Biology subjects

Vijayakumar, A.

Publications and source records attributed to Vijayakumar, A..

3 recordsLinked to original sources

bioRxiv2026

NK-like and networked CD8+ T cell immunity mediates exceptional HIV control

Durable treatment-free remission remains a defining goal for people living with HIV (PLWH). Studies of spontaneous elite controllers have revealed that functional CD8 T cells targeting structurally networked viral epitopes can mediate durable viral suppression1,2. However, rare reservoir-defined exceptional controllers within the spectrum of elite control3-5, characterized by the absence of intact provirus or proviruses confined to transcriptionally repressed genomic regions6, provide a unique opportunity to define mechanisms of cure-like immunity. Here, we integrate functional epitope mapping, single-cell transcriptomics, and infected cell elimination assays to identify networked HIV epitope targeting and a natural killer (NK)-like killer-cell immunoglobulin-like receptor (KIR) CD8 T cell subset as key features of exceptional control. This NK-like subset was selectively enriched within HIV-specific, but not CMV-specific, CD8 T cells from controllers, and was transcriptionally similar to highly cytotoxic subsets within the broader KIR+ CD8+ T cell compartment. Flow cytometry revealed increased frequencies of KIR CD8 T cells in exceptional controllers relative to antiretroviral therapy (ART)-suppressed individuals, and unexpectedly, enrichment of dual KIR+ NKG2A+ CD8 T cells. Functional depletion of KIR CD8 T cells significantly impaired the elimination of autologous HIV-infected CD4 T cells, despite preserved recognition by proliferative networked HIV-specific CD8 T cells. These findings thereby identify an NK-like KIR CD8 T cell state as a previously unrecognized component of exceptional HIV immunity that complements networked epitope targeting, providing a novel framework for immunotherapeutic HIV cure strategies.

immunology↗

bioRxiv2026

Isoform-Resolved Genetic Architecture of Epilepsy and SUDEP Reveals Divergent Brain and Heart Channelopathy Signatures

Sudden unexpected death in epilepsy (SUDEP) is the most devastating complication of epilepsy, yet the molecular features distinguishing individuals at risk remain poorly defined. Although epilepsy and SUDEP share substantial genetic overlap, fatal outcomes may arise when shared risk genes are differentially deployed across neuronal and cardiac systems. Here, we identify tissue- and isoform-level regulation as a key determinant of divergence between epilepsy and SUDEP risk. We performed a large-scale integrated analysis of genetic variants reported in epilepsy and SUDEP across 419 sequencing-based studies encompassing 35,659 individuals, and quantified gene-level burden using a Bayesian Poisson-Gamma rate ratio framework. This analysis revealed preferential enrichment of genes related to cardiac electrophysiology and contractile function in SUDEP, whereas epilepsy was dominated by genes involved in neuronal excitability and synaptic signaling. To determine how shared genetic loci are deployed across tissues, we integrated GTEx-based tissue expression profiles with long-read single-cell transcriptomic datasets from human heart and brain to resolve isoform-level expression patterns. These analyses revealed pronounced tissue-specific transcript architectures. Cardiac-associated genes, including HCN4, KCNH2, KCNE1, MYH6, MYO18B, and ATP1A2, showed heart-restricted isoform expression, whereas neuronal genes such as ADGRV1, CACNA1A, GRIN2B, HCN1, HCN2, KCNA1, SCN1A, SCN2A, and SCN8A. Importantly, several shared genes exhibited tissue-partitioned isoform expression, with distinct transcript repertoires in heart and brain, particularly across pathways related to ion transport, signaling, metabolism, and structural organization. Consistent patterns were observed in iPSC-derived cardiomyocytes and neurons, indicating that lineage-dependent deployment of shared genes is preserved in controlled systems. Together, these findings suggest that tissue-specific isoform regulation provides a mechanistic basis linking shared epilepsy genetics to SUDEP susceptibility, whereby the same genetic loci contribute to neuronal dysfunction in epilepsy and to cardiac vulnerability in SUDEP. This positions SUDEP as a neuro-cardiac interface disorder shaped by isoform-level regulatory divergence.

genetics↗

bioRxiv2023

Eosinophils are an endogenous source of IL-4 during filarial infections and contribute to the development of an optimal T helper 2 response

Interleukin-4 (IL-4) is a central regulator of type 2 immunity, crucial for the defense against multicellular parasites like helminths. This study focuses on its roles and cellular sources during Litomosoides sigmodontis infection, a model for human filarial infections. Our research uncovers eosinophils as a major source of IL-4, especially during the early phase of filarial infection. Using dblGATA mice lacking eosinophil and subsequently eosinophil-derived IL-4, we reveal their profound impact on the Th2 response. Lack of eosinophils impact Th2 polarization and resulted in impaired type 2 cytokine production. Surprisingly, eosinophil deficiency had no impact on macrophage polarization and proliferation as well as on antibody production. These findings shed new light on IL-4 dynamics and eosinophil effector functions in filarial infections. AUTHOR SUMMARYFilarial nematodes can cause severe diseases like onchocerciasis and lymphatic filariasis, posing a significant public health challenge in tropical regions, putting over a billion people at risk. The WHO categorizes these infections as neglected tropical diseases and aims to eliminate onchocerciasis transmission and lymphatic filariasis as a public health issue by 2030. To achieve this goal, we need a better understanding of the protective immune responses involved. Eosinophils have been identified as a key immune cell type in the well-established murine model for filarial infection, Litomosoides sigmodontis. However, their precise roles and interactions with other components of the type 2 immune response remain unclear. Our study reveals that eosinophils play a crucial role as a primary source of interleukin-4, the central cytokine in type 2 immunity. By using dblGATA mice, we found that the absence of eosinophils resulted in a reduced T helper 2 response but did not impact the alternative activation of macrophages or antibody production. In summary, our research uncovers an underappreciated function of eosinophils and their significant influence on type 2 immune responses.

immunology↗