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.

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.

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.
[Display omitted]
•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.

Persistent human-adapted microbes can act as immunological "keystones," organizing host defense across tissues and shaping vulnerability under immune perturbation. More generally, tissue immunity is calibrated by persistent niche-resident organisms that tune compartment-specific thresholds of cytotoxicity and peripheral tolerance; keystone organisms represent the apex subset with multi-niche scope. Here we operationalize keystone organisms as pathogens whose containment requires coordinated engagement of multiple immune arms and whose residence is structured across anatomical niches. Using 18 curated immunological and evolutionary traits across 43 organisms, unsupervised analyses resolved four reproducible archetypes and identified a compact keystone set dominated by persistent herpesviruses and Mycobacterium tuberculosis. We then translated the clinical literature into a pathogen×immune-perturbation×niche tensor capturing where and when each organism emerges under defined immune deficits. We quantified "diagnostic breadth" with two complementary summaries: immune breadth (diversity of perturbations associated with emergence) and niche breadth (diversity of anatomical sites). Clinical emergence patterns perfectly separated trait-defined keystones from all other organisms and highlighted expanded niche breadth as the primary discriminator, whereas immune breadth showed no significant group separation. Finally, a mechanistic model integrating barrier disruption, latent reservoir activation, and tissue-resident immune control predicted clinical emergence from first principles-without fitting parameters to individual pathogens-and ranked true emergences 2.9-fold above chance among its highest-confidence predictions. Together, these results link evolutionary adaptation to clinically readable patterns of reactivation, motivate archetype-aware surveillance under immunosuppression, and provide a framework for immunogen design that prioritizes conserved, functionally constrained targets. Because the clinical tensor is literature-curated and sparse, "perfect separation" refers to keystone-vs-other discrimination within this dataset and is not a claim of universal out-of-sample performance.

Mutations in human immunodeficiency virus type 1 (HIV-1) enable the virus to evade recognition and killing by human leucocyte antigen (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, where HLA-HIV-1 associations were first demonstrated, to determine if ongoing evolution has occurred over more than 30 years of observation.
Cross-sectional HIV-1 subtype B sequences sampled at two time points, early in the epidemic (1992 - 2002, n = 182) and recently (2017 - 2022, n = 119) was utilised to examine HIV-1 evolutionary dynamics overtime. In addition, HIV-1 subtype B viral load records (one measurement per individual) from a five-year period early in the epidemic (1997 - 2002, n = 673) were compared with recent data (2017 - 2022, n = 363) to determine whether any population level HIV-1 adaptation has functional impact.
The analysis identified 120 amino acid positions across the Gag, Pol and Nef genes that showed significant change in proportion over time, with most (100/120; 83.3%) showing an increase in the proportion of one or more of the non-consensus amino acids. Of these positions, 35% (42/120) included one or more amino acids (48; 34 in Pol, 9 in Gag and 5 in Nef) reported as HLA-associated viral adaptations (35/48; 72.9%) or putative compensatory adaptations (11/48, 22.9%). Over two thirds of these adaptations (68.8%; 33/48) increased in proportion over time (range 5.8% to 46%), with eight becoming the consensus sequence. We also observed the accumulation of specific compensatory mutations within epitopes presented by protective HLA alleles. Other accumulated non-consensus amino acid changes (38/120) were predicted to weaken the peptide-HLA binding affinity of known HIV T cell epitopes, suggesting that the previously published list of HLA-associated viral adaptations used in our study was not exhaustive. Only two Pol reverse transcriptase non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations showed a significant change in proportion over time (K256Q [K101Q in reverse transcriptase region]; 22.9%, P-adjusted <0.001 and K258N [K103N in reverse transcriptase region]; 7.7%, P-adjusted = 0.020). Notably, we highlight the significant accumulation of adaptations (Gag: R76K, 40.8%, P-adjusted <0.001; H219Q, 25.8%, P-adjusted = 0.020 and R286K, 24.4%, P-adjusted = 0.036) that confer adaptation to both HLA-restricted T cell immune responses and antiretroviral therapy. 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.

Co-trimoxazole is a leading global cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Co-trimoxazole-induced SCAR are associated with HLA class I alleles including HLA-B*13:01 and HLA-B*38:02 in Southeast Asian (SEA) populations. However, the global generalizability of these associations is unknown but critical for population-appropriate risk stratification and diagnosis.
To determine HLA risk factors associated with co-trimoxazole-induced SJS/TEN and DRESS in populations from the United States (US) and South Africa (SA).
We performed high-resolution HLA typing on dermatologist-adjudicated co-trimoxazole-induced SCAR patients in the US (n=63) and SA (n=26) compared to population controls. Peptide binding and docking analyses were performed using MHCcluster2.0 and CB-Dock2.
In a multiple logistic regression model, HLA-B*44:03 (Pc<0.001, OR: 4.08), HLA-B*38:01 (Pc<0.001, OR: 5.66), and HLA-C*04:01 (Pc=0.003, OR: 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the US. HLA-B*44:03 was also associated with co-trimoxazole-induced DRESS in SA (Pc=0.019, OR: 10.69). Distinct HLA-B variants with shared peptide binding specificities (SPBS) and HLA-C*04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the US, respectively. The SEA risk allele HLA-B*13:01, with SPBS to HLA-B*44:03, was identified in just 1/63 US SCAR patients.
HLA alleles with SPBS to SEA-related risk alleles including HLA-B*44:03 (SPBS with HLA-B*13:01) and HLA-B*38:01 (SPBS with HLA-B*38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and SA. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR.
HLA alleles including HLA-B*13:01 and HLA-B*38:02 are risk factors for co-trimoxazole-induced SCAR in Asian populations. However, the generalizability of these associations to other global populations is unknown but critical for population-appropriate risk stratification and diagnosis.
HLA alleles with shared peptide binding specificities (SPBS) to Asian-related risk alleles including HLA-B*44:03 (SPBS with HLA-B*13:01) and HLA-B*38:01 (SPBS with HLA-B*38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and South Africa.
HLA alleles previously associated with co-trimoxazole-induced SCAR do not identify risk across populations. However, HLA alleles with SPBS provide biological plausibility and strategies for global and population-appropriate clinical risk stratification and diagnosis of cotrimoxazole-induced SCAR.