Simon Mallal

Mutations in human immunodeficiency virus type 1 (HIV-1) enable the virus to evade recognition and killing by HLA-restricted T cells. These viral adaptations are specific to the HLA type of individuals and are therefore evident as HLA allele-HIV sequence associations at the population level. Most studies of HLA associations have been cross-sectional and may not capture selective changes that have accumulated to reach fixation at the population level, with potential impacts on viral replication and clinical outcomes. In this study, we examined the population from Western Australia to determine if ongoing evolution has occurred over more than 30 years of observation. In addition, we utilised HIV-1 subtype B viral load records (one measurement per individual) from a five-year period early in the epidemic (1997–2002) compared with recent years (2017–2022) to determine whether any population level HIV-1 adaptation has functional impact. Results showed that 120 amino acid positions across the Gag, Pol and Nef genes showed significant change in proportion over time. Of these positions, 35% included one or more amino acids reported as HLA-associated viral adaptations or putative compensatory adaptations. Over two thirds of these adaptations increased in proportion over time, with eight becoming the consensus sequence. We also observed the accumulation of specific compensatory mutations within epitopes presented by protective HLA alleles. There was a significant increase in baseline viral load between the two time periods examined (p < 0.001, OR = 2.4). These findings provide evidence of ongoing HIV-1 adaptation to human immune responses at the population level, with a likely increase in virulence, as captured by viral load. The enrichment of viral adaptations within circulating strains may lead to loss of immune targets for prevalent immune responses and has important implications for vaccine development and cure strategies.

Importance: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, potentially fatal hypersensitivity syndrome with 3% to 10% mortality, and lamotrigine, a first-line treatment for bipolar and seizure disorders, is among the top 5 causative agents of DRESS in the United States and globally. Commercial panels test HLA-B*15:02 and HLA-A*31:01 for risk of carbamazepine-associated severe cutaneous adverse reactions; however, these are not validated for lamotrigine-induced DRESS, and current reports from these commercial assays could therefore provide false reassurance. No HLA associations with lamotrigine-induced DRESS have been established in US populations.

Objective: To identify HLA genetic variants associated with lamotrigine-induced DRESS in a US population.

Design, Setting, and Participants: This matched case-control study was conducted at 2 US academic medical centers (Vanderbilt University Medical Center and Mass General Brigham). Patients with lamotrigine-induced DRESS confirmed by Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) criteria (score ≥4) were prospectively enrolled between April 2016 and June 2025. Lamotrigine-tolerant controls were matched 10:1 from the Vanderbilt BioVU biobank on sex, self-reported race, and age. HLA typing included class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DPB1, HLA-DQA1, HLA-DQB1, and HLA-DRB1) loci for case (high-resolution typing) and control (imputed from genotyping array data) participants.

Main Outcomes and Measures HLA class I and II alleles and haplotypes were tested using logistic regression with Bonferroni correction for their association with lamotrigine-induced DRESS.

Results: This study included 29 patients with lamotrigine-induced DRESS (case participants; median [IQR] age, 33 [24-56] years; 25 female [86.2%]; 2 Asian [6.9%], 2 Black [6.9%], 23 White [79.3%], and 2 unknown race [6.9%]) and 290 matched control participants. HLA-A*32:01 was associated with lamotrigine-induced DRESS (41.4% [12 case participants] vs 4.1% [12 control participants]; odds ratio [OR], 16.4; 95% CI, 6.4-42.5; Bonferroni-corrected P < .001). No other alleles or class II loci showed significant associations after correction. The A*32:01 ~ B*44:02 haplotype was enriched (OR, 18.4; 95% CI, 4.6-83.8; Bonferroni-corrected P = .001) in lamotrigine-induced DRESS.

Conclusions and Relevance: In this case-control study, HLA-A*32:01 was associated with lamotrigine-induced DRESS in a US population. Given that HLA-A*32:01 is not included in existing commercial pharmacogenomic panels, adding this marker could improve preprescription DRESS risk identification for lamotrigine.

Abstract
Introduction
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron loss and eventual paralysis. While autoimmune mechanisms have long been suspected to contribute to ALS pathology, disease-associated antigen targets have remained elusive.
Methods
We analyzed if ALS was associated with increased autoreactive T cell responses towards TDP-43, SOD1, and C9orf72, compared to healthy controls. Peptide megapools consisting of 15 amino acid peptides overlapping by 10 residues spanning the entire sequence was synthesized for each protein. Fluorospot assays were used to measure T cell responses to the peptide pools by measuring release of interferon-γ (IFNγ), interleukins 5 (IL-5) and 10 (IL-10).
Results
We demonstrate that the ALS-associated protein C9orf72 is a major antigenic target in ALS. Epitope mapping revealed multiple immunogenic regions across the C9orf72 protein. While the reactivity was found broadly in ALS subjects, the responses were particularly high ALS donors who carried the C9orf72 hexanucleotide repeat expansion mutation in the non-coding regions of the gene. Importantly, IL-10-mediated responses were significantly higher in individuals with longer predicted survival, suggesting a regulatory and potentially protective influence on disease progression.
Conclusion
Together, these findings identify the first defined target of autoreactive T cell responses in ALS, and support the hypothesis that disease trajectory is in part shaped by the balance of inflammatory and counter-inflammatory T cell activity.
Funding Source
Supported by LJI & Kyowa Kirin, Inc. (KKNA- Kyowa Kirin North America), the Swedish Research Council (salary for E.J., grant references 2024-00175), the Freedom Together Foundation (to D.S.), and in part by the Intramural Research Program, NINDS, NIH (A.
Topic Categories
Neuroimmunology (NEUR)

HLA class I alleles confer a striking risk for T cell–mediated drug hypersensitivity, yet positive predictive values are low—typically under 10% and as low as 0.12% for some drug–HLA pairs. We propose that persistent, human-adapted pathogens—notably herpesviruses—focus postnatal immune memory on conserved epitopes in the tissue niches where viral control occurs (the Keystone Epitope Theory). The phylogenetic basis for this proposal is that herpesviruses and their vertebrate hosts have co-adapted over hundreds of millions of years, and that this co-evolutionary relationship is replayed ontogenetically as each individual acquires these infections and builds tissue-specific immune memory. When a drug-altered self-peptide approximates the geometry of such a target and is presented by the same risk HLA in the same niche at sufficient density, pre-existing tissue-resident memory T cells (TRM) may be recruited, breaching local regulatory equilibria and driving immunopathology. We synthesize three strands of evidence: (i) heterologous immunity, in which virus-imprinted TRM cross-recognize drug-modified self; (ii) antigen presentation in the same tissue where antiviral memory already resides, which helps explain why injury is tissue-restricted; and (iii) public and private TCR solutions that bridge viral and self-targets. Beginning with T cell–mediated drug hypersensitivity as an empirical anchor, we extend this framework to EBV-associated multiple sclerosis and transplant rejection and conclude with proposed experimental validation strategies that may be applicable more broadly to T cell–mediated hypersensitivity and autoimmunity. From keystone protection to clinical misdirection. Postnatal immune focusing concentrates durable tissue-resident memory on conserved peptide–HLA targets in specific niches. Modified self-peptides (drug-altered or post-translationally modified) that approximate this geometry, presented by the same risk HLA in the same tissue, can recruit entrenched antiviral programs and, when mimicking ligand burden is sufficient, exceed local inhibitory set-points. The clinical result is high NPV but low PPV for HLA risk alleles. Abbreviations: TRM, tissue-resident memory T cell; PTM, post-translational modification.

We propose that persistent, human-adapted DNA organisms shape postnatal immunity by focusing responses on functionally constrained epitopes within tissue niches. Here, we examine rapidly evolving RNA viruses and tumors through that lens. We propose that their persistence is promoted by 2 coupled mechanisms: (i) immunodominance steering toward mutable “decoy” epitopes that contribute little to durable control, and (ii) antigen display control that reduces cytotoxic T lymphocyte (CTL) recognition while preserving inhibitory natural killer (NK) receptor engagement, for example via HIV Nef/Vpu effects on HLA-A and HLA-B and through HLA-E/NKG2A pathways. Tumors show analogous vulnerabilities through altered class I expression and reinforcement of inhibitory signaling. Using HIV as the primary model, we distinguish HLA-associated viral adaptation mechanisms and highlight evidence consistent with a subset of adaptations that preserve detectable T-cell recognition while being associated with reduced antiviral effector function. We then consider the degree to which this framework can be extended to hepatitis C virus (HCV), influenza, SARS-CoV-2, and tumor immunoediting. We conclude with 3 vaccine design principles: prioritize epitopes where substitutions carry measurable fitness costs, avoid immunogens dominated by mutable targets, and account for antigen presentation context and inhibitory NK signaling when evaluating epitope choice. We distinguish established observations from testable predictions and outline experiments needed to evaluate the framework. We frame the analysis conditionally on the keystone-imprinting premise, which is developed in companion work.

Lung tissue-resident memory T (TRM) cells are critical for frontline immunity, yet they undergo rapid attrition in the mouse lung. Whether this paradigm applies to humans has remained unknown. Here we present a comprehensive analysis of T cells from human lungs, characterizing the prevalence and properties of lung TRM cells specific to a broad spectrum of pathogens. Using a T cell receptor-guided approach that integrates single-cell transcriptomics with paired T cell receptor repertoire profiling, we mapped the pathogen specificity of more than 87,000 lung T cells across 40 individuals, the majority of whom harbored TRM cells specific to multiple pathogens. We confirmed that a large fraction of lung TRM clones persist in the lung for many months to years. Thus, in contrast to those of mice, human lungs retain a stable and varied pool of pathogen-specific TRM cells, suggesting that strategies to bolster these responses could provide durable protection against severe lung infections.

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.

Paramyxoviruses comprise a diverse family of viruses that threaten global human health through direct infection and zoonotic transmission. Understanding adaptive immune responses to these viruses is critical for characterizing host-pathogen interactions and evaluating vaccine performance. Here, we systematically map human CD4+ T cell epitopes across Nipah and measles viruses, two prototypic members of the Paramyxoviridae family. We identify broad epitope repertoires, including 186 Nipah and 288 measles epitopes recognized in multiple donors. Epitopes are characterized for HLA binding and inferred restrictions, and broader HLA binding correlates with immunodominance. We observe overlapping T cell targets between viruses, with N and F proteins immunodominant in both and L additionally dominant in Nipah. We define conserved T cell epitope regions (CTERs) in Nipah virus that encompass 17% of the proteome, capture over 50% of T cell responses, show high conservation across different Henipaviruses, and elicit broadly cross-reactivity, supporting broad population coverage.
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•Systematic mapping reveals broad CD4+ T cell epitopes in Nipah and measles•HLA binding promiscuity correlates with epitope immunodominance•Conserved T cell epitope regions (CTERs) capture over 50% of Nipah T cell responses•CTERs elicit cross-reactive T cells across diverse Paramyxoviruses
Tarke et al. systematically map CD4+ T cell epitopes in measles and Nipah viruses, revealing broad and overlapping immune targets. They define conserved T cell epitope regions (CTERs) that drive cross-reactive T cell responses across Paramyxoviruses, providing a framework for vaccine strategies that enhance population coverage and pandemic preparedness.

COVID-19 has individualized disease trajectories during both acute infection and long-term recovery (“long COVID”), highlighting the need for biomarkers for the disease’s heterogeneity. In this study, we introduce “metabo-time,” a quantitative metabolic signature derived from serum metabolites and lipoproteins measured via nuclear magnetic resonance (NMR) spectroscopy. Metabo-time was stablished across two longitudinal and demographically diverse cohorts and validated in independent populations. It captures patient-specific metabolic states throughout the disease course. Longitudinally, it is disrupted during acute infection and normalizes during recovery, mirroring systemic oxidative stress and immune response dynamics. Importantly, metabo-time outperforms actual recovery time in predicting patients’ individualized normalization of oxidative stress. At baseline, it distinguishes infection severity and is associated with transcriptional activity in the upper airway. These findings establish metabo-time as a robust marker for tracking COVID-19 heterogeneity and progression, with potential utility for stratifying patients and informing therapeutic strategies, particularly in the context of SARS-CoV-2 recovery.

Mammarenaviruses are classified into Old World and New World viruses (Old World arenaviruses [OWAs] and New World arenaviruses [NWAs]). Characterization of antigens recognized by human T cells is essential for identifying immunodominant targets, informing vaccine design, and performing immunological assessments. Here, we select the Lassa virus (LASV) as a prototype OWA to map the human CD4 T cell epitope repertoire. We then calculate conservation in different LASV lineages and other representative OWAs and NWAs and define conserved T cell epitope regions (CTERs) using Lassa as the OWA prototype and Junin as the NWA prototype. We show that these CTERs are able to broadly cross-recognize other OWA or NWA sequences. We validate our findings in humans immunized with an experimental glycoprotein complex (GPC) LASV vaccine or infected with lymphocytic choriomeningitis mammarenavirus (LCMV), as well as in the mouse model immunized with a stabilized GPC vaccine candidate. Our results on mammarenavirus-specific T cell immunity contribute to guiding the development of next-generation mammarenavirus vaccines.