Shared Maturation Pathways of HIV-1 Envelope-reactive V3-glycan bnAb Lineages in Human and Rhesus Macaque

Clark, M.; Li, H.; Martin, M.; Evangelous, T.; Gobeil, S.; Berry, M.; Wagh, K.; Giorgi, E.; Hogarty, M.; Zhao, C.; Wang, S.; Marchitto, L.; Ding, W.; Park, Y.; Rando, J.; Carey, J.; Connell, A.; Skelly, A.; Chen, Y.; Rohr, S.; Jiang, C.; Venkatayogi, S.; Mansouri, K.; Edwards, R. J.; Lindenberger, J.; Hora, B.; Doria-Rose, N. A.; Mascola, J.; van Gils, M. J.; Sanders, R. W.; Korber, B.; Hahn, B. H.; Saunders, K. O.; Acharya, P.; Wiehe, K.; Haynes, B. F.; Shaw, G. M.; Williams, W. B.

doi:10.64898/2026.01.29.702664

Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.01.29.702664

Shared Maturation Pathways of HIV-1 Envelope-reactive V3-glycan bnAb Lineages in Human and Rhesus Macaque

View original source ↗Export metadata ↓

Abstract

ABSTRACTUnderstanding broadly neutralizing antibody (bnAb) lineage development in rhesus macaques (RMs) infected with Simian-HIV (SHIV) may inform HIV-1 vaccine designs. We analyzed HIV-1 envelope-antibody coevolution in 18 RMs infected by SHIV.BG505 (subtype A) and found highly conserved patterns of antibody recognition and Env escape, including in three animals that developed V3-glycan bnAbs. From one RM with V3-glycan targeted plasma breadth, we isolated 203 members of a single clonal Ab lineage designated DH1030. DH1030 Abs demonstrated striking genetic, functional and structural similarities with the human V3-glycan bnAb lineage DH270, which was isolated from an individual with subtype C HIV-1 CH848 infection. Notably, human-DH270 and macaque-DH1030 bnAbs shared early improbable mutations in HCDR2 that were critical for bnAb development. Thus, key improbable mutations and convergent patterns of antibody evolution and epitope recognition were shared across primate species and distinct HIV-1 subtypes, findings that may be leveraged in new HIV-1 vaccine designs. ONE SENTENCE SUMMARYBroadly neutralizing antibodies targeting HIV-1 envelope surface protein develop via a common maturation pathway across primate phylogeny.

Explore related subjects

immunology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Clark, M., Li, H., Martin, M., Evangelous, T., Gobeil, S., Berry, M., Wagh, K., Giorgi, E., Hogarty, M., Zhao, C., Wang, S., Marchitto, L., Ding, W., Park, Y., Rando, J., Carey, J., Connell, A., Skelly, A., Chen, Y., Rohr, S., Jiang, C., Venkatayogi, S., Mansouri, K., Edwards, R. J., Lindenberger, J., Hora, B., Doria-Rose, N. A., Mascola, J., van Gils, M. J., Sanders, R. W., Korber, B., Hahn, B. H., Saunders, K. O., Acharya, P., Wiehe, K., Haynes, B. F., Shaw, G. M., Williams, W. B.. 2026-01-30. Shared Maturation Pathways of HIV-1 Envelope-reactive V3-glycan bnAb Lineages in Human and Rhesus Macaque. https://doi.org/10.64898/2026.01.29.702664

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Differential and Cooperative Immunomodulation by Saponin Adjuvants QS-21 and QS-7 in Human THP-1 Macrophages

QS-21, a triterpene glycoside saponin derived from Quillaja saponaria, is a potent immunostimulatory adjuvant incorporated in several FDA-approved vaccines. QS-7, a structurally related saponin fraction, has been reported to retain immunomodulatory activity with reduced hemolytic toxicity; however, its lower natural abundance has limited its systematic immunological characterization. To address this gap, we systematically compare responses to QS-21 and QS-7 in the THP-1 human macrophage model to resolve their distinct and cooperative contributions to antigen presenting cell (APC) activation. Following cytotoxicity profiling to establish safe and biologically relevant dosing, flow cytometry, proteomics, and transcriptomics were used to delineate the immunological programs engaged by each saponin alone and in combination. QS-7 alone induced minimal upregulation of cell surface activation markers and did not elicit a significant transcriptional signature, yet it drove dose-dependent secretion of a broad panel of pro-inflammatory cytokines and chemokines, revealing a dissociation between these two arms of macrophage activation. Strikingly, co-administration of QS-7 with QS-21 substantially potentiated macrophage activation across all parameters tested, amplifying surface marker upregulation, broadening cytokine and chemokine output to include IL-12p70 and IFN-{gamma}, and markedly expanding the pro-inflammatory transcriptional and pathway landscape induced by QS-21, while concurrently suppressing counter-regulatory lipid-sensing pathways (PPAR, RAR, FXR/RXR) that constrain inflammatory output. Collectively, these findings establish QS-7 not merely as an attenuated analog of QS-21, but as a functionally distinct immunomodulator that recalibrates both the magnitude and regulatory tone of QS-21-driven macrophage activation. These findings show that structurally distinct saponins elicit distinct and complementary macrophage responses, providing a foundation for structure-function studies. Together with synthetic biology and data-driven design, this knowledge can guide the development of new-to-nature saponin adjuvants.

immunology↗

bioRxiv2026

MAFB and MAF cooperatively orchestrate human anti-inflammatory macrophage identity via autocrine Interleukin-10

Macrophage lineage identity is governed by intricate transcriptional networks. Although the large MAF basic region-leucine zipper (bZIP) transcription factors MAFB and MAF are critical regulators of anti-inflammatory programs, their molecular coordination and non-redundant contributions within human macrophages remain poorly defined. Here, utilizing integrated proteomic, transcriptomic, and epigenomic profiling, we demonstrate that endogenous MAFB and MAF physically associate to form a stable heterodimeric complex on chromatin in human M-CSF-dependent monocyte-derived macrophages (M-Mac). Genome-wide CUT&Tag mapping reveals a hierarchical epigenomic architecture in which MAFB acts as the primary global anchor of M-Mac identity, whereas MAF provides localized transcriptional tuning. Mechanistically, both factors directly bind the IL10 locus, but functional IL-10 expression is primarily driven by MAFB. Neutralizing antibody assays reveal that endogenously produced IL-10 establishes an obligate autocrine feedback loop mandatory for both the initial acquisition and the maintenance of the M-Mac anti-inflammatory profile. Functionally, MAFB and MAF exert non-redundant control over core macrophage effectors: MAFB dictates apoptotic cell efferocytosis amd T cell activation, whereas MAF modulates phagocytosis, and acts as a brake suppressing acute pro-inflammatory cytokine/chemokine hyper-induction. Together, these findings establish a comprehensive molecular blueprint of how MAFB and MAF cooperatively fine-tune human monocyte-derived macrophage identity and functional plasticity.

immunology↗

bioRxiv2026

Peripheral Immune Cell Shifts Associated With Alzheimer's Disease Vary in Multi-Ancestry Cohorts

Background: Alzheimer's disease (AD) is heavily influenced by immune system dysregulation, yet the role of peripheral immune processes--and how these vary across ethnicities--remains understudied. Objective: To investigate ancestry-specific immune alterations in AD by profiling peripheral immune cell proportions using high-resolution deconvolution of whole blood RNA-sequencing data, characterizing disease associated cell types, and identifying enriched biological pathways. Methods: We analyzed whole blood RNA-seq data from non-Hispanic White (NHW), African American (AA), Caribbean Hispanic (CariHISP), and Peruvian (PERU) individuals, balanced between AD cases and cognitively normal controls. Immune cell proportions were estimated using CIBERSORTx and compared using linear models (propeller R package) adjusted for age, sex, and APOE genotypes in case-control models. Cell-type-specific differential expression was performed using CARseq, and pathway enrichment analyses performed using MSigDB gene sets. Results: Baseline immune composition differed substantially across cohorts for multiple innate and adaptive cell types. In a multi-ethnic AD versus control analysis, eight cell types reached FDR significance: AD was associated with decreased proportions naive B cells, CD56dim NK cells, B cells, intermediate monocyte I, and double-negative T cells, alongside significant expansion in neutrophils and non-classical monocytes. Interaction analyses revealed heterogeneous group-specific effects, with the broadest shifts in AA and CariHISP. Pathway enrichment indicated shared heme metabolism, interferon, and oxidative phosphorylation programs across groups, with distinct emphases: broad, strong heme metabolism enrichment and the highest oxidative phosphorylation signal (in myeloid populations) in AA; MYC targets in naive B cells and eosinophils in CariHISP; dendritic cell - and T follicular helper cell - centered interferon, inflammatory, and proliferative programs in NHW; and TGF-{beta} and apoptosis signatures, unique to PERU, alongside the broadest cell-type coverage. Conclusions: Peripheral immune dysregulation in AD is characterized by depletion of lymphoid and intermediate monocyte populations with concurrent neutrophil and non-classical monocyte expansion, and these patterns vary meaningfully by ancestry. These findings underscore the need for population-informed biomarkers and therapeutic strategies in AD.

immunology↗