Biology subjects

Andrabi, S.

Publications and source records attributed to Andrabi, S..

6 recordsLinked to original sources

bioRxiv2026

Early clonal dominance at priming sets the trajectory for broad HIV serum neutralization

Inducing broadly neutralizing antibodies (bnAbs) remains a central challenge in HIV vaccine development 1-3. Germline-targeting immunogens are designed to activate rare bnAb precursor B cell lineages 4-12, yet the relationships between priming efficiency, clonal dominance, and downstream serum neutralization remain poorly defined. We recently demonstrated that vaccination with an engineered V2-apex germline-targeting trimer Q23-APEX-GT2 successfully recruits and activates rare long-CDRH3 B cell precursors in outbred macaques 13. Here, we dissect the immunological mechanisms governing bnAb precursor priming and early B cell expansion and define clonal features that drive progression to serum neutralization breadth. Our antigen-specific B cell analyses showed that Q23-APEX-GT2 consistently engaged long-CDRH3 precursors, although priming efficiency varied across animals. Longitudinal deep lineage tracing across lymph node and blood compartments revealed that early recruitment of multiple diverse long-CDRH3 lineages, followed by preferential expansion and dominance of one or two clones, strongly predicted serum neutralization potency. Subsequent CAP256.SU SHIV infection efficiently recalled vaccine-seeded clones, accelerated affinity maturation, and drove broad heterologous neutralization in most animals. Notably, one macaque with diverse and expanded V2-apex lineages rapidly achieved [~]70% serum neutralization breadth. Importantly, longitudinal tracing revealed that bona fide bnAbs can emerge from vaccine-primed precursors, while also uncovering "born-wrong" bnAb-like lineages that expand yet remain non-neutralizing, despite structurally validated recognition of the V2-apex bnAb site. Together, these findings establish priming efficiency coupled with early clonal dominance as key determinants of serum bnAb induction and provide a mechanistic framework to guide rational HIV vaccine design.

immunology↗

bioRxiv2025

Structure-guided design of native-like HIV Env Single Chain Trimers for enhanced stability, immunogenicity, and versatile vaccine delivery

Stabilizing the HIV envelope (Env) trimer in its native prefusion conformation is key to eliciting broadly neutralizing antibodies (bnAbs). We present a generalizable single-chain trimer-(SCT) design platform that enables the production of stable, native-like Env trimers across diverse HIV strains. Using a structure-guided approach, we developed CAP256.SU-SCT9, based on a CAP256.SU Env shown to induce V2-apex bnAbs in humans and rhesus macaques. CAP256.SU-SCT9 trimer exhibited native-like structure, bnAb-specific antigenicity, authentic glycosylation, and compatibility with nucleic acid and nanoparticle delivery. We extended this design strategy to a panel of HIV Envs representing global diversity, and immunogens known to initiate bnAb responses in humans. Structural analyses confirmed that SCTs consistently maintained prefusion-closed conformations, favorable glycan profiles, strong binding to trimer-specific bnAbs, and low reactivity with non-neutralizing antibodies. These findings establish SCT as a versatile platform for HIV trimer immunogen design, with potential to support next-generation vaccines aimed at eliciting protective bnAb responses.

immunology↗

bioRxiv2025

Germline-targeting HIV immunogen induces cross-neutralizing antibodies in outbred macaques

Germline-targeting-(GT) is a promising strategy to activate rare broadly neutralizing antibody (bnAb)-producing B cells against HIV, but induction of such responses in outbred animals has not been achieved. Using antibody-guided structure-based design, we engineered a germline-targeting trimer immunogen Q23-APEX-GT2 that primes diverse V2-apex bnAb precursors. Q23-APEX-GT2 efficiently activated V2-apex-specific B cells in humanized knock-in mice and consistently elicited immunofocused antibody responses in rhesus macaques, priming multiple long CDRH3-loop bnAb-B cell lineages. Monoclonal antibodies from immunized macaques exhibited broad heterologous HIV trimer binding and cross-neutralization. Atomic-level structural studies confirmed precise epitope targeting and revealed CDRH3-paratope configurations that mirrored those of human V2-apex bnAbs. This study provides proof-of-principle for successful priming and maturation of authentic V2-apex bnAb precursors in outbred macaques, underscoring the potential of V2-apex-targeted vaccines. HIGHLIGHTSO_LIEngineered Q23-APEX-GT2 trimer to stimulate diverse V2-apex bnAb B cell precursors C_LIO_LIQ23-APEX-GT2 primed rare V2-apex bnAb B cells in mice and outbred rhesus macaques C_LIO_LIQ23-APEX-GT2 elicited immunofocused antibody responses and diverse V2-apex B cell lineages with desirable long-CDRH3 paratope properties C_LIO_LIQ23-APEX-GT2 alone induced V2-apex antibodies with broad HIV trimer binding and modest neutralization breadth C_LIO_LIStructural analysis confirmed bnAb site targeting, mirroring human and rhesus V2-apex bnAbs C_LI

immunology↗

bioRxiv2024

Oxidative Injury to Lung Mitochondrial DNA is a Key Contributorfor the Development of Chemical Lung Injury

The mechanisms and extent to which inhalation of oxidant gases damage the mitochondrial genome contributing to the development of acute and chronic lung injury have not been investigated. C57BL/6 mice exposed to chlorine (Cl2) gas and returned to room air, developed progressive loss of lung DNA glycosylase OGG1, significant oxidative injury to mtDNA, decreased intact lung mitochondrial (mt) DNA, generation of inflammatory pathway by DAMPs causing airway and alveolar injury with significant mortality. Global proteomics identified over 1400 lung proteins with alteration of key mitochondrial proteins at 24 h post Cl2 exposure. Intranasal instillation of a recombinant protein containing mitochondrial targeted OGG1 (mitoOGG1) post exposure, decreased oxidative injury to mtDNA, lung mitochondrial proteome, severity of the acute and chronic lung injury and increased survival. These data show that injury to the mt-genome is a key contributor to the development of acute and chronic lung injury.

physiology↗

bioRxiv2019

LKB1 negatively regulates AKT1 signaling via DBC1 and TRB3

DBC1 plays a critical role in various cellular functions notably cell proliferation, transcription, histone modification and adipogenesis. Current reports about the role of DBC1 in tumorigenesis are paradoxical and designate DBC1 both as a tumor suppressor or an oncogene. Here, using small T antigen of polyoma virus (PyST) as a tool, we have delineated a signaling mechanism that connects LKB1 to AKT1 via DBC1. We report that PyST associates with DBC1 and leads to its down-regulation. Our results also show that PyST expression promotes LKB1 activation which in turn leads to in the downregulation of DBC1 protein. Absence of DBC1 results in transcriptional upregulation and consequently enhanced protein levels of TRB3. TRB3 sequesters AKT1, and consequently the phosphorylation and activity of AKT1 is compromised. This ultimately results in inactivation of pro-survival pathways triggered via AKT1 signaling. Our studies thus provide an insight into a signaling pathway that connects LKB1, DBC1, TRB3 and AKT1.

cell biology↗

bioRxiv2018

AKT regulates mitotic progression of mammalian cells by phosphorylating MASTL

Microtubule associated serine threonine like kinase (MASTL) has been recently identified as an important regulator of mitosis. By inhibiting protein phosphatase 2A, it plays a crucial role in activating one of the most important mitotic kinases known as cyclin dependent kinase1 (CDK1). MASTL has been seen to be up regulated in various types of cancers and is involved in tumor recurrence. It is activated by CDK1 through its auto regulatory loop but the complete mechanism of its activation is still unclear. In this study, we evaluated the regulation of MASTL via AKT during mitosis. Here we report that AKT phosphorylates MASTL at T299 which plays a critical role in its activation. Our results suggest that AKT increases CDK1 mediated phosphorylation and hence activity of MASTL which in turn promotes cell proliferation.. We also show that the oncogenic potential of AKT is augmented by MASTL activation as the AKT mediated oncogenesis in colorectal cell lines can be attenuated by inhibiting and/or silencing MASTL. In brief, we report that AKT has an important role in the progression of mitosis in mammalian cells and it does so through the phosphorylation and activation of MASTL.

cancer biology↗