Xu J, Wang YX, Huang P
… +4 more, Zhang YN, Sun H, Zhan TZ, Xia CM
PLoS Pathog
· 2026 Jun · PMID 42340953
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Schistosomiasis remains a critical global health issue, necessitating novel therapies due to emerging praziquantel resistance. We previously developed a patented praziquantel derivative, DW-3-15, which demonstrated poten...Schistosomiasis remains a critical global health issue, necessitating novel therapies due to emerging praziquantel resistance. We previously developed a patented praziquantel derivative, DW-3-15, which demonstrated potent broad-spectrum schistosomicidal activity through SjHAT1 inhibition. Here, the full-length SjHAT1 cDNA is cloned by rapid amplification of cDNA ends methods. The protein encoded by the cDNA retains conserved catalytic residues of acetyltransferases although sharing 34% identity with mammalian orthologs. Enzyme activity analysis reveals that recombinant SjHAT1 exhibits 130 μU/mL histone acetyltransferase activity at 25°C for 60 min, and is completely inhibited by DW-3-15 at a concentration of 50 μM. However, DW-3-15 has no effect on the enzymatic activity of the human ortholog HAT1. Phylogenetic analyses place SjHAT1 in a distinct clade, and molecular docking results indicate significant divergence compared to its human ortholog HsHAT1. The expression profiling of SjHAT1 reveals stage- and sex-specific patterns. Fluorescence in situ hybridization localizes SjHAT1 predominantly in female vitellaria and male parenchyma near the gynecophoral canal. Knockdown of SjHAT1 reduces worm survival by 57.5% in vivo, suppresses female oviposition by 90.8% in vitro and 79.2% in vivo, and disrupts ovarian and vitelline architecture. RNA-sequencing analysis reveals that SjHAT1 knockdown disrupts β-alanyl-tryptamine (BATT) pheromone signaling via downregulation of aromatic L-amino acid decarboxylase (AADC) in males and multidrug resistance-associated protein 4 (MRP4) in females. Given that BATT is essential for inducing female sexual development and egg production, the observed transcriptional dysregulation provides mechanistic evidence for disrupted intersexual communication. Our findings identify that SjHAT1 is a central regulator of schistosome reproductive biology. These sex-specific mechanisms highlight SjHAT1 as a potential therapeutic target for treatment and control of schistosomiasis.
Mukhiya R, Loughland JR, Dooley NL
… +10 more, Pava Z, Oyong DA, Andrew DW, Hamelink J, Berry K, McCarthy JS, Barber BE, Lopez JA, Engwerda CR, Boyle MJ
PLoS Pathog
· 2026 Jun · PMID 42335170
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NK cells are innate and adaptive responders to malaria, with functional responses underpinned by NK cell heterogeneity. One driver of NK cell heterogeneity is latent CMV infection. Latent CMV infection negatively impacts...NK cells are innate and adaptive responders to malaria, with functional responses underpinned by NK cell heterogeneity. One driver of NK cell heterogeneity is latent CMV infection. Latent CMV infection negatively impacts adaptive immunity to malaria, but whether CMV-mediated changes to the NK cell compartment also impact innate responses to malaria is unknown. We investigated the impact of latent CMV infection on innate NK cell responses to the malaria parasite in vitro in malaria naïve adults, and in vivo NK cell responses during a first controlled human malaria infection. We found that transcriptional activation of NK cells by parasites was attenuated in CMV seropositive individuals. Further, during a first malaria infection, markers of NK cell activation and cytotoxicity were reduced. This attenuated response was not restricted to a single NK phenotype but occurred across diverse NK cell phenotypes. Consistent with a global NK cell attenuation, IL12 production from myeloid cells, a response that supports NK cell activation on exposure to P. falciparum parasites, was lower in CMV infected individuals. Linking NK cell activation to clinical outcomes, NK cell perforin expression was associated with parasite control in CMV seronegative individuals during first malaria infection. Data highlight the interplay between pathogens and the host-immune response that influence clinical outcomes.
Zhang C, Gan Q, He Y
… +3 more, Zhang Y, Wu X, Lv S
PLoS Pathog
· 2026 Jun · PMID 42335164
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Streptococcus pneumoniae is an important human pathogen that causes severe threat to the lives of children under 5 years old and the elder. Colonization in the nasopharynx is the prerequisite for pneumococcal disease. Ho...Streptococcus pneumoniae is an important human pathogen that causes severe threat to the lives of children under 5 years old and the elder. Colonization in the nasopharynx is the prerequisite for pneumococcal disease. However, few attentions have been paid to prevent pneumococcal disease by eliminating colonization. In this work, pneumococci were found to undergo methionine starvation in the nasopharynx. In the in vitro experiments, methionine starvation induces the cytoplasmic acidification of S. pneumoniae, which benefits bacterial survival. Intracellular acidification was also observed in pneumococci colonizing the nasopharynx. We found that increased intracellular lactate level under methionine starvation causes intracellular acidification. Surprisingly, intracellular acidification elevates intracellular level of H2O2, a metabolite commonly considered harmful for bacteria, to enhance bacterial survival under methionine starvation. H2O2 inhibits bacterial autolysis that can be induced by methionine starvation to enhance bacterial survival. To impair pneumococcal survival and colonization, sodium oxamate was used as a drug by elevating intracellular pH through inhibiting lactate production. Interestingly, we found that penicillin alone could not impair pneumococcal survival and colonization efficiently due to the inhibited killing by intracellular acidification. However, the combination of sodium oxamate and penicillin not only killed bacteria effectively, but also almost eradicated pneumococcal colonization. To the best of our knowledge, it is the first time that H2O2 production was reported to be induced by intracellular acidification to benefit bacterial survival. Besides, sodium oxamate was found to be a novel drug for eradicating pneumococcal colonization by targeting intracellular acidification, particularly in the combination with penicillin.
Shea AE, Kuo S, Gupta S
… +5 more, Smith SN, Appaji T, Mitchell T, Mobley HLT, Pearson MM
PLoS Pathog
· 2026 Jun · PMID 42335124
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Proteus mirabilis is a leading cause of complicated urinary tract infections (UTIs). Prior work showed P. mirabilis metabolizes sugars during experimental UTI, yet the role of sugar import systems in pathogenesis remains...Proteus mirabilis is a leading cause of complicated urinary tract infections (UTIs). Prior work showed P. mirabilis metabolizes sugars during experimental UTI, yet the role of sugar import systems in pathogenesis remains poorly defined. To investigate this, we generated a panel of 47 targeted mutants in predicted sugar transporter genes and assessed their growth in vitro and fitness in vivo. Growth screening in nutrient-rich and minimal media revealed carbon source-dependent defects in several phosphotransferase system (PTS) mutants, including ptsH and ptsI. Pooled insertion sequencing (In-seq) identified xapB, ptsH, and ptsI as in vivo fitness factors, with validation in a traditional murine co-challenge model. Functional studies showed that xapB, annotated as a xanthosine permease, did not support xanthosine or guanosine uptake in P. mirabilis, suggesting misannotation. Dissection of the PTS network revealed that a triple mutant lacking scrA, ulaC, and ptsG recapitulated the ptsH phenotype in vivo. To evaluate whether increased sugar availability exacerbates these defects, we modeled glucosuria using the SGLT2 inhibitor dapagliflozin in CBA/J mice. Dapagliflozin treatment significantly increased urinary glucose and enhanced P. mirabilis colonization. There was an inverse correlation between colonization and urinary glucose, but only in untreated mice. These findings reveal limitations in genome-based transporter annotation, establish a functional link between sugar import and P. mirabilis fitness during UTI, and demonstrate that host metabolic conditions such as glucosuria can influence the severity of infection.
Pham AM, Ortiz LE, Chen H
… +2 more, Christensen N, Kwun HJ
PLoS Pathog
· 2026 Jun · PMID 42335122
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Research on small DNA tumor viruses has been limited by the lack of advanced virus culture systems that support robust viral infection. Thus, studies involving Merkel cell polyomavirus (MCPyV), a human oncogenic polyomav...Research on small DNA tumor viruses has been limited by the lack of advanced virus culture systems that support robust viral infection. Thus, studies involving Merkel cell polyomavirus (MCPyV), a human oncogenic polyomavirus, primarily rely on model systems that might not fully reflect the native MCPyV skin infection. To decipher the mechanisms of natural human polyomavirus skin infection, we developed a 3D spheroid system for producing MCPyV virions derived from primary human dermal fibroblasts. The 3D spheroid microenvironment enhanced viral genome replication and genome maintenance, enabling the production and secretion of MCPyV virions that were associated with infectious extracellular vesicles (MCPyV-EVs) into the culture medium. EV-mediated MCPyV infection was moderately susceptible to antibody-mediated neutralization, implying the importance of EV-mediated MCPyV infection in host immune evasion. Proteomic analysis revealed a significant decrease in antiviral interferon-stimulated genes (ISGs) within MCPyV-EVs, indicating that MCPyV utilizes EVs as a means to enhance susceptibility of uninfected cells for viral transmission and infection. RNA-Seq gene expression analysis of primary human dermal fibroblasts with MCPyV infection suggests that the 3D microenvironment could replicate Wnt-mediated epithelial remodeling in the skin. Our results imply that Wnt-driven wound healing processes, accelerated by skin damage, UV radiation, and aging, regulate MCPyV viral replication and productive infection, which may promote the development of MCPyV-associated MCC.
Nowakowski A, Elguero E, Patterson K
… +13 more, Boissière A, Degrugillier F, Sidobre C, Arnathau C, Grentzinger P, Willaume E, Talman AM, Malleret B, Boundenga L, Ngoubangoye B, Prugnolle F, Wassmer SC, Rougeron V
PLoS Pathog
· 2026 Jun · PMID 42335105
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The health consequences of Plasmodium infections in wild great apes, particularly in asymptomatic animals, remain poorly understood. This study investigated the hematological and immune impacts of natural malaria infecti...The health consequences of Plasmodium infections in wild great apes, particularly in asymptomatic animals, remain poorly understood. This study investigated the hematological and immune impacts of natural malaria infections in 27 semi-wild chimpanzees (Pan troglodytes troglodytes) from Gabon. Using PCR and qPCR to identify infected individuals, and MinION sequencing to determine the Plasmodium species involved, results showed a 48.15% overall Plasmodium infection rate, with frequent multi-species co-infections involving Plasmodium gaboni, Plasmodium reichenowi, and Plasmodium vivax-like parasites. In addition, infected chimpanzees were younger than non-infected individuals, although no significant association was detected between age and parasitemia levels, and this interpretation should be considered cautiously given the limited number of juvenile animals included in the study. Multi-species infections, particularly triple infections involving P. vivax-like parasites, were associated with higher parasitemia levels. Profiling of 15 hematological markers and 8 cytokines/chemokines known to be associated with malarial infections in humans revealed significant alterations in infected chimpanzees, including elevated urea, reduced creatinine, and increased systemic concentrations of pro-inflammatory (TNF, IL-1β, CCL3) and anti-inflammatory (IL-10) cytokines. Ex vivo PBMC stimulation yielded higher IL-10 in infected than non-infected individuals, indicating a regulatory-skewed cytokine response at the time of sampling. These results suggest that malaria in chimpanzees is associated with systemic immune modulation and accompanied by signs of physiological stress, including potential renal dysfunction. This study challenges the assumption that chronic Plasmodium infections are entirely benign in great apes and highlights the need to integrate immunological health indicators into conservation strategies. Broader immune profiling and longitudinal studies will be essential in the future to assess long-term health outcomes and resilience in these endangered populations.
PLoS Pathog
· 2026 Jun · PMID 42330076
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Deep mutational scans across receptor-binding domains (RBDs) of diverging SARS-CoV-2 variants reveal ongoing changes to the effects of mutations, a phenomenon known as epistasis. Careful accounting for these altered muta...Deep mutational scans across receptor-binding domains (RBDs) of diverging SARS-CoV-2 variants reveal ongoing changes to the effects of mutations, a phenomenon known as epistasis. Careful accounting for these altered mutational effects is important in viral surveillance and forecasting, and more broadly, for understanding the impacts of epistasis on real-world viral evolutionary trajectories. Using a yeast-display RBD deep mutational scanning (DMS) platform, we measure the impacts of virtually all single amino acid mutations and single-residue deletions in the Omicron KP.3.1.1 and LP.8.1 RBDs on folded RBD expression and binding affinity for the human ACE2 receptor. Our comprehensive maps reveal patterns of evolutionary accessibility and constraint at single-residue resolution and, when compared to prior datasets, highlight sites whose amino acid preferences continue to change across viral variants. Notably, sites 455, 456, and 493 - which have exhibited repeated substitutions and epistatic dependencies across Omicron subvariants going back to BA.1 - again demonstrate altered patterns of mutational accessibility and constraint. Therefore, it appears that these hotspots of repeated RBD evolution have not yet converged on fixed amino acid solutions but instead remain sites of ongoing epistatic reconfiguration. We compare our measurements of direct RBD:ACE2 affinity with recently published measurements of mutation impacts on ACE2 binding in the full quaternary spike context, which also integrates the effects of spike conformational dynamics; our analysis uncovers mutations like H505W that could favor adoption of the down/closed RBD conformation as a viral strategy for future antigenic evolution.
Tian M, Davis J, Cheng HL
… +8 more, Thompson LM, Tuchel ME, Williams AC, Yin A, Wilder B, DiBiase I, Seaman MS, Alt FW
PLoS Pathog
· 2026 Jun · PMID 42330040
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In germinal centers, activated B cells modify their antigen receptors through somatic hypermutation (SHM), followed by antigenic selection that favors expansion of high affinity B cells. The affinity maturation process i...In germinal centers, activated B cells modify their antigen receptors through somatic hypermutation (SHM), followed by antigenic selection that favors expansion of high affinity B cells. The affinity maturation process is critical for development of broadly neutralizing antibodies (bnAbs) against the human immunodeficiency virus-1 (HIV-1). BnAbs have been isolated from some people living with HIV-1. Because these antibodies target conserved epitopes of the HIV-1 Envelope (Env) protein, they inhibit a broad spectrum of viruses. Eliciting bnAbs by vaccination is a top priority for HIV-1 prevention, but reproducing the lengthy maturation of bnAbs is a major challenge. The problem is typified by VRC01 class antibodies, which recognize the CD4 binding site of HIV-1 Env protein. To reach the CD4 binding site, antibodies need to navigate through adjacent glycans. Accommodating the glycans requires multiple SHMs in germinal center (GC) B cells, including infrequent events. For this reason, VRC01 vaccine development often stalls at this point. We have generated a mouse model aimed at providing a potential solution for navigating this vaccine design impediment. To this end, we made a mouse model that expresses a stalled VRC01 intermediate conditionally in GC B cells. This system has three advantages: 1) direct expression of the intermediate obviates prior immunization steps, thereby shortening the immunization scheme; 2) the conditional expression system bypasses tolerance control checkpoints that sometimes delete B cells expressing bnAbs; 3) the intermediate responds to immunization in GCs, the physiological site of affinity maturation. With this model, we established an immunization method to mature the VRC01 intermediate into heterologous neutralizing antibodies against viruses with a native glycan shield. Since high mutation load is common among bnAbs, the germinal center conditional expression system could provide a general tool for boost immunogen design to overcome roadblocks in the maturation pathway.
Zhao L, Fu J, Peddiraju S
… +6 more, Chen H, Huang K, Zhang Y, Gupta N, Jiang Q, Jia H
PLoS Pathog
· 2026 Jun · PMID 42313874
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All alveolates including apicomplexan parasites contain an inner membrane complex (IMC) underneath the plasma membrane. The IMC is synthesized de novo during asexual replication (including endodyogeny, endopolygeny, and...All alveolates including apicomplexan parasites contain an inner membrane complex (IMC) underneath the plasma membrane. The IMC is synthesized de novo during asexual replication (including endodyogeny, endopolygeny, and schizogony) and serves as a crucial scaffold for supporting cytoskeletal structures and the glideosome machinery for parasite locomotion. However, the mechanism(s) underlying the membrane biogenesis in the IMC are not well understood. Using a clinically-relevant and globally-prevalent pathogenic protist model, Toxoplasma gondii, we identified the TgVPS13A bridging the IMC to the endoplasmic reticulum (ER) - the major site of phospholipid synthesis. The multi-modular TgVPS13A plays a crucial role in the IMC biogenesis, functioning in concert with an ER-resident VAP protein (TgVAP) and a novel lipid scramblase (TgDAT1). TgDAT1 is recruited for the progeny formation sites during the early stages of budding. Conditional depletion of TgVPS13A, TgDAT1 or TgVAP results in collapse of the inner membrane complex, leading to parasite death, as visualized by endodyogeny-specific organelle markers. GFP-Lact-C2, a biosensor of phosphatidylserine and phosphatidylthreonine lipids made in the ER and enriched in the IMC, also mislocalizes upon protein depletion. In conclusion, we propose that TgVPS13A, together with TgVAP and TgDAT1, bridge the ER and IMC and mediate the inter-organelle transport of lipids, thus contributing to the organelle biogenesis and daughter budding in T. gondii.
Le NTT, Mercer RCC, Fang C
… +7 more, Sundaravadivelu A, Labadorf AT, Lin W, Kwan J, Blum B, Emili A, Harris DA
PLoS Pathog
· 2026 Jun · PMID 42313800
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Prion propagation, in which the cellular prion protein (PrPC) is conformationally converted into an infectious structure (PrPSc), has been extensively studied. However, the molecular mechanism responsible for the neuroto...Prion propagation, in which the cellular prion protein (PrPC) is conformationally converted into an infectious structure (PrPSc), has been extensively studied. However, the molecular mechanism responsible for the neurotoxicity of prions remains unclear. Synaptic loss is one of the earliest events in both in vivo and in vitro models of prion disease. We previously developed a neuronal cell culture model to analyze the mechanisms of prion-induced synaptic degeneration in a physiologically relevant setting. Using this system, we showed that exposure of hippocampal neurons to PrPSc engages a NMDAR/p38 mitogen-activated protein kinase (MAPK) signaling pathway that results in rapid, PrPC-dependent loss of synaptic transmission and retraction of dendritic spines. To comprehensively identify the components of this synaptotoxic signaling pathway, we measured changes in the phosphoproteome and transcriptome of hippocampal neurons exposed to PrPSc while they were undergoing the process of dendritic spine retraction. We then used these data as input into the L1000 and P100 databases of transcriptomic and proteomic drug signatures, leading to the discovery of 17 compounds that were able to prevent PrPSc-induced spine retraction. These compounds converged on three protein kinase targets: Ca2+/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), and glycogen synthase kinase 3β (GSK3β). Using immunocytochemical staining, we confirmed that PrPSc treatment of hippocampal neurons induced phosphorylation of the three kinases and caused their rapid translocation to dendritic spines. Along with N-methyl-D-aspartate receptors (NMDARs) on the neuronal surface, which trigger an initial influx of Ca2+ in response to PrPSc, these kinases constitute key nodes in a signaling network that mediates prion synaptotoxicity. Taken together, our results provide new insights into the mechanisms of prion neurotoxicity, and they identify novel molecular targets and inhibitory compounds that can be utilized for therapy of prion diseases.
Zhang X, Shu X, Liu Y
… +5 more, Zhao Y, Chen H, Xiong F, Kang M, Cao C
PLoS Pathog
· 2026 Jun · PMID 42308195
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Cryptococcus neoformans is the leading cause of fungal meningoencephalitis. Cellular heterogeneity during cryptococcal infection contributes to host adaptation and fungal pathogenesis. C. neoformans titan cells and seed...Cryptococcus neoformans is the leading cause of fungal meningoencephalitis. Cellular heterogeneity during cryptococcal infection contributes to host adaptation and fungal pathogenesis. C. neoformans titan cells and seed cells represent enlarged and small-sized morphotypes, respectively, which exhibit distinct transcriptional profiles and can be induced by environmental factors. In this work, we describe a distinct small morphotype of C. neoformans, referred to as ovoid cells. The formation of ovoid cells is promoted by host-related conditions such as nutrient limitation and elevated CO2 levels, which was observed during the late stage of cryptococcal infection. In addition to their smaller size compared to typical yeast cells, ovoid cells highly express OSP1, a marker distinguishes ovoid cells from other small morphotypes, including seed cells and titanides. These cells exhibit an increased budding and proliferation rate, which is consistent with transcriptome data that ovoid cells upregulate cell cycle related genes. We further demonstrate that the glucose repression signaling pathway and the cAMP/PKA pathway are involved in ovoid cell formation in C. neoformans. Ovoid cells show reduced fungal virulence but enhanced tolerance under long-term fluconazole treatment, indicating their important role in the balancing virulence and antifungal tolerance within C. neoformans populations.
Fuhrmann E, Toda S, Leins J
… +18 more, Cetraro P, Deshpande V, Rowell J, Chapman EA, Jacobsen C, Kropp KA, Lamers MM, Loliashvili E, Saleban M, Verstraten R, Vogt C, Wongwiwat W, Ouwendijk WJD, Viejo-Borbolla A, White RE, Wilson AC, Burgess HM, Depledge DP
PLoS Pathog
· 2026 Jun · PMID 42302084
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Poly(A) tails are present on most cellular and viral mRNAs, providing a platform for poly(A)-binding proteins that stimulate translation and regulate the deadenylation and stability of transcripts in the cytoplasm. Here...Poly(A) tails are present on most cellular and viral mRNAs, providing a platform for poly(A)-binding proteins that stimulate translation and regulate the deadenylation and stability of transcripts in the cytoplasm. Here we leverage nanopore direct RNA sequencing to analyse the distribution of poly(A) tail lengths on cellular and viral mRNAs across Herpesviridae and other DNA and RNA virus infections. We find that herpesvirus mRNA poly(A) tails are consistently longer than those on cellular and other viral transcripts, presenting a previously unrecognized yet widespread mechanism to potentially advantage herpesviral gene expression. This contrasts with the templated poly(A) tails on coronavirus RNAs and those on cytoplasmically transcribed poxviral mRNAs, which are more similar in length to those on host mRNAs. Herpesviral noncoding RNAs display differential poly(A) tailing patterns while individual herpesviral mRNAs also show variation in the extent to which their poly(A) tail lengths change during the virus lifecycle, suggestive of additional uncharacterised layers of poly(A) tail length regulation. Importantly, while we detect non-adenosine nucleotides within herpesviral poly(A) tails, which are known to oppose deadenylase activity, this "mixed tailing" is not at sufficient frequency to explain the widespread extended tails of herpesvirus mRNAs.
Trunfio M, Caballero G, Gomez-Moreno V
… +15 more, Mallal SA, Wanjalla CN, Jones A, Beeri K, Wells A, LaMere S, Gouaux B, Franklin DR, Corley M, Ellis RJ, Moore DJ, Letendre SL, Smith D, Chaillon A, Gianella S
PLoS Pathog
· 2026 Jun · PMID 42296122
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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-cel...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.