The researchers divided the cohort into two groups of 60 patients. Those eligible under the hospital’s early enteral nutrition protocol began tube-administered nutrition within 24 hours of surgery, initially receiving glucose solution before progressing to standard enteral formula. By postoperative day 3, the target was 25–30 kcal/kg/day and 1.2–1.5 g/kg/day of protein. The comparison group began enteral nutrition on postoperative days 3–5, with parenteral nutrition predominating during the early recovery period. The groups did not have statistically significant differences in measured characteristics including age, sex, body-mass index, tumor location, TNM stage, operation type and duration, blood loss, or the frequencies of TP53 mutations, ERBB2 positivity and KRAS mutations. However, nonsignificant baseline tests do not prove that the groups were equivalent, and the nonrandom allocation left possible confounding by clinical suitability for early feeding.

Several immune-cell measures declined after surgery in both groups, but the early-nutrition group showed better preservation of selected phenotypes. On postoperative day 7, CD3+ T cells averaged 1,235 ± 152 cells/μL with early enteral nutrition, compared with 1,086 ± 168 cells/μL with delayed nutrition. CD4+ T-cell counts were 512 ± 68 versus 456 ± 72 cells/μL, while CD56+ natural killer cells numbered 285 ± 42 versus 248 ± 38 cells/μL; all three comparisons had P < 0.001. The higher CD4+/CD8+ ratio did not result from fewer CD8+ cells, which were similar between groups at 362 ± 48 and 365 ± 52 cells/μL, respectively, with P = 0.743. Instead, the difference primarily reflected higher CD4+ counts. Between-group differences in CD3+, CD4+ and natural killer cell counts, as well as the CD4+/CD8+ ratio, were also present on postoperative day 3, but complete longitudinal interaction statistics were unavailable and the trajectories could not be analysed with the same precision as the day-7 comparisons.

Clinical outcomes pointed in the same direction. Nine of 60 patients in the early-enteral-nutrition group experienced at least one postoperative complication within 30 days, compared with 19 of 60 in the delayed-nutrition group—15.0% versus 31.7%. The reported risk ratio was 0.47, with a 95% confidence interval of 0.23 to 0.96 and P = 0.031. Individual complications were numerically less frequent with early nutrition, including pulmonary infection in 3.3% versus 10.0%, wound infection in 3.3% versus 8.3%, and delayed gastric emptying in 5.0% versus 11.7%. Because some patients had more than one event, these category percentages were not mutually exclusive. The study did not measure specific inflammatory pathways, so the lower complication rate cannot be treated as direct evidence about NFKB1 or IL6 signaling. It instead records an association between nutritional timing, postoperative immune-cell counts and clinical complications.

The early-nutrition group also showed faster recovery of gastrointestinal function and better biochemical indicators of nutritional status. Time to first flatus averaged 2.8 ± 0.6 days with early enteral nutrition and 3.9 ± 0.8 days with delayed nutrition, while first defecation occurred after 3.5 ± 0.7 versus 5.2 ± 1.1 days. Oral intake resumed after 4.2 ± 0.8 versus 6.3 ± 1.2 days, and patients reached a full oral diet after 7.1 ± 1.3 versus 9.8 ± 1.8 days; all four comparisons had P < 0.001. On postoperative day 7, serum albumin was 38.5 ± 3.2 versus 35.8 ± 3.8 g/L, prealbumin was 245.3 ± 28.6 versus 218.7 ± 32.4 mg/L, and hemoglobin was 116.8 ± 12.4 versus 108.2 ± 14.6 g/L, again with P < 0.001 for each comparison. These were clinical nutritional and hematologic measurements, not assays of nutrient transport, MTOR signaling, intestinal-barrier genes or cytokine activity.

Hospital utilization also differed between the groups. Patients receiving early enteral nutrition had a postoperative hospital stay of 10.3 ± 2.1 days, compared with 13.8 ± 2.9 days among those receiving delayed nutrition, and total hospital stays were 15.8 ± 2.6 versus 19.2 ± 3.4 days; both comparisons had P < 0.001. Nutritional support cost more in the early-nutrition group, at 4,850 ± 680 Chinese yuan versus 3,620 ± 520 yuan, but total hospitalization cost was lower at 52,380 ± 8,250 yuan versus 61,240 ± 9,850 yuan, with P < 0.001 for both comparisons. Patients given early nutrition also reported higher global health-status scores on the European Organisation for Research and Treatment of Cancer quality-of-life instrument at discharge—65.8 ± 8.2 versus 58.3 ± 9.6—and one month after surgery—78.5 ± 7.4 versus 72.1 ± 8.8. Satisfaction scores for nutritional management and perceived recovery speed were also higher. These secondary outcomes were exploratory, and the investigators did not adjust for multiple comparisons, so their nominal P values should be interpreted cautiously.

For cancer immunologists, the peripheral blood findings raise a more ambitious question: could nutrition delivered during the stress of major surgery help preserve an immune profile favorable to later checkpoint blockade? The study itself does not answer that question. No patient received immune checkpoint inhibitor therapy as part of the investigation, and the researchers did not assay tumor immune gene expression, cytokine proteins or signaling pathways. A CD4+/CD8+ ratio describes the composition of circulating T cells but does not directly measure IFNG or IL2 expression, while a natural killer cell count does not establish cytotoxicity, interferon production or perforin and granzyme activity. Likewise, postoperative complications are clinical outcomes rather than validated molecular surrogates. Any connection between early feeding, intestinal biology, inflammation and later immunotherapy response therefore remains a hypothesis requiring prospective testing with direct molecular measurements and actual treatment outcomes.

The tumor-mutation results require similarly restrained interpretation. TP53 mutations were present in 51.7% of the early-nutrition group and 55.0% of the delayed-nutrition group, ERBB2 positivity occurred in 18.3% and 16.7%, and KRAS mutations in 15.0% and 13.3%. These frequencies described the clinical context of the cohort, but no mutation-stratified outcome analyses were performed. The ERBB2-positive and KRAS-mutant subgroups were also small, preventing reliable estimation of treatment effects within those categories. The data consequently cannot show whether the observed nutritional and immune associations were consistent across molecular subgroups, nor can they establish that a particular mutation altered the effect of early enteral nutrition.

Although the results make a coherent case for further investigation, the study has major constraints. It was retrospective, single-center and nonrandomized, creating opportunities for selection bias and residual confounding, particularly because clinicians selected early feeding according to tolerance criteria. Repeated-measures models could not be reconstructed from the aggregate data, so time-by-group interaction statistics were unavailable. Only one month of follow-up was available, leaving long-term immune recovery, survival and oncologic outcomes unknown. A stronger next phase would require randomized or otherwise rigorous multicentre comparison, complete serial immune profiling with prespecified longitudinal analyses, and integration of cytokine assays, transcriptomics, spatial tumor immune profiling and mutation-defined subgroups. If subsequent trials show that early nutritional support preserves immune phenotypes while improving recovery, testing whether those changes translate into better checkpoint-blockade responses would still be necessary. For now, the study offers an observational association between feeding within 24 hours and selected postoperative immune and clinical outcomes after gastrectomy, rather than evidence that timing itself caused the improvements or that either immune marker can guide immunotherapy selection.

Subject of Research: Early enteral nutrition and postoperative peripheral immune-cell outcomes after gastrectomy for gastric cancer

Article Title: Early enteral nutrition and perioperative peripheral immune-cell dynamics after gastrectomy for gastric cancer

Article References: Jiang, H., He, Y., Tian, M., Xu, Y., & Guo, X. (2026). Early enteral nutrition and perioperative peripheral immune-cell dynamics after gastrectomy for gastric cancer. Frontiers in Genetics, 17, Article 1931867. https://doi.org/10.3389/fgene.2026.1931867

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1931867

Keywords: gastric cancer, gastrectomy, enteral nutrition, postoperative recovery, CD4+ T cells, natural killer cells, immune phenotyping, postoperative complications, enhanced recovery, cancer immunology, Early, enteral

Dolutegravir is an integrase strand-transfer inhibitor, and rilpivirine is a non-nucleoside reverse transcriptase inhibitor. Together, they form a two-drug maintenance regimen intended to replace a three-drug regimen in people whose plasma HIV-1 RNA is already controlled. Earlier open-label, randomized phase 3 studies known as SWORD-1 and SWORD-2 found dolutegravir/rilpivirine to be non-inferior to three-drug antiretroviral therapy over 48 weeks in participants receiving first- or second-line treatment who had maintained stable plasma HIV-1 RNA for at least six months before entering the studies. Subsequent reports found virologic suppression in 89% of participants at 100 weeks and 84% at 148 weeks. The fixed-dose combination was approved in the United States in 2017 and in the European Union and Japan in 2018.

Before the combination was approved in Japan, few domestic clinical studies had evaluated it, leaving limited evidence about long-term use in routine practice. The report presents the final analysis of six years of surveillance conducted through the HIV-Related Drug Cooperative Survey, a nationwide joint post-marketing program organized by manufacturers of HIV medicines under the supervision of Japan’s Ministry of Health, Labour and Welfare. Investigators obtained real-world clinical-use data from 17 specialized institutions that participated in the program and approved publication of participant information. The data-collection period ran from November 26, 2018, to November 26, 2024, while participant registration occurred between December 20, 2018, and March 31, 2022.

Participants received one tablet containing 50 mg of dolutegravir and 25 mg of rilpivirine, taken with or immediately after a meal according to the product instructions. A total of 44 people were registered. One participant who had no visit after the initial visit was excluded from the safety analysis, leaving 43 participants. Two additional participants were excluded from the effectiveness analysis because required before-and-after measurements of plasma HIV RNA and peripheral CD4+ T-cell counts were missing. Of the safety population, 42, or 97.67%, were Japanese and 39, or 90.70%, were men; the mean age was 53.3 years. The researchers did not conduct sex-based analyses because the safety group included only four women. Every participant had previously received other antiretroviral therapy and switched to dolutegravir/rilpivirine. Thirty-three participants, 76.74% of the safety group, received the combination for more than two years.

Safety was evaluated through adverse events judged by either the treating investigator or the study sponsor to have a possible causal relationship with treatment. When their seriousness assessments differed, the more severe classification was used. Four adverse drug reactions were reported in three participants, corresponding to 6.98% of the safety population. These consisted of increased weight in one person, hypertension in one, hyperuricemia in one, and aggravated hyperuricemia, recorded as condition aggravated, in the same participant with hyperuricemia. Weight increase appeared two days after treatment began, hypertension was recorded at day 393, and aggravated hyperuricemia at day 841. Hypertension had recovered, weight increase was recovering, and aggravated hyperuricemia had not recovered at the relevant assessment. None of the reactions was serious or corresponded to the important identified or potential risks listed in the Japanese risk-management plan, including depression.

Exploratory comparisons found statistically significant differences in adverse-reaction incidence when participants were grouped by treatment duration, baseline hepatic disorder, and baseline renal disorder, with reported p values of 0.003, 0.002, and 0.029, respectively. These are associations in a small observational dataset, not definitive risk estimates or evidence that the characteristics caused the reactions. The authors cautioned that no firm conclusions could be drawn because the sample was limited and only three participants experienced adverse drug reactions, with two events occurring in the same person. None of eight participants taking additional concomitant antiretroviral medicines developed a reaction, but the study could not isolate the effects of dolutegravir/rilpivirine from those of concomitant medications. Hypertension and hyperuricemia had also appeared in earlier Japanese post-marketing surveillance of other dolutegravir-containing products, but their frequencies could not be compared directly because the safety-assessment methods differed.

Among the 41 participants in the effectiveness analysis, the mean plasma HIV RNA concentration at baseline was 1.3 log copies per milliliter, equivalent to 20 copies per milliliter. Most remained below 1.7 log copies per milliliter, corresponding to 50 copies per milliliter, throughout the three years after switching. One participant had a value of 1.7 log copies per milliliter at baseline and another reached that value at 21 months. The mean peripheral CD4+ T-cell count was 563.3 cells per cubic millimeter, with a standard deviation of 207.2 cells per cubic millimeter, and remained stable over the three-year period. The proportion of participants with counts of at least 500 cells per cubic millimeter ranged from 30.8% to 100% during follow-up. One man had a count below 200 cells per cubic millimeter at nine months, but his HIV RNA remained below 20 copies per milliliter during the three years and he experienced no adverse drug reaction.

The regimen has no activity against hepatitis B virus, an important distinction because Japanese guidance recommends screening for hepatitis B before starting antiretroviral therapy and selecting agents active against both viruses for people with co-infection. Three participants had concomitant hepatitis B at baseline, but no events related to hepatitis B infection or reactivation were reported throughout surveillance. Plasma HIV RNA and CD4+ T-cell counts were measured at baseline and every three months using each institution’s established methods. Missing data were not imputed, and the longitudinal results therefore reflect available measurements rather than a complete dataset. Fisher’s exact test and the chi-square test were used for comparisons of dichotomous variables and variables with three or more categories, respectively, with a two-sided significance level of 5% and no adjustment for multiple comparisons.

Several limitations constrain the interpretation and generalizability of the findings. The cohort included only 44 registered participants at 17 specialized facilities, and its composition—predominantly Japanese men with a mean age above 50—may not represent the full diversity of people living with HIV in Japan. Survey forms did not always contain consistent laboratory data, potentially resulting in missing or overlooked abnormal results, and information on treatment discontinuation was not comprehensively captured. The study followed people who were already virologically suppressed and switching regimens rather than evaluating treatment initiation in people with uncontrolled HIV. The report also counted reactions considered potentially attributable to treatment, whereas many clinical studies report all adverse events regardless of causality, limiting direct comparisons with trial results. The analysis was primarily descriptive, and the small number of events prevents firm conclusions about the exploratory associations involving treatment duration or baseline hepatic and renal disorders.

Within those boundaries, the final six-year report supports the real-world safety and effectiveness of dolutegravir/rilpivirine as a two-drug maintenance option for selected people in Japan whose HIV RNA was controlled before the switch. Most participants maintained suppression and stable CD4+ T-cell counts, while serious or potentially important treatment-related adverse reactions were not observed. The result extends earlier phase 3 evidence into Japanese clinical practice over six years of surveillance, with detailed effectiveness follow-up reported for three years. It does not establish that the regimen is equally safe or effective for every population, nor does it resolve the small exploratory associations involving hepatic or renal disorders. Rather, the report provides a carefully bounded real-world signal that can inform physicians treating the limited group of people who received the combination through the national cooperative program.

Subject of Research: Real-world safety and effectiveness of dolutegravir/rilpivirine maintenance therapy in a small Japanese cohort living with HIV.

Article Title: Safety and Effectiveness of Dolutegravir/Rilpivirine in Japanese People Living with HIV: Final Report of 6-Year Post-marketing Surveillance Study

Article References: Sebata, A., Nagao, T., Matsukawa, T., Yoshikawa, Y., Fukuda, A., & Wang, D. (2026). Safety and Effectiveness of Dolutegravir/Rilpivirine in Japanese People Living with HIV: Final Report of 6-Year Post-marketing Surveillance Study. Advances in Therapy. https://doi.org/10.1007/s12325-026-03812-z

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03812-z

Keywords: HIV, Dolutegravir, Rilpivirine, Antiretroviral therapy, Post-marketing surveillance, Viral suppression, CD4+ T cells, Adverse drug reactions, Japan, Real-world evidence, Safety, Effectiveness

MAVS operates downstream of cytosolic viral RNA sensing and coordinates antiviral responses through type I interferon and nuclear factor kappa B (NF-κB) signaling. The review examines how this signaling intersects with activation of the NLRP3 inflammasome. In the pathway described, MAVS contributes to inflammasome activation, which is followed by caspase-1 activation, gasdermin D cleavage, cytokine release and pyroptotic cell death. These linked events provide a mechanistic explanation for how viral recognition can generate both antiviral activity and inflammatory responses. Rather than assigning MAVS a single role, the review presents it as a signaling hub whose effects depend on the cellular context and the downstream pathway that becomes engaged.

The clearest HIV-1-specific contrasts in the review emerge from the different outcomes in myeloid cells, macrophages and quiescent CD4+ T cells. In myeloid cells and macrophages, HIV-1 has evolved several mechanisms that dampen MAVS-dependent antiviral responses. This suppression can weaken innate controls on replication and create conditions favorable to viral replication and persistence. The review also emphasizes that mechanisms demonstrated in HIV-1 infection models should not be conflated with findings established in other viral systems. Its central model is therefore not that every viral sensing event converges on MAVS, but that HIV-1 regulates innate pathways in a cell type-dependent manner, suppressing antiviral activity in some compartments while allowing or promoting inflammatory pathways in others.

Abortive infection of quiescent CD4+ T cells follows a distinct route in the evidence summarized by the review. Rather than requiring MAVS, this response uses IFI16-dependent, caspase-1-mediated pyroptosis. The authors describe this MAVS-independent pathway as a major contributor to CD4+ T-cell depletion and chronic inflammation. The distinction matters because it separates MAVS-dependent signaling from inflammasome activation that can occur without MAVS. The review also discusses emerging evidence for CARD8-mediated inflammasome activation, identifying it as another potential route through which innate pathways may complement antiviral defense while influencing HIV-1 pathogenesis. These findings broaden the network under consideration beyond a single MAVS-centered axis and show that different inflammasome pathways can be associated with distinct outcomes.

The review places these mechanistic observations in the broader problem that HIV-1 is not cured by antiretroviral therapy because latent viral reservoirs persist and chronic immune activation continues alongside infection. Its proposed significance is that understanding how MAVS, inflammasomes and pyroptosis interact across different cell types may open possibilities for host-directed approaches intended to limit viral persistence and reduce chronic inflammation. That remains a research direction, not an established treatment or demonstrated clinical benefit. The evidence reviewed is primarily mechanistic and draws on multiple experimental systems; the authors explicitly distinguish observations made in HIV-1 models from evidence derived from other viral infections and from connections that still need validation in HIV-1.

Subject of Research: Cell-specific MAVS-dependent and independent inflammasome signaling in HIV-1 infection

Article Title: MAVS signaling in HIV-1 infection: linking innate viral sensing to inflammasome activation, pyroptosis and viral persistence

Article References: Nesci, S., Glogowski, P. A., Cugliari, A., Trombetti, F., & Algieri, C. (2026). MAVS signaling in HIV-1 infection: linking innate viral sensing to inflammasome activation, pyroptosis and viral persistence. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09119-5

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09119-5

Keywords: HIV-1, MAVS, Inflammasomes, Pyroptosis, Innate immunity, CD4+ T cells, NLRP3, IFI16, CARD8, Viral persistence, signaling, infection

Among participants classified as impaired, those whose impairment also affected instrumental activities of daily living had less favorable socioeconomic profiles and lower CD4+ T-cell counts than those classified with asymptomatic impairment. Because the findings came from brief cognitive and functional assessments at one clinic, they do not constitute a population-wide prevalence estimate or formal diagnoses of HIV-associated neurocognitive disorders. The researchers enrolled 72 people living with HIV at the Tropical Medicine Foundation Dr. Heitor Vieira Dourado between January 2023 and December 2024, and 71 completed the study assessments.

The median age was 51 years, with an interquartile range of 44.75 to 61.25 years. Sociodemographic and clinical information was collected through questionnaires, while brief cognitive testing comprised the International HIV Dementia Scale, the Mini-Mental State Examination and the Montreal Cognitive Assessment. The Lawton Instrumental Activities of Daily Living scale assessed functional performance.

Participants with impaired performance on at least one cognitive instrument but preserved instrumental daily living were classified as having asymptomatic neurocognitive impairment. Those with both impaired cognitive performance and reduced instrumental activity were classified as having impairment with functional impact. Anxiety and depressive symptoms were assessed with the Hospital Anxiety and Depression Scale but were not used to assign the impairment categories.

Neurocognitive impairment was more common among participants with lower income, lower educational attainment, systemic arterial hypertension and affective symptoms. Within the group classified as impaired, functional impact was associated with less favorable socioeconomic circumstances and lower CD4+ T-cell counts. Immune recovery was evaluated using current and historical CD4+ T-cell counts obtained from participants’ medical records.

These are observational associations in a relatively small, clinic-based sample, not evidence that poverty, lower education, hypertension, affective symptoms or immune status caused the impairment. The cross-sectional design also could not determine whether cognitive problems preceded enrollment, developed during treatment or reflected HIV-specific processes. The authors noted that the operational categories were based on screening and functional performance rather than a formal diagnostic assessment for HIV-associated neurocognitive disorders, or HAND.

The study examined a setting in which several documented features of the cohort could coincide: social and economic vulnerability, viral suppression through antiretroviral therapy, existing medical conditions and differences in immune recovery. The investigators did not test an intervention, and the study did not demonstrate that any particular care strategy prevented or reversed cognitive decline. Their conclusion was instead that integrated approaches addressing factors such as earlier HIV diagnosis, sustained antiretroviral therapy, social vulnerability, vascular risk factors, mental-health symptoms and functional decline may be important for this population.

That conclusion is consistent with the reported associations, although establishing which factors are causal would require evidence beyond the cross-sectional analysis. For people living with HIV, the results indicate that neurocognitive problems may remain relevant even when treatment has suppressed viral replication. The finding is also important for interpreting the measurements themselves: three brief cognitive instruments and a functional scale were used to create operational categories, and 67.6% should therefore be understood as the proportion classified as impaired within this treated cohort, not as a measurement of clinically confirmed HAND.

Anxiety and depressive symptoms, hypertension, socioeconomic conditions and CD4+ counts appeared alongside impairment in the analysis, but the supplied study cannot determine how much each factor contributed to the observed pattern. The clearest result is thus a high frequency of screening-defined impairment in the participants studied, together with an association between more extensive functional impairment, poorer socioeconomic circumstances and lower CD4+ T-cell counts.

Subject of Research: Screening-defined neurocognitive impairment among socially vulnerable adults living with HIV in Manaus

Article Title: Prevalence and risk factors of HIV-associated neurocognitive impairment in a vulnerable amazonian population: the impact of socioeconomic status and immune recovery

Article References: da Silva, C. R., Takatani, M., Queiroz, K. L. G. D., de Souza Colares, R., Chirano, L. A. R., Pereira, F. R., Pinheiro, R. D. S., Xavier, T. D. S., Guimarães, A. C., dos Santos, E. V. V., Matos, J. V. P., Barrionuevo, M. D. S. B., de Melo, M. M., de Souza, J. M., dos Reis, M. F., de Lima Ferreira, L. C., Chaves, Y. O., & Nogueira, P. A. (2026). Prevalence and risk factors of HIV-associated neurocognitive impairment in a vulnerable amazonian population: the impact of socioeconomic status and immune recovery. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14331-1

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14331-1

Keywords: HIV, neurocognitive impairment, antiretroviral therapy, viral suppression, CD4 T cells, cognitive screening, socioeconomic status, Manaus, Amazonian population, cross-sectional study, Prevalence, risk

Antiretroviral therapy effectively suppresses HIV replication, but latent viral reservoirs remain the principal barrier to a cure. In infants receiving early ART, suppression coincides with a critical period of immune-system development. The pediatric reservoir therefore differs biologically from reservoirs established in adults.

Reviewing the available evidence, the authors describe smaller reservoirs and reduced viral diversity after early treatment, alongside a greater proportion of less-differentiated infected cells and lower expression of exhaustion markers. These characteristics may help explain why pediatric reservoirs behave differently from adult reservoirs. A smaller founding population and lower viral diversity could limit the cellular and viral variation available for clonal expansion and immune-driven viral evolution.

Reservoir measurements also depend on the assays selected and on the cellular or tissue compartments examined. The review identifies cellular and tissue compartmentalization as important determinants of how reservoir persistence is interpreted. Different assays can produce differing estimates of reservoir size, composition and persistence, so apparently inconsistent results require careful comparison of methods.

The authors emphasize that a clearer account of reservoir establishment, maintenance and dynamics is needed before age-appropriate latency-reversing, immunotherapeutic and gene-based interventions can be designed and evaluated. The relatively small and less diverse reservoirs observed after early treatment, together with better-preserved immune function, may provide a more favorable setting in which to test cure-oriented strategies. Progress will nevertheless depend on distinguishing the comparatively well-supported reduction in initial seeding from the less definitive, longitudinal and observational evidence for continued reservoir decay under sustained suppression.

Subject of Research: Immunobiology and persistence of HIV reservoirs in children receiving early antiretroviral therapy

Article Title: Pediatric HIV reservoir in early ART: distinct immunobiology and its implications for HIV cure

Article References: Kamvuma, K., Obeagu, E. I., Phiri, S. B., Kapoma, C., Mudenda, S., Simpamba, E., Sichamba, P., Ademola, Y. U., Mulemena, J., Chanda, W., Nzobokela, J., Chiyenu, K., Mutalange, M., & Munsanka, S. (2026). Pediatric HIV reservoir in early ART: distinct immunobiology and its implications for HIV cure. Virology Journal. https://doi.org/10.1186/s12985-026-03336-6

Image Credits: AI Generated

DOI: 10.1186/s12985-026-03336-6

Keywords: pediatric HIV, antiretroviral therapy, viral reservoir, latent HIV, CD4⁺ T cells, immune exhaustion, viral diversity, viral suppression, HIV cure research, reservoir seeding, Pediatric, reservoir

The study focused on BACH2, one of the most prominent selected integration genes, and used a cellular model containing BACH2-integrated proviruses. Proviral transcription drove abnormal BACH2 protein levels that escaped the gene’s autoregulatory feedback, producing BACH2-dependent changes in the cell’s transcriptomic program. The authors describe this process as exaptation: viral sequences use regulatory features associated with a host gene to alter cellular identity and behavior.

When the investigators mimicked the relevant changes in primary CD4 T lymphocytes, BACH2 shifted the cells toward a proliferative, precursor memory-like state. The reprogrammed cells had traits associated with persistent HIV reservoir cells in people living with HIV, including immune-evasion characteristics and enhanced cellular survival. These experiments provide a mechanistic model for how transcriptionally active, defective proviruses could influence long-lived HIV target cells; they do not directly demonstrate the same causal process in people receiving antiretroviral therapy.

Inhibition of proviral transcriptional activity mitigated exaptation in the experimental system, indicating that viral transcription can be a point of intervention for reducing the modeled effects. The result does not establish a clinical strategy or show that transcriptional inhibition would reduce HIV reservoirs in people. Effects also depended on the integration site: analysis of another prominently selected gene, STAT5B, suggested that proviral exaptation there drove a contrasting, effector-like T-cell fate. The findings therefore support a locus-dependent model in which structurally defective but transcriptionally active proviruses can alter CD4 T-cell differentiation, expansion and survival through insertional effects involving host genes.

Subject of Research: Mechanisms by which defective, transcriptionally active HIV-1 proviruses alter CD4 T-cell state during antiretroviral therapy

Article Title: Selective persistence of HIV-1-infected T cell clones can occur through immune reprogramming driven by defective, transcriptionally active proviruses

Article References: Hamann, M. V., Brauckmann, L., Schwarz, C., Spohn, M., Stoeck, R., Leddy, S. M., Frouard, J., Adiba, M., Winzer, R., Hausmann, F., Virdi, S., Grundhoff, A., Feschotte, C., Sauter, D., Muecksch, F., Roan, N. R., Tolosa, E., & Lange, U. C. (2026). Selective persistence of HIV-1-infected T cell clones can occur through immune reprogramming driven by defective, transcriptionally active proviruses. PLOS Pathogens, 22(10), e1014618. https://doi.org/10.1371/journal.ppat.1014618

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014618

Keywords: HIV-1, proviruses, CD4 T cells, antiretroviral therapy, HIV reservoir, BACH2, STAT5B, integration sites, gene regulation, immune evasion, Selective, persistence

The study enrolled people with HIV at the HIV Unit of the Hospital Clínic de Barcelona and separated them into four clinical groups. Ten elite controllers maintained viral loads below 50 copies per milliliter for at least one year without antiretroviral therapy. Six viremic controllers maintained levels below 4,000 copies per milliliter for at least one year without treatment, while eight untreated non-controllers had loads above 5,000 copies per milliliter for more than one year.

A further nine non-controllers receiving antiretroviral therapy had loads below 50 copies per milliliter for more than one year. All participants had CD4+ T-cell counts above 450 cells/mm3, and elite and viremic controllers had been followed for more than five years at sampling. Median CD4+ T-cell counts were broadly similar across the groups, ranging from 594 cells/mm3 in treated non-controllers to 706 cells/mm3 in elite controllers, while median viral load differed substantially as defined by the study.

The cohort was composed mainly of men who acquired HIV through sexual intercourse, and six elite controllers and five viremic controllers later began antiretroviral therapy between one and nine years after sampling. Researchers found no difference in the frequency of the protective HLA-B57 and HLA-B27 alleles across the groups, and no participant had active hepatitis C virus coinfection at the time of sampling. These features limit the extent to which the molecular results can be separated from other biological and clinical differences within the small cohort.

Elite controllers had a broad, distinctive small-RNA landscape, including overexpression of specific lysine-associated tRNA isoacceptors and five PIWI-interacting RNAs. The tRNA-Lys-CTT-3-1 isoacceptor was strongly enriched in elite controllers relative to treated non-controllers, with a log2 fold change of 3.01, and relative to untreated non-controllers, with a log2 fold change of 4.32. Other lysine-, glycine-, threonine- and arginine-associated tRNAs showed trends toward overexpression, while several other isoacceptors were repressed.

The five PIWI-interacting RNAs elevated in elite controllers relative to treated non-controllers had nearly identical sequences and originated from six genomic loci associated with tRNA-Lys repeats. They were also expressed more highly than in untreated non-controllers, although by a smaller average amount. One PIWI-interacting RNA, piR-hsa-2138, was repressed in elite controllers relative to both viremic and untreated non-controllers.

Fewer changes were detected among small nuclear and small nucleolar RNAs: among elite controllers and untreated non-controllers, RN7SK and two annotated RNAs were overexpressed, two were repressed, and the H/ACA-box snoRNA SNORA6 was elevated. Because sequence reads with extensive similarity can be assigned to more than one small-RNA class, the piRNA signals linked to tRNA-Lys loci require particular caution. The clearest shared microRNA signal involved miR-99b-5p and miR-125a-5p, both of which were significantly downregulated in elite controllers relative to treated and untreated non-controllers.

MiR-125b-2-5p was also reduced relative to the treated non-controller group. No differentially expressed miRNAs were detected between the treated and untreated non-controller groups; this null comparison does not establish that antiretroviral treatment has no effect on the miRNA profile, but it shows that the principal group differences in this cohort were associated with controller status. No miRNAs were differentially expressed between viremic controllers and either elite controllers or treated non-controllers.

MiR-99b-5p, miR-221-5p and miR-501-3p were, however, lower in viremic controllers than in untreated non-controllers. The investigators noted that the small number of participants, particularly viremic controllers, could have limited group comparisons. Total-RNA sequencing showed that the microRNA signature coincided with broader changes in protein-coding gene expression.

Gene-set enrichment analyses identified common patterns in elite controllers compared with both non-controller groups, including p53 signaling, inflammatory responses, cell activation, apoptosis, cell death, responses to hypoxia and ultraviolet radiation, and oxidative-stress pathways such as NRF2 signaling. Metabolic terms involving carbohydrate metabolism and cholesterol homeostasis were also enriched. Differential-expression analysis found 106 genes differing between elite and treated non-controllers and 104 between elite and untreated non-controllers, with 26 genes deregulated in both comparisons.

Enriched transcription-factor sets included SP1, JUN-family members, SP3, CREB1 and CEBPB. These observations identify associations between cellular transcriptional states and elite control rather than proving that any one enriched pathway causes viral suppression. In the elite-controller versus treated-non-controller network, 41 differentially expressed genes were linked to miR-99b-5p and miR-125a-5p.

They included FLNA, DPM2, CDKN1A, BBC3, DUSP1 and SOD2, and pathway analysis linked the targets to p53 signaling, sterol-related processes, matrix metalloproteinase activation and metabolism of oxidative enzymes. In the comparison with untreated non-controllers, seven differentially expressed miRNAs collectively accounted for 86 linked differentially expressed genes, including miR-99b-5p and miR-125a-5p. Associated pathways included hypoxia signaling, p53-mediated apoptosis, Fc-gamma-receptor-dependent phagocytosis, OAS antiviral response and BH3-only proteins that inactivate anti-apoptotic BCL-2 family members.

Functional experiments used CEM-NKR-CCR5 cells, an immortalized human T-cell line susceptible to HIV-1. Synthetic inhibitors reduced expression of miR-99b-5p and miR-125a-5p by more than 90% when used separately or together. DPM2 and MAFB showed statistically significant increases in expression after inhibition, while other candidate targets generally changed by about 1.1- to 1.2-fold.

The cells were then exposed to two doses of the replication-competent NL4.3-Ren HIV-1 clone, and viral production was measured through luciferase activity 48 hours later and normalized to cell viability. At the lower dose, miR-99b-5p inhibition reduced replication by 18.2% with a 95% confidence interval of 3.6–30.5%, while miR-125a-5p inhibition produced an 18.4% reduction with a 6.4–28.9% interval. Combined inhibition yielded a 22.0% reduction, with an 11.7–31.1% interval.

At the higher inoculation dose, miR-99b-5p inhibition reduced replication by 17.0% with a 95% confidence interval of 5.5–27.0%. The reduction attributed to miR-125a-5p inhibition was 14.1%, with a 5.5–30.1% interval, but was not statistically significant at that dose. Combining both inhibitors produced a 20.7% reduction, with a 15.5–26.9% interval.

The abstract summarized the single and combined inhibitor effects across the experiments as 17.6%, 16.3% and 21.4%, respectively. These cell experiments support a modest antiviral effect of inhibiting the two microRNAs under the tested conditions, but they do not establish clinical efficacy in people or show that either microRNA alone produces the elite-controller phenotype. Several limitations constrain generalization from the findings.

Besides the small, predominantly male, single-center cohort, the analysis identified one untreated participant as a multivariate outlier and excluded that participant from all small-RNA analyses; another participant was excluded from the piRNA and tRNA analyses. The immortalized CEM-NKR-CCR5 model may not reproduce apoptosis, cell-cycle and other regulatory relationships observed in primary CD4+ T cells, and attempts to measure several relevant targets were unsuccessful. Primary CD4+ T cells or in vivo models would be needed to test the biological relevance of the proposed regulatory network more faithfully.

Within those limits, the study identifies a measurable post-transcriptional layer associated with natural HIV control and highlights miR-99b-5p and miR-125a-5p as candidates for further mechanistic investigation rather than established therapeutic targets.

Subject of Research: Small non-coding RNA signatures associated with natural control of HIV-1 in elite controllers

Article Title: sncRNA signatures underlying HIV-1 restriction in elite controllers

Article References: Ayala-Suárez, R., De la Torre Tarazona, E., Bermejo, M., Bargalló, M. E., Maleno, M. J., Coiras, M., Leal, L., García, F., Plana, M., García-Pérez, J., Alcamí, J., & Díez-Fuertes, F. (2026). sncRNA signatures underlying HIV-1 restriction in elite controllers. Frontiers in Cellular and Infection Microbiology, 16, Article 1926123. https://doi.org/10.3389/fcimb.2026.1926123

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1926123

Keywords: HIV-1, elite controllers, small non-coding RNAs, microRNAs, CD4+ T cells, viral restriction, miR-99b-5p, miR-125a-5p, gene regulation, antiretroviral therapy, transcriptomics, sncRNA

The study was conducted at Zhangjiagang Hospital affiliated to Soochow University between January 2022 and August 2025. The team enrolled children younger than 14 years who fulfilled DSM-5 diagnostic criteria for tic disorders at their first clinical visit and had never received tic-specific pharmacological treatment. This treatment-naive design matters: because tic-directed medications can themselves alter immune parameters, studying children before any intervention reduces a major source of confounding. Children with uncertain diagnoses, genetic or neurological disorders, clinically evident infections, chronic or malignant disease, known immunological or autoimmune disorders, or recent use of medications or vitamin supplements were excluded. The final sample comprised 29 boys and 12 girls with a mean age of 8.61 years.

Tic severity was assessed with the Yale Global Tic Severity Scale, or YGTSS, a clinician-rated instrument whose global severity score combines a total tic score, spanning motor and vocal tic domains with a possible range of 0 to 50, and an impairment score, also ranging from 0 to 50, for a possible total of 0 to 100. The mean global severity score in the cohort was 30.71, with the total tic and impairment components contributing nearly equally at 15.34 and 15.37, respectively. Because the global score merges tic manifestations and functional impairment, the primary finding should be read as an association with overall tic-related symptom burden rather than with tic frequency, intensity, or disability alone.

Alongside the severity assessment, the researchers drew on an unusually broad laboratory panel. Serum measurements covered 25-hydroxyvitamin D and its D2 and D3 fractions, plus the fat-soluble vitamins A, E, and K, each included for mechanistic reasons: vitamin D is an immunomodulatory secosteroid influencing antigen-presenting cells, cytokine production, and T-cell differentiation; vitamin A-derived retinoic acid regulates T-cell differentiation and immune tolerance; vitamin E acts as a membrane antioxidant modulating immune cell function; and vitamin K participates in sphingolipid metabolism in neural tissues. Immune variables included total lymphocyte count, T-, B-, and NK-cell percentages, CD4+ and CD8+ T-cell percentages and absolute counts, and the CD4/CD8 ratio. The mean serum 25(OH)D concentration was 20.90 ng/mL, and the mean CD4+ T-cell absolute count was 823.56 cells per microliter.

The statistical strategy was deliberately conservative for a small sample. Because the data were not normally distributed, the team used Spearman rank correlation, which captures monotonic associations without assuming linearity, and controlled for multiple testing across 15 laboratory variables using the Benjamini-Hochberg false discovery rate method. CD4+ T-cell absolute count showed the strongest inverse correlation with the YGTSS global severity score, with a Spearman rho of -0.474 and an unadjusted P value of 0.0017. Critically, this association survived FDR correction, with an adjusted P value of 0.0260. Total lymphocyte count, 25(OH)D3, and total 25(OH)D showed nominal inverse correlations but did not remain significant after correction. Vitamins A, E, and K showed essentially no association with severity at all.

The association then faced a tougher test: covariate-adjusted linear regression. Each laboratory variable was entered into a separate model adjusted for age, sex, and disease duration, with heteroscedasticity-consistent HC3 robust standard errors used to guard against non-normal residuals and influential observations in the small sample. The CD4+ T-cell association persisted after adjustment, with a coefficient of -0.018 and a 95 percent confidence interval of -0.031 to -0.005, and a P value of 0.0069. Expressed on a more interpretable scale, every 100 cells per microliter higher CD4+ count was associated with roughly 1.8 points lower on the YGTSS global severity score, assuming a linear relationship. No other laboratory variable reached nominal significance in the adjusted models. In a sensitivity analysis that additionally adjusted for total lymphocyte count, the inverse association persisted but the estimate was less precise and sat close to the nominal significance threshold.

The vitamin D results were more equivocal. When participants were grouped by serum 25(OH)D status using Endocrine Society criteria, 23 children fell below 20 ng/mL, 10 fell between 20 and 30 ng/mL, and 8 were at or above 30 ng/mL. The deficient group had the highest mean severity score at 34.43, and the overall omnibus difference among groups was significant, with a Kruskal-Wallis P value of 0.0073. But Dunn-Bonferroni pairwise testing identified only one significant contrast, between the deficient and 20-to-30-ng/mL groups, with an adjusted P value of 0.0077. The group at or above 30 ng/mL did not differ significantly from either other group, so the data showed no monotonic dose-response pattern. The authors characterized the vitamin D findings as exploratory and less robust than the CD4+ T-cell association, noting that the small and unequal group sizes may have produced unstable estimates.

What could a reduced CD4+ T-cell count mean biologically in a child with more severe tics? The authors offer several non-exclusive mechanisms. First, a lower circulating count may reflect immune redistribution or persistent immune activation, whereby activated T cells migrate from peripheral blood into inflammatory sites or lymphoid tissues. Second, it may indicate impaired immune regulation, particularly if regulatory T-cell function is reduced. Third, CD4+ alterations may interact with cytokine-mediated neuroinflammatory pathways that influence dopaminergic neurotransmission, microglial activation, and cortico-striato-thalamo-cortical circuit function, all of which are relevant to tic generation. Prior work supports this framing: a meta-analysis of pediatric Tourette syndrome reported reduced CD4+ T cells alongside increased proinflammatory cytokines such as IL-6 and TNF-alpha, and studies in children with tic disorders and allergic diseases have reported changes in CD3+ T cells, CD4+ T cells, and the CD4/CD8 ratio.

The authors are careful about what the finding does not establish. The study included no healthy control group, so the results concern severity-related associations within children with tic disorders and cannot determine whether immune or vitamin measures differ from healthy children. Lymphocyte subset values vary with age in children, and although analyses were adjusted for age, age-standardized z scores were unavailable, so the data do not show that CD4+ counts were abnormally low compared with age-matched peers. Body mass index, season of blood collection, sunlight exposure, dietary intake, allergic disease, and detailed psychiatric comorbidity data were also unavailable, and high-sensitivity C-reactive protein was available for only 24 of 41 participants, meaning subtle subclinical inflammation could not be fully excluded. Exploratory component analyses showed nominal inverse associations of CD4+ count with both the total tic score and the impairment score, but neither survived FDR correction, so the main association cannot be attributed specifically to tic manifestations or functional impairment.

The authors stress that the findings have no immediate role in diagnosing tic disorders, classifying patients, predicting clinical course, or selecting treatment, and do not support using vitamin D concentration or CD4+ T-cell count alone for any of these purposes. Current guidelines emphasize clinical assessment, functional impairment, comorbidities, and individualized management rather than biomarker-based classification. Evaluation of vitamin D status may still be appropriate when a child has established clinical risk factors for deficiency, independent of any proposed tic-related role. The observed CD4+ T-cell association should be regarded as a hypothesis-generating signal that requires validation in larger longitudinal and controlled studies with healthy controls, age-standardized immune measures, and detailed YGTSS item data. Until then, the idea that a routine blood count might whisper something about the severity of a child’s tics remains an intriguing lead rather than a clinical tool.

Subject of Research: Neuroscience

Article Title: Associations of vitamin status and T-lymphocyte subsets with tic severity in children: a cross-sectional study using the Yale Global Tic Severity Scale

Article References: Zhu, F., Gao, Y., Zhang, Z., Kang, S., Xu, W., & Zhang, J. (2026). Associations of vitamin status and T-lymphocyte subsets with tic severity in children: a cross-sectional study using the Yale Global Tic Severity Scale. Frontiers in Psychiatry, 17, Article 1903047. https://doi.org/10.3389/fpsyt.2026.1903047

Image Credits: AI Generated

DOI: 10.3389/fpsyt.2026.1903047

Keywords: tic disorders, Tourette syndrome, CD4+ T cells, vitamin D, YGTSS, pediatric neuroimmunology, Associations, vitamin, status, T-lymphocyte, subsets, severity

The research team, led by Jéssica Bilar Cavalcanti and corresponding author Hebert Fabricio Culler, enrolled 117 adults at their single center in São Paulo, Brazil. The cohort comprised 80 asymptomatic HTLV-1 carriers, 21 patients with adult T-cell leukemia/lymphoma, and 16 healthy uninfected controls. Crucially, the investigators also subdivided the carriers according to their presumed route of infection: 51 were thought to have acquired the virus vertically, through breastfeeding, while 29 had presumably acquired it sexually. This design allowed the group to ask two distinct questions at once, namely how T-cell differentiation patterns differ between healthy infection and malignant transformation, and whether the way the virus is transmitted leaves any lasting imprint on the immune cell landscape.

To interrogate these questions, the researchers isolated peripheral blood mononuclear cells and subjected them to multiparameter flow cytometry, a technique that tags individual cells with fluorescent antibodies and allows their identity to be read out at single-cell resolution. Total CD4 T-cell frequency was first measured among viable CD3-positive T cells. The team then partitioned the viable CD3-positive CD4-positive population into five differentiation subsets using a panel of three surface markers: CD45RA, which marks cells that have not yet encountered antigen or have reverted to a naive-like state; CCR7, a chemokine receptor that guides cells to lymph nodes; and CD95, a death receptor that serves as a discriminator of memory lineages. Combinations of these markers defined naive cells, stem cell memory T cells known as TSCM, central memory T cells or TCM, effector memory T cells or TEM, and terminally differentiated effector T cells known as TTE.

Statistical rigor was a notable feature of the analysis. Group comparisons used Kruskal-Wallis tests followed by Dunn’s pairwise tests with Holm adjustment, and the investigators applied false-discovery-rate correction across six outcomes to guard against spurious findings from multiple testing. Because age and sex are known to shape T-cell differentiation, median regression models estimated differences adjusted for these covariates. This layered approach means that the associations reported by the team survived corrections that many immunology studies of this size omit, lending weight to the central conclusion that the differentiation profile of circulating CD4 T cells is genuinely altered in adult T-cell leukemia/lymphoma.

The headline finding concerns the fate of the naive and memory compartments. Patients with ATLL had a median naive-cell frequency of just 2.91 percent, compared with 27.95 percent in asymptomatic carriers and 24.40 percent in healthy controls. Their central memory compartment was similarly collapsed, at 12.30 percent versus 25.35 percent in carriers and 31.85 percent in controls. In the opposite direction, effector memory cells were dramatically expanded in the patients, accounting for a median 49.80 percent of circulating CD4 T cells, roughly three times the 16.15 percent seen in carriers and the 17.80 percent seen in controls. All three of these global comparisons remained significant after false-discovery-rate correction, indicating that they are unlikely to be statistical artifacts.

Covariate adjustment sharpened rather than diluted the signal. After controlling for age and sex, ATLL remained associated with naive-cell frequencies roughly 25 percentage points lower than in asymptomatic carriers and 21.29 points lower than in healthy controls. Central memory frequencies were 12.80 points lower relative to carriers and 16.97 points lower relative to controls, while effector memory frequencies were 34.40 points and 31.85 points higher, respectively. In other words, the malignant state is characterized not by an overall expansion of CD4 T cells but by a qualitative shift in which cells dominate the circulation: long-lived naive and central memory populations contract, and terminally poised effector memory cells take their place.

Two subsets told a quieter story. Stem cell memory T cells, the earliest and most potent self-renewing branch of the memory lineage, showed no significant unadjusted global difference among the groups, and terminally differentiated effector T cells likewise did not differ. The total frequency of CD4 T cells among viable CD3 T cells showed only a nominal difference across groups, with a p-value of 0.0478, and this did not hold up after false-discovery-rate correction or covariate adjustment. The authors interpret this carefully: the pattern in ATLL reflects a redistribution of differentiation states within the circulating CD4 pool rather than a consistent increase in the number of CD4 T cells themselves. That distinction matters, because it suggests the leukemia reshapes the composition of the T-cell compartment even when bulk counts appear unremarkable.

The second major question, whether transmission route leaves an immunological fingerprint, received a negative answer. When the investigators compared asymptomatic carriers presumed to have been infected through breastfeeding with those presumed to have acquired the virus sexually, they found no statistically detectable differences in the distribution of CD4 differentiation subsets between the two groups. This finding is of practical interest in Brazil, which carries one of the highest HTLV-1 burdens in the world and where vertical transmission through breastfeeding is a major public health concern. The result suggests that, at the level of circulating T-cell differentiation measured here, the circumstances of acquisition do not visibly reorganize the carrier’s immune landscape decades later.

Mechanistically, the contraction of naive and central memory cells alongside effector memory expansion fits a picture in which the leukemic clone, derived from virally infected CD4 T cells, displaces or remodels the normal T-cell hierarchy. HTLV-1 persists largely by driving proliferation of infected cells, and viral proteins such as the basic leucine zipper factor HBZ have been implicated in modulating T-cell differentiation and survival. The study was not designed to establish causation, and its cross-sectional design means the observed redistribution could be either a driver or a consequence of malignant transformation. Nevertheless, the consistency of the naive-low, TCM-low, TEM-high signature after rigorous correction, and its independence from age and sex, marks it as a robust correlate of disease state.

The work also demonstrates the value of disciplined flow cytometry practice. The gating strategy relied on viable CD3-positive CD4-positive cells and the three-marker combination of CD45RA, CCR7 and CD95, with fluorescence-minus-one controls referenced in the study’s methods vocabulary to set boundaries between subsets, an approach that reduces subjectivity in defining populations as rare as stem cell memory T cells. Ethical oversight came from the Research Ethics Committee of Hospital das Clínicas, under approved protocol, with written informed consent from all participants. Funded by Brazilian agencies including CAPES, CNPq and FAPESP, the study involved collaboration with Imperial College London and the Instituto de Medicina Tropical of the University of São Paulo. For clinicians, the findings point toward a measurable immunophenotypic signature that could, with further validation, complement existing markers in monitoring progression from silent carriage to leukemia. For virologists, they sharpen the question of how a virus that colonizes the helper T-cell compartment ultimately rewires it, and which of the contracted or expanded subsets offer the most informative targets for early detection and therapeutic intervention.

Subject of Research: Distribution of circulating CD4 T-cell differentiation subsets in HTLV-1 infection and adult T-cell leukemia/lymphoma

Article Title: Circulating CD4 + T-Cell differentiation subsets show a distinct distribution in HTLV-1–associated adult T-Cell leukemia/lymphoma

Article References: Cavalcanti, J. B., de Lima Barros, P., Jofre, D. F., Guimarães, G. S., Marques, K. S., Rocha, A. B., de Camargo Callefi, V., Ruffo, L., Palhares, G., Passos, J. A., de Aquino, N. C., Albuquerque, S., Furlan, V., Cattena, S., de Souza França, L., de Assis, L. M., de Oliveira Garcia Mateos, S., Rosadas, C., Casseb, J. S. D. R., … Culler, H. F. (2026). Circulating CD4 + T-Cell differentiation subsets show a distinct distribution in HTLV-1–associated adult T-Cell leukemia/lymphoma. Virology Journal. https://doi.org/10.1186/s12985-026-03323-x

Image Credits: AI Generated

DOI: 10.1186/s12985-026-03323-x

Keywords: HTLV-1, adult T-cell leukemia/lymphoma, CD4 T cells, T-cell differentiation, effector memory T cells, central memory T cells, naive T cells, flow cytometry, transmission route, retrovirus, immunophenotyping, Virology Journal

Tuberculosis remains the leading cause of death from a single infectious agent worldwide, yet the only licensed vaccine, BCG, offers unreliable protection against pulmonary disease in adults, the form of illness that drives most transmission. The leading subunit candidate, M72/AS01E, showed roughly fifty percent efficacy against TB disease in a major trial, leaving an enormous gap. Most vaccine candidates in testing aim to induce CD4 T cell responses, which are known to be essential for controlling Mtb. But the UCSF researchers, led by Joel Ernst, started from an observation that inverts conventional thinking about antigen selection. Unlike most pathogens, Mtb’s CD4 T cell epitopes are strikingly conserved across strains, suggesting that T cell recognition of these dominant antigens may actually benefit the bacterium, perhaps by promoting the inflammatory lung destruction that facilitates transmission through coughing and cavitation.

From that reasoning, the team focused on a small group of Mtb antigens that do show sequence diversity within human T cell epitopes—proteins they had previously identified and dubbed rare variable antigens, or RVMAs. The diversity within these epitopes hints that T cell responses against them are more detrimental to the bacterium than responses to conserved antigens, placing the genes under diversifying selection. The researchers built a DNA vaccine, named pCas4, encoding a fusion of four such antigens: Rv0010c, RimJ, Rv2719c, and Rv0990c, using sequences from the Mtb Erdman strain cloned into a commercial pVAX1 vector. Mice received three intramuscular immunizations spaced three weeks apart before being challenged with an aerosolized dose of bacteria.

The vaccine proved immunogenic. Spleen cells from vaccinated C57BL/6 mice produced interferon-gamma in response to three of the four antigens, with RimJ inducing the strongest responses. During actual infection, the same three antigens were recognized by CD4 T cells, though the responses were weaker than those mounted against the classic immunodominant antigens ESAT-6 and Ag85B. After challenge with the matched Erdman strain, vaccinated animals showed significantly increased IFN-gamma and TNF co-producing CD4 T cell responses to Rv0010c and RimJ. Notably, the team found a naturally occurring amino acid substitution, Y105C, in RimJ between the Erdman and H37Rv strains that fell within a predicted T cell epitope and altered the strength of T cell recognition—direct experimental support for the idea that antigenic variation genuinely exists in Mtb, even between closely related lineage 4 strains.

At twelve weeks of chronic infection in standard C57BL/6 mice, pCas4 vaccination produced no reduction in bacterial burdens in lungs or spleens. What it did change was pathology: vaccinated animals had fewer and smaller lymphoid aggregates in their lungs, structures composed largely of B cells that arise in chronic infection in mice and are also seen in human and non-human primate granulomas. Flow cytometry confirmed reduced frequencies of both B cells and T cells in the lungs of vaccinated animals. The researchers interpreted this as evidence of infection tolerance—a state in which the host tolerates the pathogen with minimal tissue damage rather than eliminating it.

The most striking results came from a hypersusceptible mouse model. SP140-deficient mice, generated on the otherwise resistant C57BL/6 background, develop severe, necrotizing lung lesions resembling those seen in human tuberculosis, which normally makes them difficult to study past five weeks of infection. When the team vaccinated these animals with pCas4 and challenged them with Mtb Erdman, bacterial burdens were again unchanged at five weeks post-infection. But a sensitive necrosis assay, in which the cell-impermeable dye Sytox Green is injected intravenously to stain extracellular DNA in dead tissue, revealed significantly less necrosis in vaccinated lungs. Histology confirmed the difference: mock-vaccinated mice had large necrotic lesions filled with acellular debris, while vaccinated mice had large cellular lesions entirely devoid of necrosis, though lacking clear organization.

Immunofluorescence microscopy of lung sections revealed how the lesions differed. In mock-vaccinated SP140-deficient mice, lesions had the expected architecture of human-like granulomas: a necrotic core rich in neutrophil and macrophage markers, surrounded by a lymphocytic cuff, with CD4 T cells almost entirely excluded from the core. In vaccinated mice, intact neutrophils and pockets of macrophages coexisted with CD4 T cells distributed throughout the lesion, including the core. Quantification showed significantly reduced neutrophil staining and significantly increased CD4 T cell numbers within lesion cores. Critically, markers of tissue integrity told a story of preservation: E-cadherin staining marking alveolar epithelium was retained throughout lesions in vaccinated mice, and alpha-smooth muscle actin staining suggested the presence of myofibroblasts associated with fibrotic containment, whereas mock-vaccinated lesions showed loss of epithelium and no fibrosis. Bacterial staining within the lesion core did not differ between groups, though vaccinated animals showed increased bacterial staining in the lesion cuff, possibly reflecting a redistribution of infected cells in less organized lesions.

Earlier in infection, at twenty-one days, before necrosis would normally develop, vaccinated mice already showed a distinct immune landscape: increased frequencies of RORγt-expressing CD4 T cells, including both Th17 and Tbet-positive Th1/17 subsets, along with decreased frequencies of conventional Tbet-positive Th1 cells, neutrophils, and both subsets of monocyte-derived macrophages, MNC1 and MNC2. The monocyte-derived cells also expressed lower levels of CD11c, potentially indicating a less inflammatory state. These shifts preceded the pathological differences, suggesting they contribute to preventing necrosis. B cells turned out to be dispensable: depleting them with anti-CD20 antibody during vaccination did not abolish the reduction in necrosis, and the effect also persisted when mice were vaccinated with a plasmid encoding RimJ alone, which increased RORγt-positive CD4 T cells similarly to the four-antigen cassette. Adoptive transfer experiments confirmed that RimJ-specific CD4 T cells traffic to infected lungs and localize within lesions near bacteria.

The authors are careful about the limits of their work. They did not establish a definitive mechanism, could not prove the observed T cell and myeloid changes are required for the protection, and did not compare the RVMA approach directly to candidates like M72. Not all variable antigens worked—an earlier cassette containing Rv0012 and LrfD2 antigens failed to alter infection outcomes, apparently because those proteins are poorly antigenic in mice. Still, the implications are substantial. The findings suggest that preclinical vaccine screening based solely on bacterial burden may discard candidates that could be genuinely effective at preventing disease. They also raise a caution: because some CD4 T cell responses to Mtb may promote the pathology that drives transmission, vaccines could theoretically worsen cavitary disease. If future work confirms that responses to rare variable antigens enhance disease tolerance in humans, a prevention-of-disease vaccine built around RimJ and its relatives could offer something TB has lacked for over a century—a way to keep infected lungs intact even when the bacteria persist within them.

Subject of Research: A rare variable antigen DNA vaccine against Mycobacterium tuberculosis that reduces lung pathology without lowering bacterial burden

Article Title: A Mycobacterium tuberculosis rare variable antigen vaccine reduces lung pathology in hypersusceptible SP140−/− mice

Article References: Howard, Z. P., Mohapatra, A., Zheng, W., & Ernst, J. D. (2026). A Mycobacterium tuberculosis rare variable antigen vaccine reduces lung pathology in hypersusceptible SP140−/− mice. Frontiers in Tuberculosis, 4, Article 1814646. https://doi.org/10.3389/ftubr.2026.1814646

Image Credits: AI Generated

DOI: 10.3389/ftubr.2026.1814646

Keywords: tuberculosis, Mycobacterium tuberculosis, vaccine, rare variable antigens, CD4 T cells, lung pathology, necrosis, SP140, disease tolerance, RimJ, granuloma, prevention of disease