Central Nervous System T-cell immune architecture, and not HIV burden, tracks with cognition under long-term viral suppression.

Overview

1. Division of Infectious Diseases and Global Health, Department of Medicine, University of California San Diego, La Jolla, California, United States of America
2. Department of Clinical and Biological Sciences, University of Turin, Torino, Italy
3. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
4. Vanderbilt Technologies for Advanced Genomics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
5. Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
6. Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America
7. Department of Psychiatry, University of California San Diego, San Diego, California, United States of America
8. Division of Geriatrics and Palliative Care, Department of Medicine, University of California San Diego, La Jolla, California, United States of America

Abstract

Despite effective antiretroviral therapy, HIV persists in the central nervous system (CNS) and may contribute to neuroinflammation and cognitive impairment. How viral persistence, immune responses, and regional CNS T-cell architecture relate to cognitive functioning remains unclear. We performed a cross-sectional, multi-compartmental immune-genomic study in 12 people with HIV on long-term viral suppression enrolled in the Last Gift rapid autopsy program. Quantitative HIV reservoir measures (total-episomal DNA, unspliced-multiply spliced RNA) and paired αβ T-cell receptor repertoire (TCRR) sequencing were performed in peripheral blood mononuclear cells and five CNS regions: hippocampus, frontal motor cortex, basal ganglia, occipital cortex, and spinal cord. Cognitive performance was assessed within one year of death. Tissue-resolved associations between cognition and HIV reservoir, TCRR architecture (richness, diversity, clonality), and pathogen-specific T-cell clonotypes (HIV, CMV, EBV, and riboflavin derivatives) were evaluated using participant-clustered multivariable models. False discovery rate was applied. HIV DNA and RNA were detectable across all tissues but were not associated with cognitive performance or TCRR metrics. Peripheral TCRR architecture was unrelated to cognition, whereas higher TCRR richness and diversity in the hippocampus and spinal cord were associated with worse verbal, motor, and attention/working memory scores. Higher TCRR richness in the spinal cord was also associated with better recall. T-cell receptor clonotype frequency distributions differed across CNS regions, consistent with regional immune compartmentalization. Epitope-inference analyses revealed pathogen-dependent associations: higher number of HIV–specific T-cell clonotypes in the basal ganglia was associated with better global and attention/working memory scores, whereas riboflavin derivative–specific clonotypes in frontal motor cortex were associated with better motor performance. CMV-specific clonotypes showed nominal associations with worse learning and memory. CNS–localized T-cell receptor architecture and antigenic imprinting related more closely to neurocognitive variability than quantitative measures of HIV persistence under viral suppression, highlighting regional specialization of T-cell responses as a potential correlate of brain health.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

No file of the authors' code could be read here: it is described below, and read at its source.

Tracing map

Proposed by the machine: these links were found in the paper and verified at the source, without human review. The map will receive a Zenodo DOI once one of the paper's authors has validated it with their ORCID.

What the map holds:

• 1 repository of the authors' code, each at its verified commit, with its license and how the link was found in the paper;
• 0 scripts, each with its path and the digest of its content;
• no match between paragraphs and code yet;
• neither the text of the paper nor the code itself.

Its JSON (tracing-map.json) is deposited on Zenodo with its DOI once the map is validated.

Data

No dataset and no data link were found in the paper.

Data Availability

Raw T-cell receptor sequencing reads have been deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA1424441. De-identified clinical, cognitive, TCRR, and HIV reservoir data are provided in the Supporting Information files as supplementary Excel spreadsheets.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 18 authors, 12 MeSH terms, 4 funders, 91 references.

Cite

This paper

Trunfio, M., Caballero, G., Gomez-Moreno, V., Mallal, S. A., Wanjalla, C. N., Jones, A., Beeri, K., Wells, A., LaMere, S., Gouaux, B., Franklin, D. R., Corley, M., Ellis, R. J., Moore, D. J., Letendre, S. L., Smith, D., Chaillon, A., & Gianella, S. (2026). Central Nervous System T-cell immune architecture, and not HIV burden, tracks with cognition under long-term viral suppression. PLoS pathogens, 22(6), e1014351. https://doi.org/10.1371/journal.ppat.1014351

The tracing map gets a citation of its own once an author has validated it and it has a DOI.

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.3389/fimmu.2026.1817754

Distinct roles of dopamine receptors in HIV latency reversal in a myeloid cell model.

Journal: Frontiers in immunology

In common: other condition, 1 reference

[2] doi:10.1128/jvi.02063-25

HIV transgenic mouse monocytes display increased <i>in vivo</i> migration across the blood-brain barrier associated with increased expression of genes associated with mononuclear leukocyte movement.

Journal: Journal of virology

In common: other condition, 1 reference

[3] doi:10.1186/s12974-026-03779-2

Cannabis use by people with HIV is associated with an anti-inflammatory immunometabolic phenotype in monocyte-derived macrophages.

Journal: Journal of neuroinflammation

In common: other condition, 1 reference

[4] doi:10.3389/fnins.2026.1775047 [code]

A multimodal imaging-based integrative framework for HIV-associated cognitive impairment and treatment response.

Journal: Frontiers in neuroscience

In common: other condition, 1 reference

[5] doi:10.1186/s40035-026-00565-1

Plant-derived mitochondria mitigate aging-related neurodegeneration by reprogramming microglial mitochondrial energy metabolism.

Journal: Translational neurodegeneration

In common: other condition, 1 reference

[6] doi:10.1038/s41593-026-02289-x [code]

Cerebellar aging is spatially heterogeneous and supports cognitive resilience in later life.

Journal: Nature neuroscience

In common: cognitive, 1 reference

[7] doi:10.1093/brain/awag043

Cytomegalovirus-induced T cell responses accelerate Alzheimer's disease progression in mice.

Journal: Brain : a journal of neurology

In common: other condition, 1 reference

[8] doi:10.1128/mbio.01294-26

Single-cell analysis of Powassan virus-infected brains reveals age-dependent neuroinflammatory crosstalk and progressive Alzheimer's-like APP/Aβ accumulation.

Journal: mBio

In common: other condition, 1 reference

[9] doi:10.1158/2767-9764.crc-25-0639 [code]

Interleukin-34-Induced Arg1+ Macrophages Play a Key Role in Breast Cancer Brain Metastasis.

Journal: Cancer research communications

In common: other condition, 1 reference

[10] doi:10.1016/j.xcrm.2026.102822

Synaptophysin autoantibodies mediate synaptic dysfunction in cerebellar ataxia.

Journal: Cell reports. Medicine

In common: other condition, 1 reference

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.