Higher CD4 Research Articles

Peripheral Blood CD8+ CD28+ T Cells as an Independent Predictor of Treatment Response and Survival After Concurrent Chemoradiotherapy in Pediatric High-Grade Glioma Patients.

The tumor immune microenvironment influences the efficiency of concurrent chemoradiotherapy (CCRT) in high-grade glioma (HGG). This study investigated peripheral blood T lymphocyte subsets as clinical indicators of therapeutic response and prognosis in pediatric high-grade glioma (pHGG). This retrospective study included 77 patients with postoperative pHGG who were treated concurrently with temozolomide and external beam radiotherapy between January 1, 2012, and December 31, 2018. The median follow-up was 26 (range: 5-106) months. Peripheral venous blood samples were collected before and after CCRT. The proportions of peripheral blood T lymphocytes and their association with treatment outcome and survival were determined. Sixty-four (83.1%) patients achieved complete remission, partial remission, and stable disease, and 13 (16.9%) patients had progressive disease. Higher CD3+ T cell, CD4+ T cell, and CD8+ CD28+ T cell ratios were predictive of better response, while a higher CD8+ CD28- T cell ratio was predictive of poorer response. Binary logistic regression analysis showed that the CD8+ CD28+ T cell ratio was a significant independent predictor of CCRT response (odds ratio [OR] = 53.521, 95% confidence interval [CI] = 4.294-667.119, P = .002). Univariate and multivariate analysis of prognostic factors associated with survival showed that the CD8+ CD28+ T lymphocyte ratio was a significant independent predictor of progression-free survival (hazard ratio [HR] = 1.80, 95% CI = 1.06-3.08, P = .03), but none of the subsets were significantly associated with overall survival. Peripheral blood T lymphocytes have potential as predictors of CCRT response and prognosis in pHGG.

Graft CD8 T-cell-based risk system predicts survival in antithymocyte globulin-based myeloablative haploidentical peripheral blood stem cell transplantation.

This study investigated the cellular composition of peripheral blood grafts for anti-thymocyte globulin (ATG)-based myeloablative haploidentical haematopoietic stem cell transplantation (haplo-HSCT). Clinical characteristics were retrospectively evaluated in a training cohort with ATG-based myeloablative haplo-HSCT between January 2016 and February 2020 and confirmed in a validation cohort between March 2020 and June 2021. A higher dose of graft CD8+ T cells (≥ 0.85 × 108 kg-1) was significantly improved overall survival (OS;hazard ratio [HR], 1.750; P = 0.002) and disease-free survival (DFS; HR, 1.751; P < 0.001) in the training cohort, according to multivariate Cox regression analysis. Higher doses of mononuclear cells (MNCs) demonstrated better OS (HR, 1.517; P = 0.038) and DFS (HR, 1.532; P = 0.027). Older patient age (> 46 years), older donor age (≥ 50 years) and a higher refined disease risk index (rDRI) were also related to OS. A graft CD8+ T-cell risk system based on graft CD8+ T-cell dose, donor age and rDRI was constructed using a nomogram model after LASSO Cox regression analysis. It showed acceptable discrimination, with a C-index of 0.62 and 0.63, respectively. Graft CD8+ T-cell dose was negatively correlated with donor age (P < 0.001) and positively correlated with a higher lymphocyte percentage in the peripheral blood before mobilisation (P < 0.001). A higher CD8+ T-cell dose in peripheral blood-derived grafts improves patients' survival with ATG-based myeloablative haplo-HSCT. Younger donors with higher lymphocyte percentages improved patients' survival with an intermediate rDRI risk.

Metformin Alters Tumor Immune Microenvironment, Improving the Outcomes of Breast Cancer Patients With Type 2 Diabetes Mellitus.

This study investigated the clinical effect of metformin on breast cancer patients with preexisting type 2 diabetes mellitus (T2DM). We analyzed 177 patients with T2DM who underwent breast cancer surgery and assessed tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) in patients who underwent tumor resection with or without metformin treatment using multiplex immunohistochemistry (IHC). Patients who received metformin either pre- or postoperatively exhibited reduced distant organ recurrence and improved postoperative recurrence-free survival compared to those of patients who did not. Additionally, in a subgroup of 40 patients receiving preoperative systemic therapy, metformin treatment was associated with increased rates of pathological complete response. IHC analysis revealed significantly lower levels of cluster of differentiation (CD) 68(+) CD163(+) M2-type TAMs (p < 0.01) but higher CD3(+) and CD8(+) TIL densities in the metformin-treated group compared with the same parameters in those without metformin treatment, with a significant difference in the CD8(+)/CD3(+) TIL ratio (p < 0.01). Despite the constraints posed by our small sample size, our findings suggest a potential role for metformin in modulating the immunological microenvironment, which may contribute to improved outcomes in diabetes patients with breast cancer.

Investigating the Relationship between Medication Adherence Behaviors and the Achievement of Sustained Viral Load Suppression among People Living with HIV (PLHIV) on Antiretroviral Therapy (ART) in Akwa Ibom State, from 2018 - 2022

Background: Nigeria is still endemic for Human Immuno-Deficiency Virus (HIV), and currently among the top five countries with the highest burdens of HIV infection. For a successful HIV program, there should be good access to antiretroviral therapy (ART) and record of viral load suppression (VLS). This study aimed at investigating the relationship between medication adherence behavior (MAB) and sustained VLS among people living with HIV (PLHIV) receiving ART in Akwa Ibom State. Methods: This was a retrospective cohort study of the medical records of 1,763 PLHIV receiving ART services from January 2018 to December 2022, in selected ten health facilities in Akwa Ibom State. Relevant demographic, clinical, immunological, viral load (VL) information were obtained from the patients’ medical records and databases. The proportion of VLS and associated variables were then analyzed. Results: Out of the 2,550 PLHIV whose medical records were accessed, data for 1,763 PLHIV was accepted for analysis. A total of 795 (45.1%) male and 968 (54.9%) female participated in the study, with a mean age of 38.4 ± 5 years. While 23.8% (n = 420) have unsuppressed VL of &gt;1,000 copies/mL; 76.2% (n = 1,343) of participants achieved VLS of &lt;1,000 copies/mL. 90.4% (n = 1,213) of the virally suppressed participants recorded moderate to high medication adherence levels (X2 = 94.977, df = 2, p-value = 2.2 x 10-16). CD4 counts and HAART regimen have significant impact on VLS (p &lt; 0.05), while pregnancy status, TB Infection, duration on HAART, and WHO disease stage do not have significant effects on VLS (p &gt; 0.05). Conclusion: There was a strong evidence to reject the null hypothesis, which states that there is no positive association between MAB and sustained VLS among PLHIV on ART (p &lt; 0.05). The VLS rate in this study indicates a good HIV epidemic control. Good medication adherence level, high baseline CD4 count, and being on first line HAART regimen were strongly associated with VLS.

A cross-sectional study of the factors influencing adherence to antiretroviral therapy among adults with human immunodeficiency virus infection in a tertiary care hospital in Puducherry, India.

Combating human immunodeficiency virus/acquired immunodeficiency syndrome epidemic has been possible due to advances in prevention strategies and Antiretroviral therapy (ART). Optimal adherence to ART is a major factor in achieving the desired immunological, virological, and patient well-being outcomes. Several socio-demographic, patient, treatment, and health-care system-related factors influence nonadherent behavior to ART. This study was planned to assess (1) ART adherence level, (2) factors and reasons associated with nonadherence, and (3) impact of suboptimal adherence on treatment outcomes. This was a cross-sectional analytical study of 300 patients in a tertiary care hospital in Puducherry, India. Random sampling was used to collect data from patient treatment cards and a predesigned structured questionnaire. The pill count method was used to calculate adherence level. Nonadherence was chosen as a dependent variable and factors affecting adherence were chosen as independent variables. Test for significance was carried out by Chi-square test and Fisher's exact test. Optimal adherence was seen in 68.3%. Factors significantly associated with nonadherence were lower education level, high prior CD4 count, irregular follow-up, missing doses in the past, and being late for pharmacy pill refills. Adherence was positively associated with mean increase in CD4 count over 6 months. In our study, the adherence rate is suboptimal which can lead to failure of ART. Nonadherence was associated with a decrease in CD4 count overtime. Most of the factors significantly affecting ART adherence were patient behavior related. These factors can be used for target intervention during reinforcement adherence counseling.

Immunological Efficacy and the Impact on Weight of Dolutegravir-Based Regimen in Antiretroviral Therapy (ART)-Naïve Patients with HIV Infection.

This study aimed to assess the immunological efficacy and the impact on weight of dolutegravir (DTG)-based antiretroviral therapy (ART) regimen in ART-naive people living with HIV (PLWH). A prospective study was conducted on ART-naïve PLWH who treated with DTG-based or efavirenz (EFV)-based regimens in The Second Hospital of Nanjing. Based on previous studies, the sample size was 332 patients calculated by PASS software. Considering a 20% dropout rate, the expected sample size was 416 patients, which were 208 patients in the DTG and EFV groups, respectively. Among 416 enrolled participants, the median age was 30.0 years (25.0-43.0), 388 (93.3%) males. At baseline, patients in the DTG group had worse pre-treatment immune level, but with no significant difference in weight compared to the EFV group. After 12 months of follow-up, the CD4+ T-cell counts increased greater in the DTG group (P=0.036), while the CD4+/CD8+ T-cell ratio increased greater in the EFV group (P=0.014). There was no significant difference in the normalization of various immune indicators between the two groups. The weight gain of patients in the DTG group at different follow-up points was all significantly higher than that in the EFV group (P<0.05). Multivariate logistic regression analysis showed that DTG-based regimens (OR=4.524, 95% CI: 2.371-8.634, P<0.001), baseline VL ≥10^5 copies/mL (OR=2.563, 95% CI: 1.411-4.657, P=0.002), and baseline CD4+ T-cell counts <200 cells/μL (OR=2.595, 95% CI: 1.430-4.709, P=0.002) were risk factors for weight gain ≥5 kg during the 12-month follow-up period. After 12 months of follow-up, the increase in CD4+ T-cell counts was higher in the DTG group than in the EFV group, but the overall immunological efficacy was similar in both groups. However, attention should be paid to patients' weight, especially in patients with high baseline viral load and low CD4+ T-cell counts who were treated with the DTG-based regimen.

Prognostic significance of peripheral and tumor-infiltrating lymphocytes in newly diagnosed stage III/IV non-small-cell lung cancer.

Lymphocytes are effector cells that fight cancer by killing tumor cells. Here, we aim to explore the prognostic significance of both peripheral and tumor-infiltrating lymphocytes (TILs) in newly diagnosed stage III/IV non-small-cell lung cancer (NSCLC). In total, 105 cases of newly diagnosed stage III/IV NSCLC from July 2017 to October 2022 at the Tianjin Beichen Hospital were retrospectively investigated. Peripheral blood samples at the time of diagnosis and tumor tissue slices from these patients were collected. General peripheral blood cell composition and TILs were measured and analyzed via an automatic blood analyzer and immunofluorescence staining analysis. The overall survival (OS) time of all patients was also obtained and analyzed. The median overall survival (mOS) of all patients is 12 months. The 1-, 2-, and 3-year overall survival rates were 60.5, 28.4, and 18.6%, respectively. Peripheral lymphocyte and neutrophil percentages, serum C-reactive protein (CRP) expression, tumor size, and tumor pathology are the prognostic factors of OS for newly diagnosed stage III/IV NSCLC patients. Moreover, patients with high tumor CD4+ and CD8+ T cell infiltration survived significantly longer compared to patients with low tumor CD4+ and CD8+ T cell infiltration (p < 0.0001 and p = 0.011, respectively). Compared to low tumor CD33+ cell infiltration, high tumor CD33+ cell infiltration was associated with worse OS (p = 0.018). High tumor CD8+ T cell infiltration was associated with lower peripheral lymphocyte number, lower serum CRP expression, smaller tumor size, and better tumor pathology (p = 0.012, p = 0.040, p = 0.012, and p = 0.029, respectively). Increased numbers of peripheral lymphocytes, CD33+ cells, CD4+ TILs, and CD8+ TILs were significantly associated with OS in newly diagnosed stage III/IV NSCLC patients, which were positively associated with several basic clinical factors.

Low-affinity CD8+ T cells provide interclonal help to high-affinity CD8+ T cells to augment alloimmunity

Following solid organ transplantation, small precursor populations of polyclonal CD8+ T cells specific for any graft-expressed antigen preferentially expand their high-affinity clones. This phenomenon, termed “avidity maturation,” results in a larger population of CD8+ T cells with increased sensitivity to alloantigen, posing a greater risk for graft rejection. Using a mouse model of minor-mismatched skin transplantation, coupled with the tracking of 2 skin graft-reactive CD8+ T cell receptor-transgenic tracer populations with high and low affinity for the same peptide-major histocompatibility complex, we explored the conventional paradigm that CD8+ T cell avidity maturation occurs through T cell receptor affinity-based competition for cognate antigen. Our data revealed “interclonal CD8-CD8 help,” whereby lower/intermediate affinity clones help drive the preferential expansion of their higher affinity counterparts in an interleukin-2/CD25-dependent manner. Consequently, the CD8-helped high-affinity clones exhibit greater expansion and develop augmented effector functions in the presence of their low-affinity counterparts, correlating with more severe graft damage. Finally, interclonal CD8-CD8 help was suppressed by costimulation blockade treatment. Thus, high-affinity CD8+ T cells can leverage help from low-affinity CD8+ T cells of identical specificity to promote graft rejection. Suppressing provision of interclonal CD8-CD8 help may be important to improve transplant outcomes.

Human Immunodeficiency Virus (HIV) Viral Load Fluctuation Mirrors the Haemoglobin Levels and Predicts the Risk of Anaemia

Background: Anaemia is a common complication of HIV infection that can have a significant impact on the health and wellbeing of affected individuals. Evaluating the relationship between haemoglobin concentration, CD4 count and viral load is therefore important in order to predict and reduce the risk of anaemia in people living with HIV. Objectives: The aim of this study was to evaluate the relationship between haemoglobin concentration, CD4 count and viral load in people living with HIV. Method: This retrospective cross-sectional study was carried out at Parirenyatwa Opportunistic Infections Clinic, Zimbabwe. The study was conducted from November 2022 to April 2023. The data collected from each patient`s data base included; demographics, haemoglobin value, CD4 count and viral load count. Data collected during this study were captured on spreadsheet using Microsoft excel and the data were analyzed using the Graph Pad prism software. Results: A total of 244 participants were enrolled into the study from the Parirenyatwa Group of Hospitals Opportunistic Infections Clinic of which 102 (41.8%) were male and 142 (58.2%) were female. Participants with high CD4 count and low viral load had a mean haemoglobin of 13.3g/dL, those with low CD4 count and high viral load count had a mean haemoglobin of 8.3g/dl, those with high CD4 count and high viral load count had a mean haemoglobin of 12.5g/dl and those with low CD4 and low viral load count had a mean haemoglobin of 10.70g/dl. Conclusion: The overall finding from this study was that haemoglobin levels of people living with HIV is greatly affected by viral load and CD4 counts and that patients’ haemoglobin levels inversely tract the HIV viral loads. Low CD4 count and/ or high viral load count is associated with anaemia in people living with HIV.

Common Risk Factors for CD4 Cell Count and Hemoglobin Level among Female Adult HIV-Positive Patients: A Retrospective Longitudinal Study.

HIV is one of the most significant worldwide health concerns of the twenty-first century and a serious threat to human society. Hemoglobin level and CD4 cell count are two of the most important biomarkers of HIV progression and patient survival. The objective of this study was to identify common risk factors associated with CD4 cell count and hemoglobin level among adult female HIV-positive patients treated with ART at the University of Gondar Comprehensive Specialized Hospital, Ethiopia. The source of data in this study was secondary data conducted in the University of Gondar Comprehensive Specialized Hospital from September 2015 to March 2022 . Data exploration in this study was normal histogram plot, box plot, and Q-Q plot considered to gain some visions of the data related to CD4 cell count and hemoglobin level. A Bayesian joint model was used in this longitudinal data set to get a wide range of information about adult female HIV-patients. The mean with a standard deviation of hematocrit (%), red blood cell (106/μl), lymphocyte (%), and weight (kg) of female patients were 37.2 (3.8), 4.0 (1.6), 43.6 (11.8), and 44.9 (9.4), respectively. In this study, the random intercept model for CD4 cell count and the random intercept and slope model for hemoglobin level were considered as the best selected model. Visit time, hematocrit, weight, RBC, lymphocyte count, educational status, marital status, disclosure, and substance use were common risk factors for CD4 cell count and hemoglobin level. This study concluded that, the risk factors visit time, weight, secondary educators, tertiary educators, married patients, patients who disclosed their HIV status to family members were associated with high CD4 cell count and hemoglobin level. While, hematocrit, RBC, lymphocyte count, separated marital status, widowed marital status, and substance-addicted patients were associated with low CD4 cell count and hemoglobin level. The author recommended that FMOH or other health professionals, program planners, decision makers, project implementers, government, and nongovernmental organizations should be given special attention for adult female patinets to minimize the risk of HIV progression and improve their health status. The author also recommended that health staff should conduct health-related studies for patients to examine continuous checkups. Health professionals also should give more attention to types of ART medication to reduce the progression of disease when the patients come back again into the hospital. Finally, adult female HIV-positive patients should be given special attention based on these important factors to improve their CD4 cell count, hemoglobin level, and better health quality.

PD-1/PD-L1 governed cross-talk of exhausted CD8+ T and memory B cells in systemic lupus erythematosus

BackgroundIndeterminate readout of the quantitative interferon-γ release test (QFT) for Mycobacterium tuberculosis screening is a specific laboratory finding for systemic lupus erythematosus (SLE), which may be due to T-cell exhaustion...

Cancer-associated fibroblast spatial heterogeneity and EMILIN1 expression in the tumor microenvironment modulate TGF-β activity and CD8+ T-cell infiltration in breast cancer.

Rationale: The tumor microenvironment (TME) and its multifaceted interactions with cancer cells are major targets for cancer treatment. Single-cell technologies have brought major insights into the TME, but the resulting complexity often precludes conclusions on function. Methods: We combined single-cell RNA sequencing and spatial transcriptomic data to explore the relationship between different cancer-associated fibroblast (CAF) populations and immune cell exclusion in breast tumors. The significance of the findings was then evaluated in a cohort of tumors (N=75) from breast cancer patients using immunohistochemistry analysis. Results: Our data show for the first time the degree of spatial organization of different CAF populations in breast cancer. We found that IL-iCAFs, Detox-iCAFs, and IFNγ-iCAFs tended to cluster together, while Wound-myCAFs, TGFβ-myCAFs, and ECM-myCAFs formed another group that overlapped with elevated TGF-β signaling. Differential gene expression analysis of areas with CD8+ T-cell infiltration/exclusion within the TGF-β signaling-rich zones identified elastin microfibrillar interface protein 1 (EMILIN1) as a top modulated gene. EMILIN1, a TGF-β inhibitor, was upregulated in IFNγ-iCAFs directly modulating TGFβ immunosuppressive function. Histological analysis of 75 breast cancer samples confirmed that high EMILIN1 expression in the tumor margins was related to high CD8+ T-cell infiltration, consistent with our spatial gene expression analysis. High EMILIN1 expression was also associated with better prognosis of patients with breast cancer, underscoring its functional significance for the recruitment of cytotoxic T cells into the tumor area. Conclusion: Our data show that correlating TGF-β signaling to a CAF subpopulation is not enough because proteins with TGF-β-modulating activity originating from other CAF subpopulations can alter its activity. Therefore, therapeutic targeting should remain focused on biological processes rather than on specific CAF subtypes.

Exploratory analysis of immunomodulatory factors identifies L1CAM as a prognostic marker in alveolar soft-part sarcoma.

Alveolar soft-part sarcoma (ASPS) is a rare tumor driven by the ASPSCR1-TFE3 fusion protein, with a propensity for metastasis. Prognostic factors remain poorly understood, and traditional chemotherapies are largely ineffective. Recent interest lies in immune checkpoint inhibitors (ICIs), yet predictive biomarkers for treatment response are lacking. Previous studies have shown promising results with ICIs in ASPS, indicating a need for further investigation into biomarkers associated with immune response. To identify prognostic biomarkers in ASPS and to explore the role of immune-related markers, particularly L1CAM, in predicting patient outcomes. A retrospective cohort study of 19 ASPS patients registered in the GEIS database. The study involved the collection of clinical and histopathological data, followed by an analysis of immune markers and gene expression profiles to identify potential prognostic indicators. Clinical and histopathological data were retrospectively collected from the GEIS-26 study cohort of 19 ASPS patients. Immunohistochemistry was performed to evaluate immune markers programmed death-1 ligand (PD-L1), programmed death-1, FAS, FASL, CD8, CD3, and CD4. An HTG ImmunOncology panel was conducted on formalin-fixed paraffin-embedded samples to explore gene expression. Effects of differentially expressed genes on survival were explored by Kaplan-Meier. PD-L1 positivity was widely observed (63%) in tumors, and CD8+ lymphocytic infiltration was common. High CD8 density correlated with greater overall survival (OS) while not statistically significant. No associations were found for other immune markers. L1CAM was identified as differentially expressed in patients with low CD8 infiltration and correlated negatively with OS. High L1CAM expression correlated with poorer OS, highlighting its potential as a prognostic marker and therapeutic target in ASPS. Immunomodulatory interventions may hold promise, as evidenced by PD-L1 expression and CD8+ infiltration. Further research, including larger cohorts and international collaborations, is needed to validate these findings and explore therapeutic strategies targeting L1CAM in ASPS.

Identification and Quantification of Radiotherapy-related Protein Expression in Cancer Tissues Using the Qupath Software and Prediction of Treatment Response.

Automated measurement of immunostained samples can enable more convenient and objective prediction of treatment outcome from radiotherapy. We aimed to validate the performance of the QuPath image analysis software in immune cell markers detection by comparing QuPath cell counting results with those of physician manual cell counting. CD8- and FoxP3-stained cervical, CD8-stained oropharyngeal, and Ku70-stained prostate cancer tumor sections were analyzed in 104 cervical, 92 oropharyngeal, and 58 prostate cancer patients undergoing radiotherapy at our Institution. QuPath and manual counts were highly correlated. When divided into two groups using ROC curves, the agreement between QuPath and manual counts was 89.4% for CD8 and 88.5% for FoxP3 in cervical cancer, 87.0% for CD8 in oropharyngeal cancer and 80.7% for Ku70 in prostate cancer. In cervical cancer, the high CD8 group based on QuPath counts had a better prognosis and the low CD8 group had a significantly worse prognosis [p=0.0003; 5-year overall survival (OS), 65.9% vs. 34.7%]. QuPath counts were more predictive than manual counts. Similar results were observed for FoxP3 in cervical cancer (p=0.002; 5-year OS, 62.1% vs. 33.6%) and CD8 in oropharyngeal cancer (p=0.013; 5-year OS, 80.2% vs. 47.2%). In prostate cancer, high Ku70 group had worse and low group significantly better outcome [p=0.007; 10-year progression-free survival (PFS), 56.0% vs. 93.8%]. QuPath showed a strong correlation with manual counting, confirming its utility and accuracy and potential applicability in clinical practice.

Assessment of treatment outcomes for HIV Positives transitioned from Tenofovir/Lamivudine/Efavirenz to Tenofovir/Lamivudine/Dolutegravir in a Nigerian Tertiary Hospital

Objective: Dolutegravir, an integrase inhibitor replaced nevirapine or efavirenz (both NRTIs) in a fixed dose combination with Tenofovir/Lamivudine, as the preferred first-line option for the prevention and treatment of HIV infection. This study aimed to assess the treatment outcomes of the new Tenofovir/Lamivudine/Dolutegravir (TLD) regimen at the Federal Medical Centre Abeokuta. Methods: This retrospective study used data drawn from the treatment register of patients who transitioned from Tenofovir/Lamivudine/Efavirenz (TLE) to TLD. Data were analyzed using SPSS v23. Descriptive statistics were used to describe categorical and continuous variables. Statistically significant independent variables in univariate analyses were included in the multivariate model. The level of significance was set at p&lt;0.05. Results: The 358 cases reviewed showed a mean age of 44.29 ± 11.5 years. The majority (267; 74.6%) were females. Viral load suppression (≤1000 copies/ml) was achieved in 313 (87.4%) while on TLE but increased to 339 (94.7%) when transitioned to TLD. Also, 36.3% had a high CD4 count while on TLE, this increased to 67.3%. The mean CD4 counts (428.59±251.85) while using TLE increased exponentially when transitioned to TLD (634.89±244.72) (t-31.601; p-value- 0.001). Before the transition, 90.5% of respondents were at WHO stage 1 compared to 92.5% after the transition to TDF/3TC/DTG. Conclusion: Treatment outcome was greatly improved in terms of virologic, immunologic and clinical parameters among patients who transitioned from TDF/3TC/EFV to TDF/3TC/DTG. The outcome of this work supports and encourages the use of TDF/3TC/DTG as the preferred first-line regimen in HIV treatment for the patient’s maximum clinical benefit.

Ten-year clinical outcome, toxicity and compliance of dose-dense sequential adjuvant administration of cyclophosphamide & epirubicin followed by docetaxel in patients with early breast cancer: A hellenic cooperative oncology group observational study (HE 10/10) with concurrent investigation of significance of tumor infiltrating lymphocytes

BackgroundDose-dense sequential (dds) chemotherapy has changed the clinical outcome of patients with early breast cancer (BC). To investigate the impact of dose intensity (DI) in the adjuvant setting of BC, this observational trial (HE 10/10) was conducted assessing the long-term survival outcome, safety and toxicity of a currently widely used chemotherapeutic regimen. In addition, the prognostic significance of tumor infiltrating lymphocytes (TILs) and infiltrating CD8+ lymphocytes were also evaluated in the same cohort. Patients and methodsTotally, 1054 patients were prospectively enrolled in the current study with 1024 patients being eligible, while adequate tissue was available for 596 of them. TILs, CD8+ lymphocytes in intratumoral areas in contact with malignant cells (iCD8), CD8+ lymphocytes in tumor stroma (sCD8) as well as the total number of CD8+ lymphocytes within the tumor area (total CD8) were assessed by immunohistochemistry. ResultsWithin a median follow-up of 125.18 months, a total of 200 disease-free survival (DFS) events (19.5%) were reported. Importantly, the 10-year DFS and OS rates were 78.4% (95% CI 75.0–81.5) and 81.7% (95% CI 79.0–84.1), respectively. Interestingly, higher CD8+ T cells as well as TILs in the tumor microenvironment were associated with an improved long-term survival outcome. ConclusionsIn conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well as the prognostic significance of TILs and infiltrating CD8+ lymphocytes in BC patients with early-stage disease.

Insights to HIV-1 coreceptor usage by estimating HLA adaptation with Bayesian generalized linear mixed models.

The mechanisms triggering the human immunodeficiency virus type I (HIV-1) to switch the coreceptor usage from CCR5 to CXCR4 during the course of infection are not entirely understood. While low CD4+ T cell counts are associated with CXCR4 usage, a predominance of CXCR4 usage with still high CD4+ T cell counts remains puzzling. Here, we explore the hypothesis that viral adaptation to the human leukocyte antigen (HLA) complex, especially to the HLA class II alleles, contributes to the coreceptor switch. To this end, we sequence the viral gag and env protein with corresponding HLA class I and II alleles of a new cohort of 312 treatment-naive, subtype C, chronically-infected HIV-1 patients from South Africa. To estimate HLA adaptation, we develop a novel computational approach using Bayesian generalized linear mixed models (GLMMs). Our model allows to consider the entire HLA repertoire without restricting the model to pre-learned HLA-polymorphisms. In addition, we correct for phylogenetic relatedness of the viruses within the model itself to account for founder effects. Using our model, we observe that CXCR4-using variants are more adapted than CCR5-using variants (p-value = 1.34e-2). Additionally, adapted CCR5-using variants have a significantly lower predicted false positive rate (FPR) by the geno2pheno[coreceptor] tool compared to the non-adapted CCR5-using variants (p-value = 2.21e-2), where a low FPR is associated with CXCR4 usage. Consequently, estimating HLA adaptation can be an asset in predicting not only coreceptor usage, but also an approaching coreceptor switch in CCR5-using variants. We propose the usage of Bayesian GLMMs for modeling virus-host adaptation in general.

AGING-RELATED IMMUNE CELLS PHENOTYPES AND ALL-CAUSE MORTALITY IN THE FRAMINGHAM HEART STUDY

Abstract Almost 2 billion people will likely be above the age of 60 by 2050. Aging is a process that is intrinsically complicated. One of the measures for immune system senescence is aging related immune cells phenotypes (ARIP)s. Besides CD8/CD4 ratio, new immunosenescence phenotypes have been proposed. The associations between ARIPs and all-cause mortality during long-term follow up is understudied. We profiled immune cells using flow cytometry and prospectively investigated ten different ARIPs, namely, CD4+CD27-, CD4+CD28-CD27-, CD8+CD27-, CD8+CD28-CD27-, CD4+/CD8+ ratio, CD4+(Tnaive/(T Central Memory (Tcm)+T Effector Memory (Tem)+T Effector (Teff)), CD8+ (Tnaive/(Tcm+Tem+Teff)), Granzyme B+CD8/Granzyme B+CD4 ratio, CD8+ Tc17/Treg ratio and CD4+ Th17/Treg ratio in relation to survival outcome among 990 dementia-free Framingham Heart Study (FHS) Offspring cohort participants who attended the seventh exam (1998-2001, mean age 62 years, range 40-88, 52% female). Cox proportional hazards regression models adjusting for age and sex with robust variance to account for family correlation were used to test for association between the ARIPs and hazard of death. During up to 20 years of follow up, the survival rate was 66%. Higher CD8+ Tc17/Treg ratio was significantly associated with better survival (HR:0.82 [0.7-0.94], p&amp;lt; 0.001). Higher CD4+ Th17/Treg ratio and CD4/CD8 ratio were also nominally associated with lower risk of death (HR:0.87, [0.75-0.97], p=0.01 and HR 0.9, [0.79-0.99], p=0.04, respectively). Other ARIPs were unassociated with all-cause mortality. We conclude that further investigation of the CD8+Tc17/Treg and CD4+ Th17/Treg ratios as ARIP biomarkers for risk of all-cause mortality is justified.

CIRCULATING IMMUNE CELLS ARE ASSOCIATED WITH BRAIN MRI MEASUREMENTS IN THE FRAMINGHAM OFFSPRING

Abstract Mounting evidence supports the role of the immune system in brain health, yet little is known about the role of circulating immune cells in brain health. We investigated the association of immune cell phenotypes with brain MRI phenotypes in the Framingham Heart Study Offspring participants who attended Exam 7 (mean age 61, 52% women). Immune cells (43 analyzed here) were determined by flow cytometry and previously published. Analysis of the immune cell phenotypes with MRI measurements of 13 brain regions revealed several significant associations, adjusting for age, sex and CMV status (Model 1) in the full sample (n=703) and the CMV+ stratum (n=327). In the full sample, higher senescent/exhausted CD8+ cells (CD8+CD45RO-CCR7-CD27-(Teff), CD8+CD45RA+CD28-CD57+(TEMRA), CD8+CD27-CD28-) associated with higher cerebrum and frontal gray volumes. These associations were strengthened when cardiovascular risk factors were included in the model (Model 2). In the CMV+ stratum, two CD8+ cell types (TEMRA, and Teff) were significantly associated with higher cerebrum gray and frontal gray matter volumes in both models. Also in the CMV+ stratum, higher levels of CD8+CD45RO+CCR7+CD27+ (Central Memory) were associated with lower frontal gray matter, and higher CD3+ (T cells) cells were associated with higher temporal gray matter and higher CD8 Teff associated with lower cerebrum white volumes. There were no associations of CD4 subtypes with brain MRI measures in the full sample or the CMV+ stratum. These associations with brain volumes in adults aged 40-88 may improve understanding of the role of the immune system early in the brain aging process.

Impact of the gut microbiome on immunological responses to COVID-19 vaccination in healthy controls and people living with HIV

Although mRNA SARS-CoV-2 vaccines are generally safe and effective, in certain immunocompromised individuals they can elicit poor immunogenic responses. Among these individuals, people living with HIV (PLWH) have poor immunogenicity to several oral and parenteral vaccines. As the gut microbiome is known to affect vaccine immunogenicity, we investigated whether baseline gut microbiota predicts immune responses to the BNT162b2 mRNA SARS-CoV-2 vaccine in healthy controls and PLWH after two doses of BNT162b2. Individuals with high spike IgG titers and high spike-specific CD4+ T-cell responses against SARS-CoV-2 showed low α-diversity in the gut. Here, we investigated and presented initial evidence that the gut microbial composition influences the response to BNT162b2 in PLWH. From our predictive models, Bifidobacterium and Faecalibacterium appeared to be microbial markers of individuals with higher spike IgG titers, while Cloacibacillus was associated with low spike IgG titers. We therefore propose that microbiome modulation could optimize immunogenicity of SARS-CoV-2 mRNA vaccines.