Update, the link between HIV infection and abnormal glucose metabolism (AGM) is still unclear. This study aims to investigate the impact of HIV infection on AGM, including insulin resistance (IR), impaired fasting glucose (IFG), and diabetes mellitus (DM).

A multicenter case-control study was conducted in Zhejiang province, China. After matching, the study included 1030 people living with HIV (PLWH) and 1030 people living without HIV (PLWTH). The age-specific incidence of AGM was compared between the two groups. Poisson regression models were used to calculate the relative risk (RR) and its 95% confidence interval (CI) to assess the associations.

Compared to PLWTH, PLWH had a higher rate of IR, IFG and DM, and a higher risk of developing IR (RR: 1.83; 95% CI: 1.60-2.10), IFG (RR: 3.87; 95% CI: 2.55-6.07), and DM (RR: 1.52; 95% CI: 1.09-2.12). In the 30-44 age group, the risk of IR, IFG, and DM was the highest, with RRs of 2.04 (95%CI: 1.69-2.48), 7.46 (95%CI: 2.91-25.27), and 1.88 (95%CI: 0.90-4.10). HIV acquisition and cART usage >5 years were associated with increased risks of DM.

HIV infection is associated with early onset and high prevalence of IR and IFG. Longer duration of HIV infection and cART usage increased the occurrence of DM. These findings contribute to a better understanding of age-specific AGM and the modified glucose monitor strategies in PLWH.

HIV co-infection is a risk factor for the development of COPD. HIV enhances the deleterious effects of exposures such as tobacco smoking, as well as interacting with other drivers of COPD such as pulmonary tuberculosis, air pollution and biomass fuel burning. Recent work demonstrates that HIV also contributes independently to COPD pathogenesis by promoting oxidative stress, chronic inflammation, abnormal innate and adaptive immune responses, microbial dysbiosis, and epigenetic alterations within the lung. Consequently, people with HIV develop COPD younger, more often, and with faster rates of lung function decline compared to seronegative individuals. They may also have distinct patterns of lung function abnormalities compared to other etiotypes of COPD. Understanding the natural and pathogenetic history of HIV-associated COPD is important as its assessment, prevention and treatment are currently extrapolated from the general population. Whilst smoking cessation remains vital, further understanding may help guide unique management strategies for HIV-associated COPD. In this review, we explore its epidemiology and pathophysiology and discuss prevention and treatment approaches in this increasingly common disease.

HIV-associated neurocognitive disorders (HAND), especially asymptomatic neurocognitive impairment (ANI), the initial stage of HAND, persist among a substantial proportion of individuals living with HIV despite the introduction of combination antiretroviral therapy (cART). Resting-state functional magnetic resonance imaging (rs-fMRI) focusing on ANI among HIV-related patients is rarely reported.

60 right-handed Chinese male patients with HIV-associated ANI underwent baseline and follow-up neurocognitive examination, and rs-fMRI scans over an average interval of 1.68 years. Brain function alterations were evaluated through amplitude of low-frequency fluctuation (ALFF/fALFF), regional homogeneity (ReHo), and functional connectivity (FC) analyses.

In this study, significant reductions in ALFF were observed in the MOG, cuneus, superior frontal gyrus, and supplementary motor area in the follow-up group compared to baseline. This was accompanied by increased ALFF in the right insula. ReHo analysis revealed decreased values in the left median cingulate, right calcarine fissure, MOG, and left precentral gyrus, alongside increased ReHo in the supramarginal gyrus, postcentral gyrus, parahippocampal gyrus, and calcarine fissure. FC analysis demonstrated decreased connectivity between the precentral gyrus and calcarine cortex and between the MOG and calcarine cortex. Correlation analysis indicated that these imaging changes were correlated with declines in specific neurocognitive domains, including memory, speed of information processing, and executive function.

Our research demonstrates a gradual deterioration in brain function in HIV-positive individuals with ANI despite receiving cART. This decline correlates with worsening neurocognitive abilities, specifically visual processing and executive function.

The relationship between Human Immunodeficiency Virus (HIV) and Helicobacter pylori (H. pylori) is bidirectional and complex. Helicobacter pylori, by inducing local gastric and systemic immune responses, counteracts HIV invasion to CD4+ cells and other inflammatory cells and can reactivate HIV in latently infected immune cells. Human Immunodeficiency Virus infection, by reducing secretion of pro-inflammatory cytokines, reduces the incidence of H. pylori-induced gastric pathology. Gastric lymphoma regressed in some cases of people living with HIV (PLWH) after H. pylori eradication. Triple therapy for H. pylori could be associated with a strong immune. Treatment for both H. pylori and HIV can reduce the activation of either organism. However, the primary resistance to antibiotics such as levofloxacin, clarithromycin and metronidazole is higher among PLWH. This review highlights the need for further research and guidelines on the appropriate antibiotics in HIV-H. pylori co-infection particularly in PLWH who receive multiple antibiotic prophylaxis.

The immune index is an important marker of HIV immune function. Long-term clinical experience revealed that in urinary malignancy patients with AIDS who underwent radical surgery for malignant tumors, the preoperative and postoperative immune indices changed to different degrees, which affected patient prognosis. A total of 48 AIDS patients who underwent radical resection of malignant tumors in the Department of Urology of Beijing You 'an Hospital between 2015 and 2023 were included, including 25 patients with kidney cancer, 12 patients with bladder cancer and 11 patients with prostate cancer. A paired t test was used to study the changes in the immune indices CD4 + T, CD8 + T, CD3 + T and CD4+/CD8 + T cells before and after surgery for different malignant tumors in the urinary tract. The chi-square test was used to study the effects of clinical variables such as age, sex, hypertension status, diabetes status, duration of operation, duration of HIV infection, duration of medication and viral load on preoperative and postoperative immune indices. The area under the ROC curve of the four immune indicators before and after surgery was compared to evaluate the influence of immune indicators on patient prognosis. Survival curves were drawn to study the prognostic risk of immune indicators. The mean CD4 + T, CD8 + T and CD3 + T-cell counts decreased before and after surgery in patients with renal, bladder and prostate cancer, and P < 0.05 according to paired t tests indicated statistical significance, while the CD4+/CD8 + T-cell ratio was not significantly different according to paired t tests. Clinical variables such as age, sex, hypertension status, diabetes status, duration of operation, duration of HIV infection, duration of medication and viral load had no statistically significant effects on the preoperative or postoperative immune indices. The area under the ROC curve of the four immune indices was compared, and the results showed that CD8 + T cells [preoperative AUC of 0.678 (P < 0.05) and postoperative AUC of 0.702 (P < 0.05)] were superior to the other indices. Survival curve analysis revealed that a decrease in CD4 + T, CD8 + T and CD3 + T cells after surgery led to a decrease in the survival rate of patients, but the results were not statistically significant. CD4 + T, CD8 + T and CD3 + T cells decreased before and after surgery in patients with malignant tumors of the urinary system complicated with AIDS, and CD8 + T cells had a statistically significant effect on patient prognosis compared with other immune indices.

Anal squamous intraepithelial lesions are identifiable and treatable precancerous lesions that lack defined risk factors determining screening necessity.

Assess the prevalence and risk factors associated with low- and high-grade anal squamous intraepithelial lesions and anal squamous-cell carcinoma.

Retrospective cohort analysis of veterans with HIV between 1999 and 2023.

National multicenter study of the Department of Veterans Affairs.

Veterans with HIV who had >1 year of follow-up and no anal squamous intraepithelial lesions or anal cancer diagnosis before the study period.

Primary outcomes include the prevalence, disease-free survival rates, and HRs associated with risk factors for developing anal squamous intraepithelial lesions and/or anal cancer.

A total of 48,368 patients were analyzed. The mean age of patients at study initiation was 47.8 years, with a mean follow-up of 12.3 years. Seven thousand five hundred seventy-two patients (16%) had at least 1 anal cytopathology or histopathology result. The prevalence of anal disease was recorded for low-grade disease (n = 1513; 3.1%), high-grade disease (n = 1484; 3.1%), and cancer (n = 664; 1.4%). Mean (SD) times to first incident low-grade disease, high-grade disease, and cancer were 8.5 (6.0), 9.1 (6.0), and 9.7 (6.2) years, respectively. Five-year, 10-year, and 20-year disease-free survival rates for the development of low-grade disease, high-grade disease, or cancer were 97.5%, 94.5%, and 88.4%, respectively. Cox regression modeling demonstrated that CD4/CD8 ratios of <0.5 were associated with an increased risk of anal cancer (HR, 3.93; 95% CI, 3.33-4.63; p < 0.001).

Retrospective study that focused almost exclusively on male US veterans. Results might not apply to non-male, non-US populations.

National analysis of more than 48,000 veterans with HIV demonstrates that 16% had anal cytopathology or histopathology results with an anal cancer prevalence of 1.4%. CD4/CD8 ratios of <0.5 correlate strongly with the severity of anal disease and can help identify patients at the highest risk for anal cancer to prioritize screening efforts. See Video Abstract.

ANTECEDENTES:Las lesiones intraepiteliales escamosas anales son lesiones precancerosas identificables y tratables que carecen de factores de riesgo definidos que determinen la necesidad de detección.OBJETIVO:Evaluar la prevalencia y los factores de riesgo asociados con las lesiones intraepiteliales escamosas anales de grado bajo y alto y el carcinoma de células escamosas anal.DISEÑO:Análisis de cohorte retrospectivo de veteranos con VIH entre 1999 y 2023.ESTABLECIMIENTO:Estudio multicéntrico nacional del Departamento de Asuntos de Veteranos.PACIENTES:Veteranos con VIH que tuvieron >1 año de seguimiento y sin lesiones intraepiteliales escamosas anales ni diagnóstico de cáncer anal antes del período de estudio.PRINCIPALES RESULTADOS Y MEDIDAS:Los resultados primarios incluyen la prevalencia, las tasas de supervivencia libre de enfermedad y los cocientes de riesgo asociados con los factores de riesgo para desarrollar lesiones intraepiteliales escamosas anales y/o cáncer anal.RESULTADOS:Se analizaron 48.368 pacientes. La edad promedio de los pacientes al inicio del estudio fue de 47,8 años con un seguimiento medio de 12,3 años. 7.572 (16%) pacientes tuvieron al menos un resultado de citopatología o histopatología anal. Se registró la prevalencia de enfermedad anal para enfermedad de bajo grado (n = 1.513, 3,1%), enfermedad de alto grado (n = 1.484, 3,1%) y cáncer (n = 664, 1,4%). Los tiempos medios hasta el primer incidente de enfermedad de bajo grado, enfermedad de alto grado y cáncer fueron 8,5 (DE = 6,0), 9,1 (DE = 6,0) y 9,7 (DE = 6,2) años, respectivamente. Las tasas de supervivencia libre de enfermedad a 5 años, 10 años y 20 años para el desarrollo de enfermedad de bajo grado, enfermedad de alto grado o cáncer fueron 97,5%, 94,5% y 88,4%, respectivamente. El modelo de regresión de Cox demostró que los índices CD4/CD8 <0,5 se asociaban con un mayor riesgo de cáncer anal (HR: 3,93, IC del 95 %: 3,33-4,63, p < 0,001).LIMITACIONES:Estudio retrospectivo que se centra casi exclusivamente en veteranos estadounidenses de sexo masculino. Los resultados podrían no aplicarse a poblaciones no masculinas ni estadounidenses.CONCLUSIONES:El análisis nacional de más de 48 000 veteranos con VIH demuestra que el 16 % tenía resultados de citopatología o histopatología anal con una prevalencia de cáncer anal del 1,4 %. Los índices CD4/CD8 <0,5 se correlacionan fuertemente con la gravedad de la enfermedad anal y pueden ayudar a identificar a los pacientes con mayor riesgo de cáncer anal para priorizar los esfuerzos de detección. (Traducción-Dr Yolanda Colorado ).

The global burden of cervical cancer is highest in low- and middle-income countries. Women living with human immunodeficiency virus (HIV) infection are particularly affected by cervical cancer despite availability and adherence to antiretroviral therapy. Immune profile correlates of survival and treatment response have not been widely explored in patients with and without HIV infection. This study recruited women with cervical cancer undergoing definitive chemoradiation (CRT) in Botswana. Clinical characteristics and blood samples were collected. Flow cytometry was performed on samples prior to initiation, at completion, and 3 months after CRT. Logistic regression analysis identified immune markers that differed by HIV status and correlated with overall survival (OS). The study enrolled 131 consecutive women (HIV+ N = 89 and HIV− N = 42). From initiation to 3 months after CRT, a significant decrease in CD4 frequency (72%–60.55%, P < 0.001) and an increase in CD8 frequency (20.9%–31.5%, P < 0.001) were seen in women without HIV, whereas no significant changes in CD4 frequency (52.5%–50.9%) or CD8 frequency (39.9%–41.4%) were observed in those with HIV. Peripheral T cells underwent similar activation across the cohort regardless of HIV status. Improved OS was associated with reduced frequency of IL-2–expressing CD4 T-cell subsets. In women living with HIV, enhanced OS was associated with the presence of proinflammatory CD8 T cells. CRT induces peripheral T-cell activation and distinct cytokine profiles that differ by HIV status. Despite similar OS, HIV infection may differentially affect immune response to CRT in women with well-managed HIV.

Chemoradiation affects the immune system of patients with cervical cancer with well-controlled HIV infection differently than those without HIV, yet their survival does not differ. This finding is an important step in understanding how management of HIV infection can modify cancer outcomes, particularly in settings with a high burden of HIV.

HIV-1 infection induces persistent immune system activation despite antiretroviral therapy. New immunomodulatory targets might be required to restore immune competence. The dendritic cells immunoreceptor (DCIR) can bind HIV-1 and regulate immune functions and extracellular vesicles (EVs) production. EVs have emerged as biomarkers and a non-invasive tool to monitor HIV-1 progression. In people living with HIV-1, an increase in the size and abundance of EVs is associated with a decline in the CD4/CD8 T cells ratio, a key marker of immune dysfunction. Analysis of host nucleic acids within EVs has revealed an enrichment of microRNA-155 (miR-155) during HIV-1 infection. Experiments have demonstrated that miR-155-rich EVs enhance HIV-1 infection in vitro. A humanized NSG-mouse model was established to assess the in vivo impact of miR-155-rich EVs. Co-production of the virus with miR-155-rich EVs heightened the viral load and lowered the CD4/CD8 ratio in the mice. Upon euthanasia, EVs were isolated from plasma for size and quantity assessment. Consistent with findings in individuals with HIV-1, increased EV size and abundance were inversely correlated with the CD4/CD8 ratio. Next, by using the virus co-product with EV-miR-155, we tested a DCIR inhibitor to limit infection and immune damage in a humanized mouse model. DCIR inhibition reduced infection and partially restored immune functions. Finally, viral particles and various EV subtypes can convey HIV-1 RNA. HIV-1 RNA was predominantly associated with large EVs (200-1000 nm) rather than small EVs (50-200 nm). Viral loads in large EVs strongly correlated with blood and tissue markers of immune activation. The humanized mice model has proven its applicability to studying the roles of EVs on HIV-1 infection and investigating the impact of DCIR inhibition.

Both B-cell- and T-cell-mediated immunity are crucial for the effective clearance of viral infection, but little is known about the dynamic characteristics of SARS-CoV-2-specific B-cell and T-cell responses in people living with HIV (PLWH) after a full course of inactivated SARS-CoV-2 vaccination.

In this study, fifty people living with HIV (PLWH) and thirty healthy controls (HCs) were enrolled to assess B-cell and T-cell responses at the day before the vaccination (T0), two weeks after the first dose (T1), two months after the first dose (T2), the day of the third dose (T3), one month after the third dose (T4), three months after the third dose (T5) and 12 months (T6) after the third dose.

SARS-CoV-2-specific B-cell and T-cell responses were induced in people living with HIV (PLWH), and these responses lasted at least one year after the third vaccine dose. However, the peak frequencies of Spike-specific B-cell and T-cell responses in PLWH were lower than those in HIV-negative controls. In addition, the expansion of activated B cells, memory B cells and plasma cells after primary vaccination was observed, but the percentages of these cells were decreased at T6 and were comparable to those at T0. Additionally, the percentages of activated T cells, exhausted T cells and SARS-CoV-2-specific T cells with enhanced functional activity were increased following the administration of inactivated SARS-CoV-2 vaccine. In addition, PLWH had lower percentages of plasma cells, RBD-specific B cells, circulating Tfh (cTfh) cells and CD38+ cTfh cells, and the percentages of the latter two types of cells were positively correlated with the titer of neutralizing antibodies, indicating these differences may account for the weaker immune responses induced in PLWH.

These data suggest that specific B-cell and T-cell responses could be sustained for at least one year after receiving the third vaccination. Our findings emphasize that the weak SARS-CoV-2-specific B-cell and T-cell responses induced in PLWH have implications for clinical decision-making and public health policy for PLWH with respect to SARS-CoV-2 infection.

Despite antiretroviral therapy (ART), people with HIV (PWH) on ART experience higher rates of morbidity and mortality vs. age-matched HIV negative controls, which may be driven by chronic inflammation due to persistent virus. We performed bulk RNA sequencing (RNA-seq) on peripheral CD4+ T cells, as well as quantified plasma immune marker levels from 154 PWH on ART to identify host immune signatures associated with immune recovery (CD4:CD8) and HIV persistence (cell-associated HIV DNA and RNA). Using a novel dimension reduction tool - Pairwise Controlled Manifold Approximation (PaCMAP), we defined three distinct participant transcriptomic clusters. We found that these three clusters were largely defined by differential expression of genes regulated by the transcription factor NF-κB. While clustering was not associated with HIV reservoir size, we observed an association with CD4:CD8 ratio, a marker of immune recovery and prognostic factor for mortality in PWH on ART. Furthermore, distinct patterns of plasma IL-1β, TNF-α and GCSF were also strongly associated with the clusters, suggesting that these immune markers play a key role in CD4+ T cell transcriptomic diversity and immune recovery in PWH on ART. These findings reveal novel subgroups of PWH on ART with distinct immunological characteristics, and define a transcriptional signature associated with clinically significant immune parameters for PWH. A deeper understanding of these subgroups could advance clinical strategies to treat HIV-associated immune dysfunction.

CD4+ T-cell lymphocytopenia and immune dysfunction are factors that drive the onset and persistence of Kaposi sarcoma (KS) in people with (PWH) and without HIV. Standard chemotherapy agents for KS can contribute to increasing CD4+ T cell lymphocytopenia. IL-7 is a cytokine that is essential in T-cell development, proliferation and homeostasis. In PWH, IL-7 administration leads to increased numbers of circulating central memory and naïve T-cell phenotypes.

In this multicenter phase I study with a 3+3 dose escalation design, participants with KS with or without HIV received up to four intramuscular injections of IL-7 (NT-I7) every 9 weeks. The primary endpoint of the study was to evaluate safety over three escalating dose levels (DL) of NT-I7 (DL1:480 µg/kg, DL2: 960 µg/kg and DL3: 1200 µg/kg) and identify a maximum tolerated dose. Secondary endpoints included evaluation of antitumor activity per the modified AIDS Clinical Trials Group Criteria and assessment of the effect of NT-I7 on the kinetics of CD4+ and CD8+ T-cells.

Eight cisgender male participants (five with HIV infection) were enrolled. Six participants were treated at DL1, and two were treated at DL2. The study was closed to accrual after enrolment of the second participant on DL2 due to termination of study funding. Four of the eight participants (three in DL1 and one in DL2) completed all four doses of the NT-I7. With regard to treatment-emergent adverse events (AEs), all participants had

CONCLUSIONS

Preliminary data demonstrate safety and activity of IL-7 in patients with KS and activity specifically among individuals HIV-associated KS.

TRIAL REGISTRATION NUMBER

NCT04893018.

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During antiretroviral therapy (ART), the HIV reservoir shows variability, with cells carrying intact genomes decaying faster than those with defective genomes, particularly in the first years. The host factors influencing this decay remain unclear.

Observational study of 74 PWH on ART, 70 (94.6%) of whom were male. Intact proviruses were measured using the intact proviral DNA assay, and 32 inflammatory cytokines were quantified using Luminex immunoassay. Linear spline models assessed the impact of baseline cytokine levels and their trajectories on intact HIV kinetics over seven years.

Baseline Gal-9 was the strongest predictor, with lower levels predicting faster decay. A 10-fold decrease in baseline Gal-9 correlated with a 45% (95% CI, 14%-84%) greater annual decay of intact HIV genomes. Higher baseline interferon-inducible T-cell α chemoattractant (ITAC), interleukin 17 (IL-17), and macrophage inflammatory protein 1α (MIP-1α) levels also predicted faster decay. Longitudinal increases in MIP-3α and decreases in IL-6 were linked to a 9.5% and 10% faster decay, respectively.

The association between lower baseline Gal-9 and faster intact HIV decay suggests targeting Gal-9 could enhance reservoir reduction. The involvement of MIP-3α and IL-6 highlights a broader cytokine regulatory network, suggesting potential multi-targeted interventions.

Diffuse panbronchiolitis (DPB) is an uncommon respiratory disorder characterized by the presence of respiratory bronchiolitis and persistent inflammation in adjacent tissues, which can be effectively treated with early diagnosis and intervention. DPB is a rare complication associated with thymoma that remains poorly understood, especially when it occurs in conjunction with acquired cellular immune deficiency.

We present a case of DPB in a patient with thymoma following thymectomy and radiation therapy. A 47-year-old Chinese man underwent thymectomy due to the presence of a mediastinal mass, and pathological examination confirmed a type B2 thymoma. He also underwent 25 sessions of radiation therapy. The patient's respiratory symptoms, including cough, expectoration, and shortness of breath, worsened significantly after radiation treatment. Immune dysfunction, marked by CD4+ T cell immunodeficiency with normal immunoglobulin levels, was observed. Chest computed tomography revealed diffuse nodules with tree-in-bud signs and new consolidation within the irradiated area, leading to a diagnosis of combined DPB and radiation pneumonitis. The patient's symptoms and lung imaging findings significantly improved after the initiation of low-dose oral azithromycin for DPB and low-dose glucocorticoid therapy for radiation pneumonitis.

Clinicians should consider DPB in patients with thymoma and cellular immunodeficiency. Both thymectomy and radiation therapy can contribute to the development of DPB. Early treatment with macrolides can improve patient prognosis.

Long-term management of people living with HIV (PLWHs) often relies on CD4+ T cell counts for assessing immune recovery, yet a single metric offers limited information. This study aimed to explore the association between the CD4/CD8 ratio and T lymphocyte activities in PLWHs.

125 PLWHs and 31 HIV-uninfected controls (UCs) were enrolled and categorized into four groups based on their CD4/CD8 ratios: extremely low ratio (ELR) group: 0.4 < CD4/CD8; low ratio (LR) group: 0.4 ≤ CD4/CD8<0.7; medium ratio (MR) group: 0.7 ≤ CD4/CD8<1; high ratio (HR) group: CD4/CD8 ≥ 1. The activation and proliferation phenotypes, mitochondrial functions, and inflammatory indexes of CD4+ T cells and CD8+ T cells were measured, and correlations between the CD4/CD8 ratio and T cell functions were analyzed.

T cell activation and proliferation were significantly elevated in the ELR group compared to UCs. However, the ELR group had a larger proportion of T cells with lipid peroxidation, mitochondrial lipid reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) abnormalities compared to the other groups. As the CD4/CD8 ratio increased, mitochondrial lipid peroxidation damage decreased and MMP was restored. Additionally, the ELR group had more inflammatory markers in CD4+ T cells. Correlation analysis revealed that the CD4/CD8 ratio was associated with multiple T cell functions, and its correlation coefficient with mitochondrial function was higher than that of CD4+ T cell count.

The CD4/CD8 ratio is closely related to T lymphocyte functions and is significantly superior to the CD4+ T cell count in reflecting the mitochondrial lipid peroxidation level and mitochondrial functions within T lymphocytes.

The study aims to investigate the demographic characteristics, the variations in their immune status, and mortality risk among HIV-1 infection long-term non-progressors (LTNP).

Eligible LTNP and typical progressors (TP) were recruited in Guangxi by December 2018. Participants were followed up until December 2022, monitoring ART status, CD4+ T cell counts, and survival/death outcomes. Multivariate logistic, Cox regression, and Kaplan-Meier method were employed to scrutinize associated factors and mortality risk of LTNP.

A total of 212 LTNP and 390 TP were included. LTNP cohort predominantly comprised males (84.43%), those diagnosed with HIV at age ≤ 40 years (93.87%), and those infected through injection drug use (59.91%). The mortality rate of LTNP were lower than TP (12.74% vs. 27.18%). TP had a higher mortality risk compared to LTNP (adjusted hazard ratio [aHR] = 4.051, 95% CI: 2.284-7.186, P < 0.001). The mortality risk was also elevated in the ART-naïve group versus the ART-experienced ones (aHR = 3.943, 95%CI: 2.658-5.850, P < 0.001). Notably, the CD4/CD8 ratio in the LTNP group did not fully recover (< 1.0) despite ART. However, LTNP with ART-experienced had a significantly lower mortality risk compared to ART-naïve LTNP group (Log-rank: P = 0.003).

ART effectively restores and maintains normal CD4+ T cell levels among LTNP, thereby decreasing mortality risk. Nonetheless, the CD4/CD8 ratio in LTNP exhibits incompletely recovered post-ART. These findings provide a scientific foundation for promoting ART in LTNP population.

Our objective was to evaluate the trajectory of immunology in patients with HIV with different baseline CD4 T-cell count strata after antiretroviral therapy (ART) under long-term viral suppression.

This was a sub-analysis focused on patients with virological suppression for at least 5 years after ART. Data were obtained from the Yunnan HIV cohort in China. Patients were categorized according to prespecified baseline CD4 T-cell counts. The trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio changing over time were fitted using a B-spline regression model. The Cox proportional hazards regression model was used to assess the association of baseline CD4 T-cell count with the risk of both immunological responder (IR) and CD4/CD8 ratio normalization.

A total of 2618 patients with a median follow-up of 7.25 years (interquartile range [IQR] 5.92-8.75) were included. Over a period of 12 years, the mean CD4 T-cell count remained above 500 cells/μL in all groups. The mean CD4/CD8 ratio was solely normalized in patients whose baseline CD4 T-cell counts were above 350 cells/μL. Patients with higher baseline CD4 T-cell counts showed higher risks of both IR and CD4/CD8 ratio normalization than those with the lowest (all p trend <0.001). A higher baseline CD4 T-cell count predicted a shorter time for both IR and CD4/CD8 ratio normalization.

Long-term, sustained viral suppression may not be able to fully normalize immunological functions in patients with HIV. A high baseline CD4 T-cell count benefits IR and CD4/CD8 ratio normalization.

Common Variable Immunodeficiency Disease (CVID) and other immunodeficiencies can present in subtle and variable ways. Whether or not a genetic lesion can be identified, there are not well understood biomarkers that quantitatively describe how severe a deficiency is. Here we discuss two possible ranking systems, CD4/CD8 T cell ratios and Immune Health Grades, and how such data maybe applicable to some immunodeficiencies.

This is not a systematic review, but we identify papers relating to immunodeficiencies with enough data to comment on the CD4/CD8 and Immune Health Grade. We also summarized relevant data publicly available from USIDNET, a website that compiles data on immunodeficiencies, and provide two new cases that illustrate ways that this information can alter clinical assessment.

We review the HIV literature on CD4/CD8 T cell data and how this correlates with both immunologic function and comorbidity better than CD4 count alone. The ratio aslso relates to a new system called Immune Health Grades (IHG) derived from young adult to elderly subjects from many NIH cohorts without HIV. CVID is often thought of as an antibody problem, but in fact most patients also have low CD4/CD8 ratio and other cellular abnormalities. We review IDNET to categorize nine molecular immunodeficiencies including two subcategories of CVID into low, normal, or high ratios. Finally, we present two new cases in the literature of patients with recurrent infection and discuss how viewing the cases through the "lens" of CD4/CD8 ratio and IHG can facilitate clinical decisions.

Emerging data suggests at least some immunodeficiencies can be grouped by how abnormal their CD4/CD8 ratio or IHG. This represents a clinically available biomarker that can be tracked to see if the condition is worsening or not.

Genvoya, Biktarvy and Dovato are novel single-tablet antiretroviral therapy(ART). The aim of this study is to explore the therapeutic effects of these novel drugs on HIV/AIDS.

This retrospective cohort study, conducted at a single center, included a total of 200 HIV-treated patients who transitioned to these new antiretroviral drugs from July 2021 to August 2023. Data were extracted from electronic medical records at Ditan Hospital. The Genvoya group comprised 22 patients, and all subsequent switches in this group were to Biktarvy. The primary HAART group consisted of 178 patients initially treated with a first-line triple Highly Active Antiretroviral Therapy (HAART) regimen during the same period. This group was further subdivided into HAART+Dovato, HAART+Biktarvy, and HAART+Genvoya groups based on the switching regimen. The primary outcomes focused on changes in viral load and immune efficacy, while secondary safety indicators included blood/liver function, lipid parameters, renal function, blood glucose, blood uric acid, etc. KEY FINDINGS: The viral suppression rate was 100 % after the drug change treatment, and CD4+ T cell counts increased significantly across all four groups. Over the 6-month treatment period, there were increases in creatinine (Cr), low-density lipoprotein (LDL), high-density lipoprotein (HDL), erythrocyte count, and glomerular filtration rate (eGFR). Conversely, Alanine transaminase (ALT), Aspartate aminotransferase (AST), C-reactive protein (CRP), albumin (ALB), and blood glucose (Glu) levels decreased.

Genvoya, Biktarvy and Dovato are recommended for the treatment of HIV/AIDS and have a good safety profile.

Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (P = 0.048) and 96 (P = 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; P = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770).Trial registration: ClinicalTrials.gov identifier: NCT04098770.Trial registration: ClinicalTrials.gov identifier: NCT02651376.

HIV-associated neurocognitive disorders (HAND) is hypothesized to be a result of myeloid cell-induced neuro-inflammation in the central nervous system that may be initiated in the periphery, but the contribution of peripheral T cells in HAND pathogenesis remains poorly understood.

We assessed markers of T cell activation (HLA-DR + CD38+), immunosenescence (CD57 + CD28-), and immune-exhaustion (TIM-3, PD-1 and TIGIT) as well as monocyte subsets (classical, intermediate, and non-classical) by flow cytometry in peripheral blood derived from individuals with HIV on long-term stable anti-retroviral therapy (ART). Additionally, normalized neuropsychological (NP) composite test z-scores were obtained and regional brain volumes were assessed by magnetic resonance imaging (MRI). Relationships between proportions of immune phenotypes (of T-cells and monocytes), NP z-scores, and brain volumes were analyzed using Pearson correlations and multiple linear regression models.

Of N = 51 participants, 84.3% were male, 86.3% had undetectable HIV RNA < 50 copies/ml, median age was 52 [47, 57] years and median CD4 T cell count was 479 [376, 717] cells/uL. Higher CD4 T cells expressing PD-1 + and/or TIM-3 + were associated with lower executive function and working memory and higher CD8 T cells expressing PD-1+ and/or TIM-3+ were associated with reduced brain volumes in multiple regions (putamen, nucleus accumbens, cerebellar cortex, and subcortical gray matter). Furthermore, higher single or dual frequencies of PD-1 + and TIM-3 + expressing CD4 and CD8 T-cells correlated with higher CD16 + monocyte numbers.

This study reinforces evidence that T cells, particularly those with immune exhaustion phenotypes, are associated with neurocognitive impairment and brain atrophy in people living with HIV on ART. Relationships revealed between T-cell immune exhaustion and inflammatory in CD16+ monocytes uncover interrelated cellular processes likely involved in the immunopathogenesis of HAND.

Persistence of a low CD4/CD8 ratio is associated with an increased morbimortality in people living with HIV (PLWH) under effective antiretroviral therapy. We aimed to explore the immunological significance of a persistently low CD4/CD8 ratio, even despite normal CD4 levels, and assess whether these features vary from those associated to a low nadir-CD4, another well-established predictor of disease progression.

CD4-recovered PLWH were classified by CD4/CD8 ratio after three-years of ART (viral suppression, CD4≥500; R < 0.8, n = 24 and R > 1.2, n = 28). sj/β-TRECs ratio and inflammatory-related markers were quantified. PBMCs were immunophenotyped by CyTOF and functionally characterized by ELISPOT. Subjects were also reclassified depending on nadir-CD4 (N ≤ 350/N > 350).

R < 0.8 showed a differential inflammatory profile compared to R > 1.2 (increased β2-microglobulin, D-dimers and IP-10 before ART). R < 0.8 presented lower baseline thymic function, being inversely correlated with post-ART inflammation. R < 0.8 at follow-up showed most alterations in CD8 subsets (increasing frequency and exhibiting a senescent phenotype [e.g., CD57+, CD95+]) and enhanced T-cell IFNγ/IL-2 secretion. However, comparing N ≤ 350 to N > 350, the main features were altered functional markers in CD4 T-cells, despite no differences in maturational subsets, together with a restricted T-cell cytokine secretion pattern.

Persistence of low CD4/CD8 ratio in successfully-treated PLWH, with normal CD4 counts, is associated with baseline inflammation and low thymic function, and it features post-therapy alterations specific to CD8 T-cells. Differently, subjects recovered from low nadir-CD4 in this setting feature post-therapy alterations on CD4 T-cells. Hence, different mechanisms of disease progression could underlie these biomarkers, potentially requiring different clinical approaches.

Optimal control of microbial infections requires mucosal-associated invariant T (MAIT) cells. People living with HIV (PWH) on antiretroviral therapy (ART) can be divided into 2 groups: immune responders (IR) who recover or retain CD4 T cell numbers, and immune non-responders (INR) who do not. Compared to IR, INR have fewer MAIT cells and increased systemic inflammation and microbial translocation, but how these factors affect MAIT cells is unknown.

MAIT cells from IR, INR, and from controls without HIV were enumerated and characterized by flow cytometry. To determine the links among MAIT cells, inflammation, and microbial translocation, the correlations of MAIT cell numbers to previously published soluble inflammatory markers and plasma microbial genetic sequences were assessed by Spearman analysis. In vitro assays were used to support our findings.

MAIT cell numbers were significantly negatively correlated with levels of IL-6 and IP-10 (markers of inflammation); CD14, LPS, and FABP2 (markers of microbial translocation); and with abundance of Serratia and other Proteobacteria genetic sequences in plasma. In a separate analysis of PWH on ART receiving the IL-6 receptor antagonist tocilizumab (TCZ), we found that blocking IL-6 signaling with TCZ increased IL-7 receptor expression on MAIT cells and reduced plasma IL-7 levels, consistent with improved uptake of IL-7 in vivo.

Our findings suggest inflammation and microbial translocation in PWH on ART lead to a loss of MAIT cells via impaired IL-7 responsiveness, resulting in further increased microbial translocation and inflammation.

Human immunodeficiency virus (HIV) infection remains a major public health concern despite a significant decline in HIV-related mortality and morbidity. These significant advances are linked mostly to effective antiretroviral therapy (ART). However, these treatments are not without consequences on other microorganisms in our body, especially when they must be used for life. Balanced gut microbiota is essential for maintaining human health through symbiotic relationship with the host cells.

This review focuses on ART and its potential impact on the intestinal microbial population of HIV-infected individuals. Therefore, we retrieved studies focusing on the impact of HIV ART on the gut microbiota, that were published from 2010 to 2021.

It was observed that most studies on HIV ART and associated gut microbiota have been cross-sectional, and the findings, in general, showed significant damages caused by the ART to the gut microbial community (dysbiosis), with the impact varying in different studies. These changes also revealed dysfunction in microbial translocation and some immune markers, including T lymphocyte rates and the overall inflammation balance.

There are significant gaps in our understanding of the impact of HIV ART on gut microbiota. Thus, a longitudinal study is likely needed with a considerable sample size from different settings and classes of ART to better understand the impact of HIV ART on the gut microbiota, and develop remedial (restorative) and adjunctive host-directed strategies during HIV ART.

Despite effective antiretroviral therapy, people with HIV (PWH) experience persistent systemic inflammation and increased morbidity and mortality. Modulating the gut microbiome through fecal microbiota transplantation (FMT) represents a novel therapeutic strategy. We aimed to evaluate proteomic changes in inflammatory pathways following repeated, low-dose FMT versus placebo.

This double-masked, placebo-controlled pilot study assessed the proteomic impacts of weekly FMT versus placebo treatment over 8 weeks on systemic inflammation in 29 PWH receiving stable antiretroviral therapy (ART). Three stool donors with high Faecalibacterium and butyrate profiles were selected, and their individual stools were used for FMT capsule preparation. Proteomic changes in 345 inflammatory proteins in plasma were quantified using the proximity extension assay, with samples collected at baseline and at weeks 1, 8, and 24. Concurrently, we characterized shifts in the gut microbiota composition and annotated functions through shotgun metagenomics. We fitted generalized additive models to evaluate the dynamics of protein expression. We selected the most relevant proteins to explore their correlations with microbiome composition and functionality over time using linear mixed models.

FMT significantly reduced the plasma levels of 45 inflammatory proteins, including established mortality predictors such as IL6 and TNF-α. We found notable reductions persisting up to 16 weeks after the final FMT procedure, including in the expression of proteins such as CCL20 and CD22. We identified changes in 46 proteins, including decreases in FT3LG, IL6, IL10RB, IL12B, and IL17A, which correlated with multiple bacterial species. We found that specific bacterial species within the Ruminococcaceae, Succinivibrionaceae, Prevotellaceae families, and the Clostridium genus, in addition to their associated genes and functions, were significantly correlated with changes in inflammatory markers.

Targeting the gut microbiome through FMT effectively decreased inflammatory proteins in PWH, with sustained effects. These findings suggest the potential of the microbiome as a therapeutic target to mitigate inflammation-related complications in this population, encouraging further research and development of microbiome-based interventions. Video Abstract.

Torque teno virus (TTV) viral load (VL), a component of the human virome, increases during immune suppression or dysregulation. This study aimed to explore TTV VL in youths living with vertically acquired HIV (YWVH) and its potential as an immunovirological marker. We performed an observational, retrospective study involving YWVH under antiretroviral treatment (ART) from the Spanish Cohort of HIV-infected children, adolescents, and vertically HIV-infected patients transferred to Adult Units (CoRISpe-FARO), compared to HIV-negative healthy donors (HD). Plasma TTV VL was assessed by qPCR. T-cell phenotype was analysed on cryopreserved peripheral blood mononuclear cells by flow cytometry. Correlations with baseline CD4 and CD8 and long-term virological evolution were examined. A total of 57 YWVH were compared with 23 HD. YWVH had a median CD4 T-cells of 736 cells/mm3 [IQR: 574-906], a median of 17 years [IQR: 14-20.5] since ART initiation, and 65 months [IQR: 39-116] under HIV-RNA virological control. TTV VL was higher among YWVH and in males compared with females (p < 0.05). Among YWVH, TTV VL correlated with CD4 and CD8 counts and the CD4/CD8 ratio (p = 0.002; r = - 0.39, p = 0.037; r = 0.277, p = 0.005; r = - 0.37 respectively). TTV VL correlated with activation expression markers (HLA-DR+/CD38+) on CD4 (p = 0.007, r = 0.39) and the soluble proinflammatory cytokine IL-6 (p = 0.006, r = 0.38).

Micronutrients have significant functional implications for the human immune response, and the quality of food is a major factor affecting the severity and mortality caused by HIV in individuals undergoing antiretroviral therapy. A decrease in CD4 lymphocyte count and an increase in CD8 lymphocyte count are the hallmarks of HIV infection, which causes the CD4/CD8 ratio to invert from a normal value of >1.6 to <1.0. In this study, we tried to analyze whether the nutritional status of HIV-positive patients has an impact on the CD4/CD8 ratio inversion by utilizing a machine learning (ML) algorithm.

In this study, 55 confirmed HIV-positive patients who had not started their anti-retroviral therapy were included after obtaining their informed, written consent. Moreover, 55 age-and sex-matched relatives and caregivers of the patients who tested negative in the screening were enrolled as controls. All individual patient data points were analyzed for model development with an 80-20 train-test split. Four trace elements, zinc (Zn), phosphate (P), magnesium (Mg), and calcium (Ca), were utilized by implementing a random forest classifier. The target of the study was the inverted CD4/CD8 ratio.

The data of 110 participants were included in the analysis. The algorithm thus generated had a sensitivity of 80% and a specificity of 83%, with a likelihood ratio (LR+) of 4.8 and LR-of 0.24. The utilization of the ML algorithm adds to the limited evidence that currently exists regarding the role of micronutrients, especially trace elements, in the causation of immune risk. Our inherent strength lies in the fact that this study is one of the first studies to utilize an ML-based decision tree algorithm to classify immune risk in HIV patients.

Our study uniquely corroborated the nutritional data to the immune risk in treatment-naïve HIV patients through the utilization of a decision tree ML algorithm. This could subsequently be an important classification and prognostic tool in the hands of clinicians.

Infectious gastroenteritis is the major cause for diarrhea in piglets. The protection of spray-dried plasma (SDP) on viral gastroenteritis during the progression of rotavirus (RV) infection remain unclear. In this study, 64 weanling piglets were randomly assigned to control diets (n = 40) and SDP diets (n = 24) for 14 days, and then pigs were challenged with RV on day 15. Pigs were sacrificed on day 14 (normal condition), day 18 (manifestation stage), and day 21 (convalescent stage) of the trial. Prior to RV infection, SDP increased ADG, M1 macrophages and CD4+ T cells in different organs without increasing proinflammatory cytokines, indicating a more robust immunity with less inflammation. During the manifestation of infection, SDP enhanced mucosal immunity by increasing M1 macrophages, M1/M2 ratio and cytokines in mucosa and increasing intraepithelial CD8+ T cells for RV clearance. During the convalescence, SDP promoted M2 macrophage polarization and reduced pro-inflammatory cytokines to facilitate intestinal repair and prevent prolonged inflammation. Collectively, SDP enhanced mucosal immunity to promote viral clearance and maintained immune homeostasis to prevent long-lasting inflammation as a therapeutically approach for infectious gastroenteritis.

Despite the success in the management of HIV with antiretroviral therapy (ART), people with HIV (PWH) have a heightened state of immune activation and inflammation, and an estimated 10%-40% demonstrate poor CD4 T-cell reconstitution, thereby increasing their mortality and morbidity risk burden. Soluble immunoregulatory proteins that function in lymphocyte activation or inhibition are elevated in PWH and associate with T-cell dysfunction, HIV persistence, and are predictive of comorbid outcomes. Here, we measured a panel of 35 circulating immunoregulatory proteins in 116 PWH with variations in CD4 T-cell counts (poor CD4 trajectory: <200 cells/μl, n = 34 or immune competent: CD4 >500 cells/μl, n = 82) by Luminex. Participants were enrolled in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort, had initiated ART on enrollment, and had been on suppressive ART for 1 year. Using non-parametric analysis, we found that the levels of CD276, ICOSL, BAFF, OX40, galectin-1, and galectin-9 were significantly higher in PWH with poor CD4 trajectories compared to individuals with immune-competent CD4 T-cell count. Notably, in logistic models, ICOSL and OX40 remained significant after adjusting for age and baseline plasma HIV RNA. Furthermore, Extreme Gradient Boosting machine learning models comprising co-stimulatory and inhibitory checkpoint proteins yielded high accuracy in classification of individuals with poor CD4 trajectories. In summary, we identified a novel signature of circulating immunoregulatory proteins indicative of poor CD4 trajectories that may serve as potential targets to monitor and manage immune perturbations more accurately in PWH during suppressive ART.

It is essential to track immune perturbations related to insufficient CD4 T-cell recovery in PWH on suppressive ART as those with incomplete reconstitution are at a greater risk of non-AIDS-related morbidity and mortality. Several inflammatory soluble mediators have associated with poor immune reconstitution and adverse morbid outcomes in PWH, yet their implementation into routine clinical care to guide management remains inconsistent. Circulating immune checkpoint proteins have been linked to dysregulated immune pathways during suppressive ART and may serve as improved surrogate markers of clinical relevance. Here we investigate soluble lymphocyte-associated immunoregulatory proteins in virally suppressed PWH with no reported co-morbid outcomes and varying CD4 T-cell counts, to reveal underlying pathways that remain perturbed despite ART. This novel signature of immunoregulatory markers pertaining to poor CD4 T-cell trajectories uncover previously overlooked immune checkpoints as important targets for clinical monitoring of PWH in the setting of durable viral suppression by ART.

This research utilized network pharmacology to investigate the potential of Fuzheng Qudu prescription (FZQDP) in treating lung cancer (LC).

The components and their targets of FZQDP were analyzed for their relationship with LC-related targets using bioinformatics tools. Mouse Lewis lung carcinoma (LLC) cells were cultured in vitro and treated with FZQDP or cisplatin (DDP) before applying the MTT assay to determine FZQDP concentrations, and the IC50 value. According to the IC50 value, the effect of FZQDP on apoptosis and cell cycle was detected by flow cytometry. Mouse tumor growth was recorded using live animal imaging, and measurements of tumor and spleen weight were used to calculate the tumor inhibition rate and spleen index. The effects on mouse liver and kidneys were observed by analyzing levels of AST, ALT, BUN, and CRE in blood and hematoxylin and eosin (H & E) stained sections. Additionally, levels of IL-2, IL-10, IL-6, and IFN-γ in serum, along with the frequencies of CD4+ and CD8+ T cells in the spleen, were measured using Mouse multiple Cytokine Assay and flow cytometry, respectively.

SRC, STAT3, MAPK3, and MAPK1 could be crucial targets of FZQDP in the treatment of LC. FZQDP demonstrated inhibition of LC cell proliferation and tumor growth, as well as enhancement of apoptosis and induction of G2 phase cell cycle arrest. Furthermore, FZQDP led to elevated levels of IL-2 and IFN-γ, increased frequencies of CD4+ T cells and decreased levels of IL-6 and IL-10. Importantly, FZQDP did not exhibit any noticeable hepatotoxic or nephrotoxic effects in mice.

FZQDP may target multiple signaling pathways to treat LC. In a LC mouse model, FZQDP was found to inhibit tumor growth and improve immune function.

Objective: To determine whether HIV-infected individuals versus individuals with HIV/HCV coinfection, in the era of interferon-free therapies, exhibit an increased incidence of comorbidities and non-AIDS-related events. Methods: A retrospective analysis was conducted by collecting data from clinical records of Spanish patients at a tertiary hospital involving HIV/HCV-coinfected and HIV-infected patients, all with effectively controlled HIV. Coinfected patients underwent HCV clearance using direct-acting antivirals (DAAs) and had no history of interferon treatment. The incidences of hypertension, diabetes mellitus, cardiovascular disease, kidney disease, liver disease, non-AIDS cancer, and death were compared between the groups. Multivariate adjustments for all factors potentially impacting outcomes were used to assess the risk of clinical event onset. Propensity score (PS) analyses were also conducted to support the multivariate model results. Results: Data were available from 229 HIV/HCV-coinfected patients and 229 HIV-infected patients. Both cohorts were comparable in terms of age, gender distribution, follow-up, and HIV-related characteristics. Multivariate models and PS showed that previous exposure to HCV was not associated with the onset of any clinical events studied. Significant differences between HIV/HCV-coinfected and HIV-infected were not found for survival according to the log-rank test (p = 0.402). Conclusions: Successful HCV elimination using DAAs improved the outlook regarding comorbidities and survival across HIV/HCV-coinfected cohorts. Early HCV detection and DAA therapy could enhance clinical results. These findings provide an optimistic perspective for those living with HIV/HCV coinfection and underscore the importance of continuing efforts toward early detection and DAA treatment initiation.