Treatment with Elapegademase Restores Immunity in Infants with Adenosine Deaminase Deficient Severe Combined Immunodeficiency.

PURPOSE: Patients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene glycol-modified (PEGylated) ADA while awaiting definitive treatment with hematopoietic stem cell transplant (HSCT) or gene therapy. Beginning in 1990, ERT was performed with PEGylated bovine intestinal ADA (ADAGEN®). In 2019, a PEGylated recombinant bovine ADA (Revcovi®) replaced ADAGEN following studies in older patients previously treated with ADAGEN for many years. There are limited longitudinal data on ERT-naïve newborns treated with Revcovi. METHODS: We report our clinical experience with Revcovi as initial bridge therapy in three newly diagnosed infants with ADA-SCID, along with comprehensive biochemical and immunologic data. RESULTS: Revcovi was initiated at twice weekly dosing (0.2 mg/kg intramuscularly), and monitored by following plasma ADA activity and the concentration of total deoxyadenosine nucleotides (dAXP) in erythrocytes. All patients rapidly achieved a biochemically effective level of plasma ADA activity, and red cell dAXP were eliminated within 2-3 months. Two patients reconstituted B-cells and NK-cells within the first month of ERT, followed by naive T-cells one month later. The third patient reconstituted all lymphocyte subsets within the first month of ERT. One patient experienced declining lymphocyte counts with improvement following Revcovi dose escalation. Two patients developed early, self-resolving thrombocytosis, but no thromboembolic events occurred. CONCLUSION: Revcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data.

The role of immune reconstitution in relapse after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Leukemia relapse following stem cell transplantation remains a significant barrier to long-term remission. Timely and balanced immune recovery after transplantation is crucial for preventing leukemia relapse. AREAS COVERED: After an extensive literature search of PubMed and Web of Science through October 2023, we provide an overview of the dynamics of immune reconstitution and its role in controlling leukemia relapse. We also discuss strategies to promote immune reconstitution and reduce disease recurrence following allogeneic hematopoietic stem cell transplantation. EXPERT OPINION: Immune reconstitution after transplantation has substantial potential to prevent relapse and might predict disease recurrence and prognosis. High dimensional cytometry, multi-omics, and T cell repertoire analysis allow for a more comprehensive and detailed understanding of the immune system's dynamics post-transplantation, and contribute to the identification of rare immune cell subsets or potential biomarkers associated with successful immune reconstitution or increased risk of complications. Strategies to enhance the immune system, such as adoptive immunotherapy and cytokine-based therapy, have great potential for reducing leukemia relapse after transplantation. Future research directions should focus on refining patient selection for these therapies, implementing appropriate and timely treatment, investigating combination approaches to maximize therapeutic outcomes, and achieving a robust graft-versus-leukemia (GVL) effect while minimizing graft-versus-host disease (GVHD) for optimal results.

Long-Term Clinical Outcomes and B Cell Immune Reconstitution Following Allo-HCT With Prophylactic, Post-Transplant Rituximab.

Chronic graft-versus-host disease (cGVHD) remains a significant source of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Post-transplant, prophylactic rituximab has successfully decreased cGHVD rates in clinical trials, but the durability of this strategy is uncertain. The long-terms effect of post-HCT B cell depletion on immune reconstitution, B cell function, and infectious complications are also unknown. In this study, we provide 10 yr follow-up and correlative analyses on patients given post-HCT, prophylactic rituximab. The objective of the study is to examine the durability of cGVHD protection as well as the long-term effect of rituximab prophylaxis on protective immune reconstitution, B cell function, and alloantibody formation. We analyzed 35 patients given prophylactic rituximab on phase II clinical trial. Clinical outcomes included cGVHD development, relapse and survival outcomes, and infectious outcomes. Correlative analyses included B cell subset analysis, development of antibodies to infectious antigens, and, for male patients receiving female donor grafts, development of antibodies to HY antigens. To further investigate the effect of rituximab on immune reconstitution and function, we also analyzed 43 similarly transplanted patients who did not receive post- or peri-HCT rituximab as a comparator group. For patients who received rituximab, the 8-yr cumulative incidence of cGHVD and freedom from immunosuppression were 20.0% and 76.2%, respectively. Importantly, no late incidences of cGVHD developed beyond 14 mo post-HCT. Relative to patients who did not receive rituximab, post-HCT rituximab was associated with increased B cell aplasia at 1 yr post-HCT (42.9% versus 11% of patients, P = .037); by 3 yr post-HCT, this aplasia resolved. Patients who received rituximab also had a significantly lower proportion of IgD+/CD38+ transitional B cells at 3 yr post-HCT (78.8% versus 89.9%, P = .039); at 10 yr post-HCT, this percentage remained markedly decreased at 50.7%. Rituximab prophylaxis altered B cell function. In male patients receiving female donor grafts, fewer patients developed HY antibodies at 3 yr post-HCT (20% versus 78%, P = .04). At 10 yr post-HCT, HY antibody production remained decreased at 33%. Rituximab prophylaxis was also associated with significantly lower antibody response to tetanus and EBV infectious antigens as well as lower IgG levels. Despite these changes, post-HCT was not associated with increased infections, although patients who received rituximab required intravenous immunoglobulin (IVIG) supplementation more frequently than those who did not (62.9% versus 32.6% of patients, P = .01). Prior data on the efficacy and feasibility of rituximab prophylaxis are durable, with persistent reduction in cGVHD. Rituximab prophylaxis also results in lasting B cell immunologic changes, with altered B cell subset composition and decreased alloantibody formation. Associated infectious risks were not increased, perhaps mitigated by high IVIG use.

The impact of omidubicel on immune reconstitution and infections in cord blood transplant patients.

INTRODUCTION: The success of an allogeneic hematopoietic stem cell transplantation (alloHCT) is measured by cure from the underlying malignancy, immune reconstitution (IR), and freedom from graft-versus-host disease, without the continued need for immunosuppressive therapy. AREAS COVERED: Effective IR is critical to the success of alloHCT wherein poor IR can potentially increase the risk of infection and disease relapse. Different stem cell sources give rise to varying patterns of IR. Particularly with umbilical cord blood transplant, delayed IR is commonly seen with associated increased infection rates and non-relapse mortality, attributable to low CD34+ cell doses and predominance of naïve T cells in the graft. Recent FDA approval of omidubicel, an expanded cord blood graft, was granted due to rapid hematologic recovery and a reduced incidence of high-grade infections associated with improved IR. This review focuses on IR and infections seen with omidubicel and compares those to IR after alloHCT with other graft sources. EXPERT OPINION: Characteristics of omidubicel, such as ready availability, high infused CD34+ cell dose, and rapid hematologic and immune recovery improve upon the shortcomings of standard umbilical cord blood transplantation. We feel that the data support the emergence of omidubicel as an alternative donor product.

Modulation of cytomegalovirus immune evasion identifies direct antigen presentation as the predominant mode of CD8 T-cell priming during immune reconstitution after hematopoietic cell transplantation.

Cytomegalovirus (CMV) infection is the most critical infectious complication in recipients of hematopoietic cell transplantation (HCT) in the period between a therapeutic hematoablative treatment and the hematopoietic reconstitution of the immune system. Clinical investigation as well as the mouse model of experimental HCT have consistently shown that timely reconstitution of antiviral CD8 T cells is critical for preventing CMV disease in HCT recipients. Reconstitution of cells of the T-cell lineage generates naïve CD8 T cells with random specificities among which CMV-specific cells need to be primed by presentation of viral antigen for antigen-specific clonal expansion and generation of protective antiviral effector CD8 T cells. For CD8 T-cell priming two pathways are discussed: "direct antigen presentation" by infected professional antigen-presenting cells (pAPCs) and "antigen cross-presentation" by uninfected pAPCs that take up antigenic material derived from infected tissue cells. Current view in CMV immunology favors the cross-priming hypothesis with the argument that viral immune evasion proteins, known to interfere with the MHC class-I pathway of direct antigen presentation by infected cells, would inhibit the CD8 T-cell response. While the mode of antigen presentation in the mouse model of CMV infection has been studied in the immunocompetent host under genetic or experimental conditions excluding either pathway of antigen presentation, we are not aware of any study addressing the medically relevant question of how newly generated naïve CD8 T cells become primed in the phase of lympho-hematopoietic reconstitution after HCT. Here we used the well-established mouse model of experimental HCT and infection with murine CMV (mCMV) and pursued the recently described approach of up- or down-modulating direct antigen presentation by using recombinant viruses lacking or overexpressing the central immune evasion protein m152 of mCMV, respectively. Our data reveal that the magnitude of the CD8 T-cell response directly reflects the level of direct antigen presentation.

Immune reconstitution, vaccine responses, and rituximab use after ex-vivo CD34-selected myeloablative allogenic hematopoietic cell transplantation.

Myeloablative T cell depleted (CD34-selected) hematopoietic cell transplantation (HCT) is associated with less acute and chronic graft versus host disease (GVHD). We aimed to examine vaccine responses in relation to immune reconstitution and post HCT rituximab administration in this population. This single center retrospective study included 251 patients with hematological malignancies who received a first CD34-selected HCT between 2012 and 2015. Of 251 patients, 190 were alive 1 year after HCT. Among the entire population, 77 (30.7%) patients were vaccinated. After vaccine administration, 35/44 (80%), 30/75 (40%), 27/36 (75%), 33/65 (51%), 34/51 (51%), 22/28 (79%) and 20/34 (59%) of evaluable patients had protective antibody titers for haemophilus influenzae type B (Hib), Pneumococcus, Tetanus, Diphtheria, Pertussis, hepatitis A (HAV), and hepatitis B (HBV) respectively. Responders to the pneumococcal vaccine had a higher CD45RA T cell count than non responders, with 12/18 patients (66.7%) vs 11/32 (34.4%) p = 0.04. For pneumococcal vaccine, there was also a trend to higher total lymphocyte B cell count in responders vs non responders p = 0.06. Rituximab post HCT was given to 59/251 (23.5%) patients. No difference was found in immune reconstitution patterns for rituximab use between vaccine responders and not. Recipients of CD34-selected HCT may respond to vaccination, and T and B cell subsets could be useful to predict vaccine response.

[Immune Reconstitution after BTKi Treatment in Chronic Lymphocytic Leukemia].

OBJECTIVE: To analyze the immune reconstitution after BTKi treatment in patients with chronic lymphocytic leukemia (CLL). METHODS: The clinical and laboratorial data of 59 CLL patients admitted from January 2017 to March 2022 in Fujian Medical University Union Hospital were collected and analyzed retrospectively. RESULTS: The median age of 59 CLL patients was 60.5(36-78). After one year of BTKi treatment, the CLL clones (CD5 +/CD19 +) of 51 cases (86.4%) were significantly reduced, in which the number of cloned-B cells decreased significantly from (46±6.1)×109/L to (2.3±0.4)×109/L (P =0.0013). But there was no significant change in the number of non-cloned B cells (CD19 + minus CD5 +/CD19 +). After BTKi treatment, IgA increased significantly from (0.75±0.09)g/L to (1.31±0.1)g/L (P <0.001), while IgG and IgM decreased from (8.1±0.2)g/L and (0.52±0.6)g/L to (7.1±0.1)g/L and (0.47±0.1)g/L, respectively (P <0.001, P =0.002). BTKi treatment resulted in a significant change in T cell subpopulation of CLL patients, which manifested as both a decrease in total number of T cells from (2.1±0.1)×109/L to (1.6±0.4)×109/L and NK/T cells from (0.11±0.1)×109/L to (0.07±0.01)×109/L (P =0.042, P =0.038), both an increase in number of CD4 + cells from (0.15±6.1)×109/L to (0.19±0.4)×109/L and CD8 + cells from (0.27±0.01)×109/L to (0.41±0.08)×109/L (both P <0.001). BTKi treatment also up-regulated the expression of interleukin (IL)-2 while down-regulated IL-4 and interferon (IFN)-γ. However, the expression of IL-6, IL-10, and tumor necrosis factor (TNF)-α did not change significantly. BTKi treatment could also restored the diversity of TCR and BCR in CLL patients, especially obviously in those patients with complete remission (CR) than those with partial remission (PR). Before and after BTKi treatment, Shannon index of TCR in patients with CR was 0.02±0.008 and 0.14±0.001 (P <0.001), while in patients with PR was 0.01±0.03 and 0.05±0.02 (P >0.05), respectively. Shannon index of BCR in patients with CR was 0.19±0.003 and 0.33±0.15 (P <0.001), while in patients with PR was 0.15±0.009 and 0.23±0.18 (P <0.05), respectively. CONCLUSIONS: BTKi treatment can shrink the clone size in CLL patients, promote the expression of IgA, increase the number of functional T cells, and regulate the secretion of cytokines such as IL-2, IL-4, and IFN-γ. BTKi also promote the recovery of diversity of TCR and BCR. BTKi treatment contributes to the reconstitution of immune function in CLL patients.

Long-term lymphocyte subset number reconstitution is unique but comparable between umbilical cord blood and unrelated bone marrow transplantation.

The number of umbilical cord blood transplantation (U-CBT) procedures has been growing annually, but little research has been done on long-term immune recovery after U-CBT. Infection risk is high in U-CBT recipients, and this can be partially attributed to immature immunocompetent cells in umbilical cord blood. In this study, we analyzed lymphocyte subset (LST) number to determine the long-term recovery timeline. We included 36 U-CBT and 10 unrelated bone marrow transplantation (U-BMT) recipients who survived more than 2 years after transplantation, and followed them for up to 10 years post-transplant. Recovery kinetics in the early phase post-transplant was different for each LST. Recovery of CD19+ B cells was faster after U-CBT than after U-BMT in the first 5 years after transplantation. Although CD4+ T cells increased in the first several months after U-CBT, long-term cell count recovery was impaired in approximately 20% of patients. Thus, although the LST recovery pattern after U-CBT was unique, LST number recovery was statistically comparable between U-CBT and U-BMT past 5 years post-transplantation.

Early M-protein immune reconstitution after autologous haematopoietic stem cell transplantation is a good prognostic marker for patients with high-risk cytogenetic multiple myeloma.

The presence of transient abnormal protein banding (M-protein immune reconstitution) in serum immunofixation electrophoresis after autologous haematopoietic stem cell transplantation in patients with multiple myeloma has been reported. The purpose of this study was to investigate the impact of post-transplant M-protein immune reconstitution on the prognosis of patients with multiple myeloma. M-protein immune reconstitution was observed in 25.9% (75/290) of patients. The CR rate and MRD negativity were higher in the M-protein immune reconstitution group (85.3% vs. 69.3%, p = 0.013, 81.9% vs. 66.5%, p = 0.014). Although there were no significant differences between the groups, the overall median survival time was longer in the M-protein immune reconstruction group (80 vs. 72 m, p = 0.076; not reached vs. 105 m, p = 0.312). Among patients in the cytogenetic high-risk group, the occurrence of M-protein immune reconstitution predicted better PFS and OS (80 vs. 31 m, p = 0.010; not reached vs. 91 m, p = 0.026). Additionally, in revised-International Staging System stage III patients, PFS and OS were better in those who achieved M-protein immune reconstitution (80 vs. 20 m, p = 0.025; 57 vs. 32 m, p = 0.103). The better prognosis of M-protein immune reconstitution patients may be associated with the acquisition of a deeper response. In high-risk patients, early acquisition of M-protein immune reconstitution may suggest a better prognosis.

Influence of ATLG serum levels on CD3/CD19-depleted hematopoietic grafts and on immune recovery in pediatric haplo-HSCT.

ABSTRACT: Anti-T lymphocyte globulin (ATLG) significantly reduces the risk of engraftment failure in allogeneic hematopoietic stem cell transplant (HSCT) but hampers posttransplant immune reconstitution. We hypothesized that in patients receiving haploidentical CD3/CD19-depleted grafts, these double-edged effects could be better balanced by attaining high ATLG serum concentrations before transplant but as low as possible on the day of transplant. Therefore, we moved the start of ATLG application to day -12 and determined serum concentrations of T-cell-specific ATLG in pediatric patients treated with 3 established dosing regimens (15, 30, or 60 mg/kg). Corresponding mean T-cell-specific ATLG serum concentrations at day 0 were 1.14, 2.99, or 12.10 µg/mL, respectively. Higher ATLG doses correlated with higher peak levels at days -8 and -7 and reduced graft rejection, whereas lower ATLG doses correlated with significantly faster posttransplant recovery of T and natural killer cells. The rate of graft-versus-host disease remained low, independent of ATLG doses. Moreover, in vitro assays showed that ATLG concentrations of 2.0 µg/mL and lower only slightly reduced the activity of natural killer cells, and therefore, the function of such effector cells might be preserved in the grafts. Pharmacokinetic analysis, compatible with linear first-order kinetics, revealed similar half-life values, independent of ATLG doses. Hence, the day on which a desired ATLG serum level is reached can be calculated before HSCT. Our retrospective study demonstrates the relevance of dosing and time of administration of ATLG on engraftment and immune recovery in ex vivo CD3/CD19-depleted haploidentical HSCT.

Plasma Cytokine Expression and Immune Reconstitution in Early and Delayed Anti-HIV 96-Weeks Treatment: A Retrospective Study.

HIV is an immunodeficiency disease with emergence of inadequate corresponding reconstruction therapies. Pyroptosis of CD4+T cell is mainly caused by immune activation and inflammation that cannot be reduced by successful antiretroviral therapy (ART) alone. Coinfections because of CD4+T cell reconstitution failure can occur. Anti-inflammatory treatment determines the success of immune reconstitution. In our experiment, only a few cytokines could recover to normal level following a 2-year antiretroviral treatment in early ART initiation, which is consistent with current findings about adjuvant HIV anti-inflammatory therapy. Early infection is often accompanied by a more severe inflammatory response. Innate immunity cytokines like granulocyte macrophage-colony stimulating factor, IFN-γ induced protein 10 kDa, and tumor necrosis factor-α exhibited the most elevated levels among all kinds of inflammatory cytokines. The correlation analysis showed at least eight cytokines contributing to the changes of CD4/CD8 ratio.

Comorbidity of Myasthenia gravis and Graves' disease as immune reconstitution-associated autoimmune disease in HIV infection: A case report and literature review.

BACKGROUND: Comorbidity of Myasthenia gravis (MG) and Graves' disease (GD) in treated HIV-infected individuals has rarely been described and little study has been done on the link between HIV-related immune reconstitution and autoimmune diseases occurring post antiretroviral therapy. CASE PRESENTATION: Here we report on a 33-year-old Chinese man with HIV infection who had been virologically suppressed since 2018. The patient was diagnosed with GD and was treated in 2020. Early in 2022, he developed fluctuating weakness and fatigue involving the bilateral extraocular muscles and limbs. With a positive neostigmine test, he was considered to have MG, but showed a poor response to oral medication. After multiple failed medication attempts, a thymectomy was finally performed to resolve his symptoms. The consecutive onset of immunological events may have partially resulted from immune reconstitution after viral control. CONCLUSIONS: This is a rare case of HIV-related immune reconstitution-associated autoimmune disease (IRAD) with comorbidity of MG and GD which was reported initially. Cooperation with multidisciplinary teams is essential to avoid misdiagnosis and to promote the overall health of HIV-infected patients.

Hematopoiesis and immune reconstitution after CD19 directed chimeric antigen receptor T-cells (CAR-T): A comprehensive review on incidence, risk factors and current management.

Impaired function of hematopoiesis after treatment with chimeric antigen T-cells (CAR-T) is a frequent finding and can interest a wide range of patients, regardless of age and underlying disease. Trilinear cytopenias, as well as hypogammaglobulinemia, B-cell aplasia, and T-cell impairment, can severely affect the infectious risk of CAR-T recipients, as well as their quality of life. In this review, we provide an overview of defects in hematopoiesis after CAR-T, starting with a summary of different definitions and thresholds. We then move to summarize the main pathogenetic mechanisms of cytopenias, and we offer insight into cytomorphological aspects, the role of clonal hematopoiesis, and the risk of secondary myeloid malignancies. Subsequently, we expose the major findings and reports on T-cell and B-cell quantitative and functional impairment after CAR-T. Finally, we provide an overview of current recommendations and leading experiences regarding the management of cytopenias and defective B- and T-cell function.

Gender and the length of time since autologous hematopoietic stem cell transplantation-What is their influence on the immune reconstitution in multiple myeloma patients?

INTRODUCTION: In the literature there is lack of information on the influence of gender and time since autologous hematopoietic stem cell transplantation (HSCT) on the immune reconstitution in multiple myeloma (MM) patients. OBJECTIVE: The aim of this study was to assess the diversity of the immune reconstitution according to gender in MM patients after autologous HSCT on the day of the clinic discharge and on the 29th day after discharge, as well as to investigate the changes in the immune system in females and males after staying at home for 28 days. METHOD: The studied population comprised 13 females and 13 males after autologous HSCT. On the day of the clinic discharge and on the 29th day after discharge blood samples were taken to analyse 22 immunological parameters. Statistical analysis was performed using STATISTICA 10 StatSoft Poland. For multiple comparisons, the Bonferroni correction was used. RESULTS: No statistically significant differences were observed in the analysed immunological parameters between the studied females and males with MM on the day of the clinic discharge and on the 29th day after discharge. However, on the 29th day after the clinic discharge compared to the day of the clinic discharge, statistically significant differences were found in 8 immunological parameters among females and 6 immunological parameters among males. CONCLUSION AND RECOMMENDATION: Our results indicate that the immune reconstitution is similar but not the same in patients of both genders. Statistically significant differences in the immune response in the studied females and males imply that gender may play a role in the immune reconstitution and that the results obtained in MM patients should be analysed separately in females and males. In order to explain the observed changes in the immune system according to gender, further research should be carried out on a larger population. This would most probably make it possible to find their clinical application.

Inhibition of RIP1 improves immune reconstitution and reduces GVHD mortality while preserving graft-versus-leukemia effects.

Graft-versus-host disease (GVHD) remains the major cause of morbidity and nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT). Inflammatory cytokines mediate damage to key GVHD targets such as intestinal stem cells (ISCs) and also activate receptor interacting protein kinase 1 (RIP1; RIPK1), a critical regulator of apoptosis and necroptosis. We therefore investigated the role of RIP1 in acute GVHD using samples from HCT patients, modeling GVHD damage in vitro with both human and mouse gastrointestinal (GI) organoids, and blocking RIP1 activation in vivo using several well-characterized mouse HCT models. Increased phospho-RIP1 expression in GI biopsies from patients with acute GVHD correlated with tissue damage and predicted NRM. Both the genetic inactivation of RIP1 and the RIP1 inhibitor GNE684 prevented GVHD-induced apoptosis of ISCs in vivo and in vitro. Daily administration of GNE684 for 14 days reduced inflammatory infiltrates in three GVHD target organs (intestine, liver, and spleen) in mice. Unexpectedly, GNE684 administration also reversed the marked loss of regulatory T cells in the intestines and liver during GVHD and reduced splenic T cell exhaustion, thus improving immune reconstitution. Pharmacological and genetic inhibition of RIP1 improved long-term survival without compromising the graft-versus-leukemia (GVL) effect in lymphocytic and myeloid leukemia mouse models. Thus, RIP1inhibition may represent a nonimmunosuppressive treatment for GVHD.

CD70-induced differentiation of proinflammatory Th1/17/22/GM lymphocytes associated with disease progression and immune reconstitution during HIV infection.

Immune overactivation is a hallmark of chronic HIV infection, which is critical to HIV pathogenesis and disease progression. The imbalance of helper T cell (Th) differentiation and subsequent cytokine dysregulation are generally considered to be the major drivers of excessive activation and inflammatory disorders in HIV infection. However, the accurate factors driving HIV-associated Th changes remained to be established. CD70, which was a costimulatory molecule, was found to increase on CD4+ T cells during HIV infection. Overexpression of CD70 on CD4+ T cells was recently reported to associate with highly pathogenic proinflammatory Th1/Th17 polarization in multiple sclerosis. Thus, the role of CD70 in the imbalance of Th polarization and immune overactivation during HIV infection needs to be investigated. Here, we found that the elevated frequency of CD70 + CD4+ T cells was negatively correlated with CD4 count and positively associated with immune activation in treatment-naïve people living with HIV (PLWH). More importantly, CD70 expression defined a population of proinflammatory Th1/17/22/GM subsets in PLWH. Blocking CD70 decreased the mRNA expression of subset-specific markers during Th1/17/22/GM polarization. Furthermore, we demonstrated that CD70 influenced the differentiation of these Th cells through STAT pathway. Finally, it was revealed that patients with a high baseline level of CD70 on CD4+ T cells exhibited a greater risk of poor immune reconstitution after antiretroviral therapy (ART) than those with low CD70. In general, our data highlighted the role of CD70 in Th1/17/22/GM differentiation during HIV infection and provided evidence for CD70 as a potential biomarker for predicting immune recovery.

[Differences in biochemical indexes and AIDS-related complications at baseline in HIV- infected patients with different levels of immune reconstitution after antiretroviral therapy].

Objective: To observe the differences in biochemical indexes and AIDS-related complications at baseline in HIV-infected patients with different levels of immune reconstitution to antiretroviral therapy (ART). Methods: The subjects were treat-naïve adult HIV-infected patients who were followed up for more than 24 months in the Guangzhou Eighth People's Hospital affiliated infection clinic at Guangzhou Medical University from January 2010 to December 2017. CD4+ T lymphocyte count at baseline at <200, 200-350, and >350 cells/µl levels were divided into poor, partial, and good immune reconstitution groups. The Kruskal-Wallis H and chi-square tests were used to analyze the differences in baseline sociodemographic characteristics, biochemical indexes, and AIDS-related complications among different groups. The SPSS 20.0 software was used for statistical analysis. Results: Among the 3 900 HIV-infected individuals, 385 cases (9.9%), 1 206 cases (30.9%), and 2 309 cases (59.2%) were grouped into poor, partial and good immune reconstitution groups, respectively. The baseline biochemical indexes of leukocyte, platelet, hemoglobin, TG, TC, FPG, AST, ALT and total bilirubin in the poor immune reconstitution group were significantly different from those in the good immune reconstitution group (all P<0.05). The proportion of AIDS-related complications at baseline in the poor immune reconstitution group, such as tuberculosis, pneumocystis yeli pneumonia, disseminated mycosis, esophageal candidiasis, extrapulmonary tuberculosis, dermatitis, oral candidiasis, oral mucous leukoplakia, continuous diarrhea for more than 1 month and continuous or intermittent fever for more than 1 month, was significantly higher than that in the good immune reconstitution group (all P<0.05). Conclusions: The biochemical indexes and AIDS-related complications in HIV-infected patients with different levels of immune reconstitution were significantly different at baseline. Attention should be paid to monitoring abnormal biomedical indicators and AIDS-related complications at baseline.

Longitudinal analysis of immune reconstitution and metabolic changes in women living with HIV: A real-world observational study.

BACKGROUND: Women comprise more than half of people living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) worldwide and incomplete immune recovery and metabolic abnormalities affect them deeply. Studies of HIV antiretroviral therapy (ART) have a low female representation in China. We aimed to investigate immune reconstitution and metabolic changes of female HIV-positive cohort in China longitudinally. METHODS: HIV-positive women who initiated ART from January 2005 to June 2021 and were followed up regularly at least once a year were included in this study. Immunological indicators (cluster of differentiation 4 [CD4] counts and CD8 counts), viral load (VL), and metabolic indicators were collected at follow-up. All data were collected from the China Disease Prevention and Control Information System (CDPCIS). VL was tested half a year, 1 year after receiving ART, and every other year subsequently according to local policy. CD4/CD8 ratio normalization was considered as the primary outcome and defined as a value ≥1. Incidence rate and probability of CD4/CD8 ratio normalization were estimated through per 100 person-years follow-up (PYFU) and Kaplan-Meier curve, respectively. Multivariate Cox regression was used to identify independent risk factors associated with CD4/CD8 ratio normalization. We further studied the rate of dyslipidemia, hyperuricemia, diabetes, liver injury, and renal injury after ART initiation with the chi-squared tests or Fisher's exact probability tests, and a generalized estimating equation model was used to analyze factors of dyslipidemia and hyperuricemia. RESULTS: A total of 494 female patients with HIV/AIDS started ART within 16 years from January 2005 to June 2021, out of which 301 women were enrolled with a median duration of ART for 4.1 years (interquartile range, 2.3-7.0 years). The overall incidence rate of CD4/CD8 ratio normalization was 8.9 (95% confidence interval [CI], 7.4-10.6) per 100 PYFU, and probabilities of CD4/CD8 normalization after initiating ART at 1 year, 2 years, 5 years, and 10 years follow-up were 11.7%, 23.2%, 44.0%, and 59.0%, respectively. Independent risk factors associated with CD4/CD8 normalization were baseline CD4 cell counts <200 cells/µL, CD8 counts >1000 cells/µL, and more than 6 months from the start of combined ART (cART) to first virological suppression. Longitudinally, the rate of hypercholesterolemia (total cholesterol [TC]) and high triglyceride (TG) showed an increasing trend, while the rate of low high-density lipoprotein cholesterol (HDL) showed a decreasing trend. The rate of hyperuricemia presented a downtrend at follow-up. Although liver and renal injury and diabetes persisted during ART, the rate was not statistically significant. Older age and protease inhibitors were independent risk factors for increase of TC and TG, and ART duration was an independent factor for elevation of TC and recovery of HDL-C. CONCLUSIONS: This study showed that women were more likely to normalize CD4/CD8 ratio in comparison with findings reported in the literature even though immune reconstruction was incomplete.