. 2025 Nov 20:2024.10.04.616739. doi: , 10.1101/2024.10.04.616739. PMID:41332666[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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