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.

HBV pgRNA profiles in Chinese HIV/HBV coinfected patients under pre- and posttreatment: a multicentre observational cohort study.

Data on hepatitis B virus (HBV) pregenomic (pgRNA) levels in HIV/HBV coinfected patients pre- and post-combined antiretroviral therapy (cART) are limited. This study aimed to evaluate the distribution of HBV pgRNA levels in treatment-naive coinfected patients and explore the changes that occur after the initiation of cART by examining patients from multicentre cohort studies performed in China. We included HIV/HBV coinfected subjects from the China AIDS Clinical Trial cohorts established from 2008 to 2014. Clinical and serological markers of HIV and HBV infection and biochemical data were acquired at baseline and after 96 and 240-480 weeks of cART. The correlations between HBV pgRNA and HBV DNA levels as well as HBsAg levels were calculated using Spearman's bivariate correlation analysis, and multivariate regression analysis was performed to determine factors associated with undetectable HBV pgRNA levels before cART and HBeAg loss after cART. A total of 132 HIV/HBV coinfected patients were enrolled, and 100 individuals were HBeAg-negative. A total of 34.4% (32/93) of patients were positive for HBV pgRNA, and the median HBV pgRNA level was 4.92 (IQR: 4.21-6.12) log10 copies/mL before cART. The median HBV pgRNA level was significantly lower in HBeAg-negative individuals than in HBeAg-positive individuals (4.22 (IQR: 2.70-4.84) log10 copies/mL vs. 5.77 (IQR: 4.63-6.55) log10 copies/mL, p = 0.002). HBV pgRNA was moderately correlated with HBsAg (r = 0.594, p = 0.001), and positively associated with HBV DNA (r = 0.445, p = 0.011). The factors independently associated with undetectable HBV pgRNA level before cART were HBV DNA (OR: 5.61, 95% CI: 1.50-20.96, p = 0.01) and HBeAg status (OR: 5.95, 95% CI: 1.52-23.25, p = 0.01). A total of 87.5% (28/32) of patients were followed for a median duration of 138 (IQR: 54-240) weeks, and the HBV pgRNA levels became undetectable in seven patients. The 132 patients were observed for 695.5 person-years, and no HBsAg loss occurred. Thirteen individuals achieved HBeAg loss, four patients had undetectable levels of HBV pgRNA pre-cART, and the level of six individuals became undetectable during the 48-week (IQR: 48-264) follow-up period. HBeAg status was significantly associated with HBV pgRNA level in HIV/HBV coinfected patients pre- and post-cART. Additionally, undetectable HBV pgRNA level may be associated with HBeAg loss after cART.

An updated immunosenescence exploration in healthy Chinese donors: circular elevated PD-1 on T cell and increased Ki67 on CD8+ T cell towards aging.

Immunosenescence is a process of immune dysfunction that occurs along with aging. Many studies have focused on the changes of different lymphocyte subsets in diseases and immune aging. However, the fluctuation in the number and phenotype of lymphocyte subset caused by aging have not been comprehensively analyzed, especially the effects of new indicators such as PD-1 and Ki67 in peripheral blood have been rarely reported. We further investigated the humoral and cellular immune parameters of 150 healthy donors over 18 years old. Age was associated with decreased CD4+CD45RA+CD62L+ T cells, decreased CD4+CD45RA+CD31+ T cells, and increased memory CD4+ or CD8+ T cells, dominated by male CD8+ T cells. The loss of CD28 expression on T cells and the transverse trend of activated CD38 and HLA-DR were also related to the increased age. In addition, CD8+ T cells in men were more prominent in activation indicators, and the difference between the old and young groups was obvious. CD4+CD25+CD127- T cells percentage tended to decrease with age and did not differ significantly between gender. Interestingly, we found that age was positively associated with PD-1+ T cells and showed significant age-related variability in men. Similarly, the percentage of CD8+ki-67+ also showed an increasing trend, with significant differences between the young group and other elderly groups in males. Our findings can provide immunological clues for future aging research, offering new insights for clinical monitoring and prevention of certain diseases.

Comprehensive transcriptomic analyses identify the immunosuppressive effects of LLDT-8 in ART-treated SIV-infected rhesus macaques.

BACKGROUND: Chronic immune activation plays a significant role in the pathogenesis and disease progression of human immunodeficiency virus (HIV), and the existing interventions to address this issue are limited. In a phase II clinical trial, (5R)-5-hydroxytriptolide (LLDT-8) demonstrated promising potential in enhancing CD4+ T cell recovery. However, the therapeutical effects of LLDT-8 remained to be systemic explored. METHODS: To assess the treatment effects of LLDT-8, we conducted flow cytometry and RNA-seq analyses on eight Chinese rhesus monkeys infected with simian immunodeficiency virus (SIV). Additionally, we performed comprehensive transcriptomic analyses, including cross-sectional and longitudinal differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and deconvolution analysis using peripheral blood mononuclear cell (PBMC) samples from 14-time points. These findings were further validated with RNA-seq analysis on patients who received LLDT-8 treatment, along with in vitro cellular experiments using human PBMCs. RESULTS: Flow cytometry analysis revealed that LLDT-8 treatment significantly reduced the percentage of HLA-DR+CD38+CD8+ T cells in SIV-infected rhesus monkeys (P < 0.001). The cross-sectional and longitudinal analysis identified 2531 and 1809 DEGs, respectively. GSEA analysis indicated that LLDT-8 treatment led to significant downregulation of proliferation-related pathways, such as E2F targets, G2M checkpoint, and mitotic spindle pathways. WGCNA analysis identified two modules and 202 hub genes associated with CD8 activation levels. Deconvolution analysis showed a significant decrease in the proportion of CD8+ T cells and activated CD4+ T cells during LLDT-8 treatment. Gene ontology results demonstrated that the common DEGs between LLDT-8-treated patients and rhesus monkeys were primarily enriched in cell activation and cell cycle progression. Furthermore, in vitro cellular experiments validated the consistent impact of LLDT-8 in inhibiting proliferation, activation (HLA-DR and CD38 expression), exhaustion (PD-1 expression), and IFN-γ production in human CD4+ and CD8+ T cells. CONCLUSION: LLDT-8 exhibited notable efficacy in alleviating immune activation in both an in vivo animal model and in vitro human cell experiments. These findings suggest that LLDT-8 may hold potential as a drug for managing systemic immune activation associated with SIV/HIV infection, warranting further prospective clinical exploration.

Peripheral PD-1+NK cells could predict the 28-day mortality in sepsis patients.

Background: Unbalanced inflammatory response is a critical feature of sepsis, a life-threatening condition with significant global health burdens. Immune dysfunction, particularly that involving different immune cells in peripheral blood, plays a crucial pathophysiological role and shows early warning signs in sepsis. The objective is to explore the relationship between sepsis and immune subpopulations in peripheral blood, and to identify patients with a higher risk of 28-day mortality based on immunological subtypes with machine-learning (ML) model. Methods: Patients were enrolled according to the sepsis-3 criteria in this retrospective observational study, along with age- and sex-matched healthy controls (HCs). Data on clinical characteristics, laboratory tests, and lymphocyte immunophenotyping were collected. XGBoost and k-means clustering as ML approaches, were employed to analyze the immune profiles and stratify septic patients based on their immunological subtypes. Cox regression survival analysis was used to identify potential biomarkers and to assess their association with 28-day mortality. The accuracy of biomarkers for mortality was determined by the area under the receiver operating characteristic (ROC) curve (AUC) analysis. Results: The study enrolled 100 septic patients and 89 HCs, revealing distinct lymphocyte profiles between the two groups. The XGBoost model discriminated sepsis from HCs with an area under the receiver operating characteristic curve of 1.0 and 0.99 in the training and testing set, respectively. Within the model, the top three highest important contributions were the percentage of CD38+CD8+T cells, PD-1+NK cells, HLA-DR+CD8+T cells. Two clusters of peripheral immunophenotyping of septic patients by k-means clustering were conducted. Cluster 1 featured higher proportions of PD1+ NK cells, while cluster 2 featured higher proportions of naïve CD4+T cells. Furthermore, the level of PD-1+NK cells was significantly higher in the non-survivors than the survivors (15.1% vs 8.6%, P<0.01). Moreover, the levels of PD1+ NK cells combined with SOFA score showed good performance in predicting the 28-day mortality in sepsis (AUC=0.91,95%CI 0.82-0.99), which is superior to PD1+ NK cells only(AUC=0.69, sensitivity 0.74, specificity 0.64, cut-off value of 11.25%). In the multivariate Cox regression, high expression of PD1+ NK cells proportion was related to 28-day mortality (aHR=1.34, 95%CI 1.19 to 1.50; P<0.001). Conclusion: The study provides novel insights into the association between PD1+NK cell profiles and prognosis of sepsis. Peripheral immunophenotyping could potentially stratify the septic patients and identify those with a high risk of 28-day mortality.

Benefits of high-dose intravenous immunoglobulin on mortality in patients with severe COVID-19: An updated systematic review and meta-analysis.

Background: The clinical benefits of high-dose intravenous immunoglobulin (IVIg) in treating COVID-19 remained controversial. Methods: We systematically searched databases up to February 17, 2022, for studies examining the efficacy of IVIg compared to routine care. Meta-analyses were conducted using the random-effects model. Subgroup analysis, meta-regression, and trial series analysis w ere performed to explore heterogeneity and statistical significance. Results: A total of 4,711 hospitalized COVID-19 patients (1,925 IVIg treated and 2786 control) were collected from 17 studies, including five randomized controlled trials (RCTs) and 12 cohort studies. The application of IVIg was not associated with all-cause mortality (RR= 0.89 [0.63, 1.26], P= 0.53; I2 = 75%), the length of hospital stays (MD= 0.29 [-3.40, 6.44] days, P= 0.88; I2 = 96%), the needs for mechanical ventilation (RR= 0.93 ([0.73, 1.19], P= 0.31; I2 = 56%), or the incidence of adverse events (RR= 1.15 [0.99, 1.33], P= 0.06; I2 = 20%). Subgroup analyses showed that overall mortality among patients with severe COVID-19 was reduced in the high-dose IVIg subgroup (RR= 0.33 [0.13, 0.86], P= 0.02, I2 = 68%; very low certainty). Conclusions: Results of this study suggest that severe hospitalized COVID-19 patients treated with high-dose IVIg would have a lower risk of death than patients with routine care. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021231040, identifier CRD42021231040.

CD4+ T cell counts and soluble programmed death-1 at baseline correlated with hepatitis B surface antigen decline in HIV/HBV coinfection during combined antiretroviral therapy.

Background: Several studies have described the rapid decline and clearance of hepatitis B surface antigen (HBsAg) in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection after initiating combined antiretroviral therapy (cART). Early decline of HBsAg levels is associated with HBsAg seroclearance in the treatment of chronic HBV infection. This study aims to evaluate the HBsAg kinetics and the determinants of early HBsAg decline in patients with HIV/HBV coinfection during cART. Methods: A total of 51 patients with HIV/HBV coinfection were enrolled from a previously established HIV/AIDS cohort and followed for a median of 59.5 months after cART initiation. Biochemical tests, virology and immunology assessments were measured longitudinally. The kinetics of HBsAg during cART were analyzed. Soluble programmed death-1 (sPD-1) levels and immune activation markers (CD38 and HLA-DR) were measured at baseline, 1-year and 3-year during treatment. HBsAg response was defined as a decline of more than 0.5 log10 IU/ml at 6 months from the baseline after initiation of cART. Results: HBsAg declined faster (0.47 log10 IU/mL) in the first six months and attained a decrease of 1.39 log10 IU/mL after 5-year therapy. Seventeen (33.3%) participants achieved a decline of more than 0.5 log10 IU/ml at the first 6 months of cART(HBsAg response) of which five patients achieved HBsAg clearance at a median of 11 months (range: 6-51 months). Multivariate logistic analysis showed the lower baseline CD4+ T cell levels (OR=6.633, P=0.012) and sPD-1 level (OR=5.389, P=0.038) were independently associated with HBsAg response after cART initiation. The alanine aminotransferase abnormality rate and HLA-DR expression were significantly higher in patients who achieved HBsAg response than in those who did not achieve HBsAg response after cART initiation. Conclusion: Lower CD4 + T cells, sPD-1, and immune activation were related to a rapid HBsAg decline in patients with HIV/HBV-coinfection after the initiation of cART. These findings imply that immune disorders induced by HIV infection may disrupt immune tolerance to HBV, leading to a faster decline in HBsAg levels during coinfection.

Altered plasma metabolites and inflammatory networks in HIV-1 infected patients with different immunological responses after long-term antiretroviral therapy.

Background: Chronic metabolic changes relevant to human immunodeficiency virus type 1 (HIV-1) infection and in response to antiretroviral therapy (ART) remain undetermined. Moreover, links between metabolic dysfunction caused by HIV and immunological inflammation in long-term treated individuals have been poorly studied. Methods: Untargeted metabolomics and inflammatory cytokine levels were assessed in 47 HIV-infected individuals including 22 immunological responders (IRs) and 25 non-responders (INRs) before and after ART. The IRs and INRs were matched by age, gender, baseline viral load, and baseline CD4+T cell counts. Another 25 age-matched uninfected healthy individuals were also included as controls. Results: Among the 770 plasma compounds detected in the current study, significant changes were identified in lipids, nucleotides, and biogenic amino acids between HIV-infected patients and healthy controls. Principal Component Analysis (PCA) and the Random Forest (RF) model suggested that levels of selected metabolites could differentiate HIV-infected patients clearly from healthy controls. However, the metabolite profiles identified in our patients were similar, and only three metabolites, maltotetraose, N, N-dimethyl-5-aminovalerate, and decadienedioic acid (C10:2-DC), were different between IRs and INRs following long-term ART. The pathway enrichment analysis results revealed that disturbances in pyrimidine metabolism, sphingolipid metabolism, and purine metabolism after HIV infection and these changes did not recover to normal levels in healthy controls even with suppressive ART. Correlation analysis of the metabolism-immune network indicated that interleukin (IL)-10, D-dimer, vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and TNF-RII were positively correlated with most of the significantly changed lipid and amino acid metabolites but negatively correlated with metabolites in nucleotide metabolism. Conclusions: Significant changes in many metabolites were observed in HIV-infected individuals before and after ART regardless of their immunological recovery status. The disturbed metabolic profiles of lipids and nucleotides in HIV infection did not recover to normal levels even after long-term ART. These changes are correlated with modified cytokines and biomarkers of chronic non-AIDS events, warranting tryout of interventions other than ART.

Clinical and immunological characteristics of HIV/syphilis co-infected patients following long-term antiretroviral treatment.

Objective: This study aims to analyze the efficacy of anti-syphilis treatment and the impact of syphilis events on HIV virology and immunology in HIV/syphilis co-infected patients on long-term antiretroviral therapy (ART) and to investigate the incidence and factors of syphilis recurrence/re-infection/serofast state. The insights derived from this investigation can potentially guide strategies for preventing and managing syphilis and AIDS. Methods: A retrospective case-control study was conducted at the AIDS clinic of Peking Union Medical College Hospital from January 2003 to December 2022. The study involved 86 HIV/syphilis co-infected patients and 86 HIV mono-infected patients matched based on age, baseline CD4 + T cell counts, and viral load. We examined the clinical characteristics of HIV/syphilis co-infected patients, evaluated the efficacy of anti-syphilis treatment, and analyzed the dynamic changes in HIV virology and immunology. The Generalized Estimating Equations (GEE) model investigated the factors associated with HIV/syphilis co-infection and syphilis recurrence/reinfection/serofast state. Results: Syphilis serofast state was observed in 11.6% (10/86) of HIV/syphilis co-infected patients after treatment, and 33.7% (29/86) had syphilis recurrence or re-infection. The overall effectiveness of syphilis treatment stood at 76.8% (63/82). Notably, the effectiveness of syphilis treatment displayed a significant correlation with baseline syphilis titers exceeding 1:128 (p = 0.003). Over the 10-year follow-up period on ART, the HLA-DR + CD8+/CD8 + % levels in the HIV/syphilis co-infected group were markedly higher than those in the HIV mono-infected group (p < 0.05). However, no significant differences were observed between the two groups regarding HIV viral load, CD4+ T cell counts, CD8+ T cell counts, CD4/CD8 ratio, and CD38 + CD8+/CD8 + % (p > 0.05). GEE analysis model revealed that elevated HLA-DR + CD8+/CD8 + % levels were associated with HIV/syphilis co-infection (OR = 1.026, 95% CI = 1.007-1.046; p = 0.007) and syphilis recurrence/reinfection/serofast state (OR = 1.036, 95% CI = 1.008-1.065; p = 0.012). Conclusion: While HIV/syphilis co-infected patients typically receive adequate treatment, the incidence of syphilis recurrence and reinfection remain notably elevated. A heightened HLA-DR + CD8+/CD8+ % is a notable risk factor for HIV/syphilis co-infection and syphilis recurrence/reinfection/serofast state. Therefore, it is advisable to reinforce health education efforts and ensure regular follow-ups for people living with HIV undergoing ART to monitor syphilis infection or increased risk of syphilis infection.

Immune Responses to HBV Vaccine in People Living with HIV (PLWHs) Who Achieved Successful Treatment: A Prospective Cohort Study.

BACKGROUND: Understanding immune responses after HBV vaccination is important to prevent HBV infection in PLWH and to achieve successful treatment. METHODS: Thirty-two PLWHs with CD4+ cell count > 350 cells/µL and HIV RNA < 200 copies/mL were vaccinated with 20 µg of HBV vaccine at weeks 0, 4, and 24 in this prospective study. We measured total HIV DNA levels, HBsAb titers and HBsAg-specific T-cell responses during follow-up time. RESULTS: All patients achieved protective HBsAb titer after immunization. The magnitude of the IFN-r and TNF-a response to HBsAg was 22.0 (IQR: 6.5-65.0) and 106.50 (IQR: 58.5-203.0) spot-forming cells (SFC)/105 PBMC, respectively at week 0. The level of IFN-r secreted at weeks 12 and weeks 36 to 48 was comparable with that at week 0. However, IFN-r response was higher at weeks 12 than that at weeks 36 to 48 (p = 0.02). The level of TNF-a secreted at weeks 12 was higher than that at week 0 (p < 0.001). Total HIV DNA levels were 2.76 (IQR: 2.47-3.07), 2.77 (IQR: 2.50-3.09), 2.77 (IQR: 2.41-2.89) log10 copies/106 PBMCs at weeks 0, 12, 36 to 48, respectively. No correlation was observed between IFN-r and TNF-a levels and HBsAb titer as well as total HIV DNA levels after immunization. CONCLUSION: Humoral immunity was satisfactory, but cellular immunity and decline in HIV reservoir were not optimal after HBV vaccine immunization in these patients.

(5R)-5-hydroxytriptolide for HIV immunological non-responders receiving ART: a randomized, double-blinded, placebo-controlled phase II study.

Background: Therapeutic approaches to HIV-suppressed immunological non-responders (INRs) remain unsettled. We previously reported efficacy of Chinese herbal Tripterygium wilfordii Hook F in INRs. Its derivative (5R)-5-hydroxytriptolide (LLDT-8) on CD4 T cell recovery was assessed. Methods: The phase II, double-blind, randomized, placebo-controlled trial was conducted in adults patients with long-term suppressed HIV infection and suboptimal CD4 recovery, at nine hospitals in China. The patients were 1:1:1 assigned to receive oral LLDT-8 0.5 mg or 1 mg daily, or placebo combined with antiretroviral therapy for 48 weeks. All study staff and participants were masked. The primary endpoints include change of CD4 T cell counts and inflammatory markers at week 48. This study is registered on ClinicalTrials.gov (NCT04084444) and Chinese Clinical Trial Register (CTR20191397). Findings: A total of 149 patients were enrolled from Aug 30, 2019 and randomly allocated to receiving LLDT-8 0.5 mg daily (LT8, n = 51), 1 mg daily (HT8, n = 46), or placebo (PL, n = 52). The median baseline CD4 count was 248 cells/mm3, comparable among three groups. LLDT-8 was well-tolerated in all participants. At 48 weeks, change of CD4 counts was 49 cells/mm3 in LT8 group (95% confidence interval [CI]: 30, 68), 63 cells/mm3 in HT8 group (95% CI: 41, 85), compared to 32 cells/mm3 in placebo group (95% CI: 13, 51). LLDT-8 1 mg daily significantly increased CD4 count compared to placebo (p = 0.036), especially in participants over 45 years. The mean change of serum interferon-γ-induced protein 10 was -72.1 mg/L (95% CI -97.7, -46.5) in HT8 group at 48 weeks, markedly decreased compared to -22.8 mg/L (95% CI -47.1, 1.5, p = 0.007) in placebo group. Treatment-emergent adverse events (TEAEs) were reported in 41 of 46 (89.1%) participants in HT8 group, 43 of 51 (84.3%) in LT8, and 42 of 52 (80.7%) in PL group. No drug-related SAEs were reported. Interpretation: LLDT-8 enhanced CD4 recovery and alleviated inflammation in long-term suppressed INRs, providing them a potential therapeutic option. Fundings: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, Shanghai Pharmaceuticals Holding Co., Ltd., and the National key technologies R&D program for the 13th five-year plan.

Immunological changes after COVID-19 vaccination in an HIV-positive patient.

Vaccination is an essential measure to stop the coronavirus disease 2019 (COVID-19) pandemic. We report a case of viral activation and CD4+ T cell loss in a treatment-naïve HIV-positive patient after receiving inactivated COVID-19 vaccine (Sinopharm). The vaccine should probably be given only to people living with HIV receiving antiretroviral therapy.

Safety and efficacy of long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection: a systematic review and meta-analysis protocol.

BACKGROUND: Current antiretroviral regimens have, for the most part, achieved optimal antiretroviral efficacy and tolerability, transforming HIV infection from a deadly disease into a manageable chronic condition. However, adherence to daily oral drug intake remains an issue, as it is the most important determinant for sustained viral suppression and prevention of the emergence of drug-resistant viral strains. The long-acting injection antiretroviral cabotegravir and rilpivirine combination, a novel drug delivery approach, is about to revolutionise the therapy for people living with HIV. In this protocol, we aim to generate a clinically useful summary of the interventions based on their efficacy. METHODS AND ANALYSIS: We searched the literature for eligible studies published from inception up to 16 August 2022 through PubMed, EMBASE, Cochrane Library, Scopus and ClinicalTrials.gov. Two methodologically trained researchers will select the qualified studies for data extraction independently. Cochrane Risk of Bias tool will be used to assess the risk of bias in included studies. Statistical heterogeneity will be computed by Cochrane X2 and I2 tests. Sensitivity analysis will be conducted to evaluate the stability of the results. Publication biases will be evaluated by Begg's and Egger's tests. The quality of evidence will be assessed by the Grading of Recommendations Assessment, Development and Evaluation system. The RevMan V.5.3 and Stata V.14.0 software will be applied for statistical analyses. ETHICS AND DISSEMINATION: Ethical approval will not be required for this systematic review because the data used are not linked to the individual patient. The results of this review will be disseminated by being published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022310414.

Comparison of Renal Function Biomarkers of Serum Creatinine and Cystatin C in HIV-Infected People on Dolutegravir-Containing Therapy.

Objectives: HIV-1-infected Chinese patients who were treated naïve with combination dolutegravir (DTG) and tenofovir disoproxil fumarate (TDF) group, DTG without TDF group, TDF without DTG, as well as patients switched to DTG-containing therapy from other drugs were included. Design: The dynamics of serum creatinine, cystatin C (CysC) level, eGFRcr and eGFRCysC at the baseline, 4 w, 12w, 24w, 36w and 48w for different group of patients were collected and evaluated. Methods: Changes in serum creatinine, levels, eGFRcr and eGFRCysC were analyzed among groups and in different time-points. Intra-group correlation coefficient and Bland-Altman plot were used to compare the results of eGFRcr and eGFRCysC. Results: Thirty-seven treated-naïve HIV-patients in combined DTG and TDF group (group 1), 23 in DTG without TDF patients (group 2) and 47 patients on TDF without DTG group (control group, group 3) along with 31 patients whose ART switch to DTG-containing regimens (group 4) were collected. Serum creatinine was significantly elevated in the group 1 and group 2 instead of group 3 from baseline to 48w. Mean decreased change of eGFR calculated by serum creatinine proved the same conclusion. However, there were no differences in serum cystatin C and eGFRCysC between baseline and at 48 weeks in DTG-containing groups. Moreover, the proportion of eGFRcr decreased over 30% was significantly higher in DTG-treatment group. Conclusion: We demonstrated the clinical benefits of CysC for assessing the glomerular filtration rate when evaluating renal function in HIV-1-infected patients treated with whether DTG combined with TDF or not.

Comparative Transcriptional Analysis Identified Characteristic Genes and Patterns in HIV-Infected Immunological Non-Responders.

Purpose: The incomplete immune reconstitution is a complex phenomenon among human immunodeficiency virus (HIV)-infected patients despite the fact that they have achieved persistent viral suppression under the combined antiretroviral therapy. This study aims to screen and verify the immunological characteristics and underlying mechanisms of immunological non-responders (INRs). Methods: The RNA-seq and the differentially expressed genes (DEGs) analysis were used to explore potential characteristics among INRs. Gene Ontology (GO) enrichment, ingenuity pathway analysis (IPA) analysis, Gene set enrichment analysis (GSEA) analysis, and the weighted gene co-expression network analysis (WGCNA) were used to explore the potential mechanism. The transcriptional meta-analysis was used to analyze the external efficiency. Results: The RNA-seq identified 316 DEGs among INRs. The interferon signaling pathway was enriched via GO and IPA analysis among DEGs. The combined GSEA and WGCNA analysis confirmed that the IFN response was more correlated with INR. Furthermore, IFI27 (IFN-α Inducible Protein 27, also known as ISG12) was chosen based on combined DEG analysis, WGCNA analysis, and the transcriptional meta-analysis conducted on other published datasets about INRs. The expression of IFI27 was significantly negatively correlated with the CD4+ T-cell counts of PLWH, and the predictive efficiency of IFI27 level in distinguishing PLWH with poor immune recovery was also with significant power (AUC = 0.848). Conclusion: The enhanced expression of IFI27 and the IFN response pathway are among the important immunological characteristics of INRs and exhibited promising efficiency as biomarkers for CD4+ T-cell recovery.

Combined multi-omics and network pharmacology approach reveals the role of Tripterygium Wilfordii Hook F in treating HIV immunological non-responders.

BACKGROUND: The HIV-1 infected immunological non-responders (INRs) are characterized by poor immune reconstitution after long-term treatment. Tripterygium Wilfordii Hook F (TwHF) pill is a traditional Chinese patent drug with extensive immunosuppressive effects and has been clinically proven efficacy in treating INRs. PURPOSE: The therapeutic mechanism of TwHF pills in the treatment of INRs was investigated by the combined multi-omics analysis on clinical samples and network pharmacology approach. METHODS: Clinically, the peripheral blood mononuclear cells (PBMC) samples of TwHF-treated INRs from different time points were collected to conduct the transcriptomic and proteomic profiling. Key effector pathways of TwHF were enriched and analyzed by the ingenuity pathway analysis (IPA). Computationally, the TwHF-related compounds were obtained from traditional Chinese medicine databases, and literature search and structural prediction were performed to identify TwHF-related targets. Integrated with the INR-related targets, the 'TwHF-compounds-targets-INR' network was constructed to analyze core effector targets by centrality measurement. Experimentally, the effects of TwHF compounds on the T cells activation and expression of identified targets were evaluated with in vitro cell culture. RESULTS: 33 INRs were included and treated with TwHF pills for 17 (IQR, 12-24) months. These patients experienced rapid growth in the CD4+ T cell counts and decreased T cell activation. The multi-omics analysis showed that the interferon (IFN)-signaling pathway was significantly inhibited after taking TwHF pills. The network pharmacology predicted the central role of the signal transducer and activator of transcription 1 (STAT1) in the 'TwHF-compounds-targets-INR' network. Further bioinformatic analysis predicted STAT1 would regulate over 58.8% of identified down-regulated genes. Cell experiments validated that triptolide (TPL) would serve as the major bioactivity compound of TwHF pills to inhibit the immune cell activation, the production of IFN-γ, the expression of downstream IFN-stimulated genes, and the phosphorylation of STAT1. CONCLUSION: Our research is the first to systemic verify the mechanisms of TwHF in treating INRs. The IFN signaling pathway and the STAT1 would be the major effector targets of TwHF pills in treating INRs. The TPL would be the major bioactive compound to inhibit the IFN response and the phosphorylation of STAT1. Our observations suggest the basis for further application of TPL analogous in treating INRs.

The pattern and magnitude of T cell subsets reconstitution during ten years of ART with viral suppression in HIV-infected patients.

BACKGROUND: The extent of immune reconstitution in human immunodeficiency virus (HIV) infected persons receiving long-term antiretroviral therapy (ART) with controlled viral load has been controversial. We studied the extent and speed of T cell subsets retrieval after long-term antiretroviral treatment. METHODS: 662 HIV-infected patients followed at least 2 years whose plasma HIV-1 RNA load <50 copies/mL were evaluated for longitudinal and functional phenotypic indices of immune restoration. Determinants of change in magnitude and importance of recovery have been evaluated using mixed linear regression models. RESULTS: Almost all robust immune restorations achieved occurred after 2-3 years of ART. The median CD4 lymphocyte count increased 449 cells/µl (IQR 303-604) from 226 cells/µl (IQR 83-336) at baseline during the third year (P < 0.001); CD4+T lymphocyte rises during the sixth and tenth years were not significant. Naive and memory CD4+T cells'reconstitution occurred in the sixth and eighth years of ART but no significant change thereafter. The change of CD45RA+Naïve and CD45RA-memory CD4+T cell reconstitution is different in baseline CD4+T cell counts <100 cells/µl group and in baseline CD4+T cell counts >100 cells/µl group. Activation antigen expression (CD38 or HLA-DR) on CD8 lymphocytes declined mostly during the first till second year, and after 4 years, activation antigen expression on patient lymphocytes showed no significant change. The proportion of CD4 cells expressing CD28 climbed during the first years and reached normal levels in the second year. CONCLUSIONS: Immune restoration was dependent on the capacity of immune system during the first 2-3 year of ART. But the significant change of CD4 and compartments of CD4+T cells could persist until 6-8 years. The pattern of CD38+CD8+, HLA-DR+CD8+, CD28+CD4+ T cells could quickly return to normal level and no significant change after sufficient time of ART. In general, the immune response compared to the baseline status may be the overall effect from the age and time of antiretroviral treatment.

Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with droplets and contact as the main means of transmission. Since the first case appeared in Wuhan, China, in December 2019, the outbreak has gradually spread nationwide. Up to now, according to official data released by the Chinese health commission, the number of newly diagnosed patients has been declining, and the epidemic is gradually being controlled. Although most patients have mild symptoms and good prognosis after infection, some patients developed severe and die from multiple organ complications. The pathogenesis of SARS-CoV-2 infection in humans remains unclear. Immune function is a strong defense against invasive pathogens and there is currently no specific antiviral drug against the virus. This article reviews the immunological changes of coronaviruses like SARS, MERS and other viral pneumonia similar to SARS-CoV-2. Combined with the published literature, the potential pathogenesis of COVID-19 is inferred, and the treatment recommendations for giving high-doses intravenous immunoglobulin and low-molecular-weight heparin anticoagulant therapy to severe type patients are proposed.