Risk factors and longitudinal changes of dyslipidemia among Chinese people living with HIV receiving antiretroviral therapy.

BACKGROUND: Antiretroviral therapy (ART) improved the prognosis of people living with human immunodeficiency virus (HIV) (PLWH). Life-long treatment is required in PLWH and is accompanied by various metabolic abnormalities in the disease course. Data about the epidemiology and the dynamic changes of dyslipidemia in PLWH receiving antiretroviral therapy were scarce in Asian countries. This study aimed to explore the risk factors of dyslipidemia and analyze the longitudinal changes of dyslipidemia among Chinese PLWH receiving HAART. METHODS: We conducted a longitudinal analysis of PLWH enrolled in two large multicenter clinical trials across China, and outpatients followed at the clinic of Peking Union Medical College Hospital. Demographic data and clinical parameters were collected. The risk factors and longitudinal changes in lipid profiles associated with HIV-1 infection were analyzed. The definition of dyslipidemia was made based on the National Cholesterol Education Program, Adult Treatment Panel (NCEP-ATP) III guidelines. RESULTS: A total of 1542 PLWH were included. The median follow-up was 6 years. At baseline, the concentrations of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were 4.1 ± 0.91 mmol/L, 1.2 (interquartile ranges [IQR] 0.85-1.75) mmol/L, 1.1 ± 0.37 and 2.4 ± 0.76 mmol/L, respectively. The rate of hypercholesterolemia, hyperglyceridemia, high LDL-C, and low HDL-C were 10.18%, 26.39%, 9.08%, and 44.94%, respectively. The overall prevalence of dyslipidemia was 69.3%, which raised to 84.3% after antiretroviral therapy, substantially higher. CD4/CD8 ratio < 0.3 and viral load > 105 copies/mL were risk factors associated with any subtype of dyslipidemia. A negative correlation between CD8+CD38+ percentage and HDL-C concentration was found. The regimens including efavirenz (EFV) and tenofovir (TDF) showed better lipid profiles. Longitudinal analysis revealed that both the level and the percentage of abnormal TG and HDL-C occurred drastic change in the first 6 months after ART initiation (from 4.07 to 4.41, from 1.11 to 1.28mmol/L, from 26.39 to 31.1% and from 44.94 to 29.5%, respectively). CONCLUSIONS: The prevalence of dyslipidemia is high in PLWH and increases after ART, mainly represented as high TG and low HDL-C and associated with advanced stage of HIV-1 infection. The greatest changes in lipids occurred in the early stage after initiating ART therapy. The results suggest that dyslipidemia should be monitored and managed when starting ART.

Whole blood as an alternative to peripheral blood mononuclear cell for detection of total HIV-1 DNA.

BACKGROUND: A more time saving, convenient, reproducible, and scalable method is needed to assess total HIV-1 DNA levels. METHODS: Frozen whole blood and peripheral blood mononuclear cell (PBMC) samples both 200 µl at the same point were used to detect total HIV-1 DNA. Automatic extraction of total HIV-1 DNA was used to ensure the consistency of sample extraction efficiency. The detection reagent was HIV-1 DNA quantitative detection kit and real-time quantitative PCR was utilized. RESULTS: Of the 44 included patients, 42 were male and 2 were female, with a median age of 33 years. Thirty-three cases were collected after receiving antiviral treatment, with a median duration of treatment of 3 months, and the other 11 cases were collected before antiviral treatment. The median viral load was 1.83 log10 copies/mL, the median CD4 and CD8 count were 94 and 680 cells/µL, and the median CD4/CD8 ratio was 0.18. The results of the two samples were 3.02 ± 0.39 log10 copies/106 PBMCs in PBMC samples and 3.05 ± 0.40 log10 copies/106 PBMCs in whole blood samples. The detection results of the two methods were highly correlated and consistent by using paired t test (P = 0.370), pearson correlation (r = 0.887, P < 0.0001) and intra-group correlation coefficient (ICC = 0.887, P < 0.0001) and bland-altman [4.55% points were outside the 95% limits of agreement (- 0.340 ~ 0.390)]. CONCLUSIONS: The results of the whole blood sample test for total HIV-1 DNA are consistent with those of PBMC samples. In a clinical setting it is recommended to use whole blood samples directly for the evaluation of the HIV reservoir.

The effects of antiretroviral therapy initiation time on HIV reservoir size in Chinese chronically HIV infected patients: a prospective, multi-site cohort study.

BACKGROUND: The effect of ART initiation time on HIV-1 DNA reservoir in chronically infected individuals is not well understood. Determining the potential influencing factors associated with a low HIV-1 DNA level in chronic infection is an important step toward drug-free control. METHODS: A prospective study included 444 chronically HIV-infected adults was performed. Participants were divided into two groups: early initiation group (EIG) or delayed initiation group (DIG) based on their baseline CD4 count; 350 to 500 and < 350 cells/mm3, respectively. Total HIV-1 DNA was measured by quantitative PCR. Using the Mann-Whitney U test, the HIV-1 DNA level at week 48 was compared between the two groups. The influencing factors of the HIV-1 DNA and factors associated with achieving a low HIV-1 level at week 48 were analyzed. RESULTS: The HIV-1 DNA at week 48 in EIG was significantly lower than in DIG [2.12 (1.80-2.51) vs 2.58 (2.21-2.87) log10 copies/106peripheral blood mononuclear cells (PBMCs); p = 0.001]. Early ART initiation was positively associated with lower HIV-1 DNA at week 48 (p = 0.025). Similarly, baseline HIV-1DNA (p = 0.001) was positively associated with HIV-1DNA at week 48 and baseline CD4/CD8 ratio (p = 0.001) was inversely associated with HIV-1DNA at week 48. Early ART initiation (p = 0.003) and baseline HIV-1 DNA level (p < 0.001) were positively associated with achieving HIV-1 DNA < 100 copies/106 PBMCs at week 48. CONCLUSION: Early ART initiation is positively associated with a smaller size of viral reservoir and a higher possibility of achieving a low HIV-1DNA level at week 48 in Chinese chronically HIV-1 infected adult. TRIAL REGISTRATION: NCT01844297 ; Registered 1 May, 2013.

Fluorometric determination of sulfadiazine by using molecularly imprinted poly(methyl methacrylate) nanobeads doped with manganese(II)-doped ZnS quantum dots.

The surface of poly(methyl methacrylate) nanospheres (PMMA-NSs) was molecularly imprinted with sulfadiazine by a surface imprinting method. Simultaneously, Mn(II)-doped ZnS quantum dots were incorporated into the imprinted PMMA-NSs. The morphology of the fluorescent nanoprobe was characterized by transmission electron microscopy which revealed good spheroidal core-shell structure and a homogeneous distribution of the QDs. Following binding of sulfadiazine, fluorescence (best measured at excitation/emission maxima of 335/592 nm) is increasingly quenched. The detection range is 5-40 µmol·L-1 of sulfadiazine, and the detection limit is 0.24 µmol·L-1. The fluorescence quenching mechanism is discussed, and a photo-induced electron transfer process is shown to account for quenching. The fluorescent probe was applied to the determination of sulfadiazine in spiked tap water with recoveries and RSDs of 96.6-100.2% and 2.7-3.9%, respectively. The detection of sulfadiazine in spiked lake water exhibited the recoveries and RSDs with 99.3-104.8% and 1.8-4.2%, respectively. Graphical abstract Schematic presentation of synthesis of PMMA-Ns, Mn-doped ZnS QDs, MQPs, and the elution diagram of SD from MQPs, and the relative reagents including: sodium dodecyl benzene sulfonate(SDBS), (3-aminopropyl)triethoxysilane(APTES), 3-mercaptopropionic acid (MPA), tetraethylorthosilicate(TEOS)and sulfadiazine(SD), and nanoparticles including: polymer(methyl methacrylate) nanospheres(PMMANs), MIPs@QDs@PMMANs(MQPs) and carbon quantum dots(CQDs).

A higher CD4/CD8 ratio correlates with an ultralow cell-associated HIV-1 DNA level in chronically infected patients on antiretroviral therapy: a case control study.

BACKGROUND: The HIV-1 DNA reservoir is an important marker that reflects viro-immunological status and can be affected by multiple viral or cellular factors. Determining the potential factors associated with the size of the HIV-1 DNA reservoir benefits the surveillance of disease progression and antiretroviral treatments. METHODS: We conducted a case control study to explore the factors that may affect the level of HIV-1 DNA. The level of HIV-1 total DNA in peripheral blood at 5 time points was quantified by quantitative PCR. Chronically HIV-1-infected patients whose cell-associated HIV-1 DNA levels were below the detection limit after receiving antiretroviral therapy (ART) for 96 weeks were identified (group 1), and patients who still had detectable levels of cell-associated HIV-1 DNA after ATR treatment were used as the control (group 2). RESULTS: Twenty-one patients with ultralow levels of cell-associated HIV-1 DNA [<20 copies/106 peripheral blood mononuclear cells (PBMCs)] presented with a lower CD8+ T-cell count (average: 511 ± 191 versus 715 ± 256 cells/µL, p = 0.013) and a higher CD4/CD8 ratio (average: 1.04 ± 0.37 versus 0.72 ± 0.32, respectively, p = 0.002) at week 96. In the multivariate analysis, patients with a higher CD4/CD8 ratio at week 96 were more likely to have levels of HIV-1 DNA below the detection limit (per 0.1 increase, OR = 1.29, 95% CI, 1.05-1.59, p = 0.017). CONCLUSION: After matching baseline HIV-1 DNA levels, a higher CD4/CD8 ratio at week 96 was the only factor associated with an ultralow level of HIV-1 DNA. The CD4/CD8 ratio can be used as an easy biomarker to help monitor patients on ART who will be selected to participate in eradication studies.

[The correlation between HLA-DR or CD38 expression in CD8(+)T cells and CD4(+)T cells count in treatment-naive HIV/AIDS patients].

OBJECTIVE: To analyze the correlation between CD4(+)T cell count and HLA-DR or CD38 expression on peripheral CD8(+)T cells in treatment-naive Chinese HIV/AIDS patients. METHODS: A total of 471 treatment-naive HIV-infected patients and 53 healthy volunteers were enrolled. HLA-DR or CD38 expression on peripheral CD8(+)T cells, CD4(+)T cell count, naive CD4(+)T cell subsets and CD28 expression on T cells were measured by flow cytometry. Plasma HIV RNA load was quantified by real-time PCR (COBAS TaqMan RT-PCR). Mann-Whitney U test and Spearman's rank correlation test were used for statistical analysis. RESULTS: CD38 expression intensity on CD8(+)T cells was negatively correlated with CD4(+)T cell count (r = -0.53, P < 0.001) and naive CD4(+)T cell count (r = -0.48, P < 0.001). CD38 expression on CD8(+)T cells also displayed significantly negative correlation with CD28 expression on CD8(+)T cells (r = -0.46, P < 0.001). HLA-DR expression on CD8(+)T cells did not show significant correlation with CD4(+)T cell count. Only weak positive correlation was found between CD38 intensity on CD8(+)T cells and plasma HIV RNA load. CONCLUSIONS: Compared with HLA-DR, CD38 expression on CD8(+)T cells shows more significant negative correlation with CD4(+)T cell count in treatment-naive patients. CD38 and HLA-DR may play different roles on the persistent immune activation in HIV infection.

Tripterygium wilfordii Hook F extract in cART-treated HIV patients with poor immune response: a pilot study to assess its immunomodulatory effects and safety.

BACKGROUND: Despite combination antiretroviral therapy (cART), 20% of HIV-infected patients are unable to achieve adequate immunologic recovery, in which immune activation plays a crucial role. We hypothesize that extract of Tripterygium wilfordii Hook F (TwHF), a Chinese medication used to treat autoimmune diseases, has immunomodulatory effects that may help CD4 cell recovery. METHODS: Eighteen cART-treated HIV-infected patients virally suppressed for over 12 months with suboptimal CD4 cell recovery were enrolled. TwHF extract was administered at a dosage of 10 mg three times daily for 12 months. T-cell subsets and activation markers were evaluated at baseline and during follow-up. The trial was registered at Clinicaltrials.gov (NCT02002286). RESULTS: TwHF extract was associated with a mean increase in CD4 cell count of 88 cells/µl (95% confidential interval [CI], 72-105 cells/µl) after one year of treatment. A significant increase in the mean rate of CD4 cell recovery (26 before vs 75 cells/µl/year after TwHF use, P < 0.001) was observed. Analysis of 13 patients with activation profiles suggested that TwHF extract was associated with a decrease in T-cell immune activation which was temporally correlated with CD4 cell recovery. No discontinuation of TwHF extract was reported. CONCLUSION: Use of TwHF extract in HIV-infected patients was associated with a reduction in T-cell activation and improved CD4 recovery with an excellent safety profile.

[A multicenter study of correlation between peripheral lymphocyte counts and CD(+)4T cell counts in HIV/AIDS patients].

OBJECTIVE: To evaluate the accuracy of lymphocyte count as a surrogate for CD(+)4T cell count in treatment-naїve HIV-infected adults. METHODS: A total of 2 013 HIV-infected patients were screened at 23 sites in China. CD(+)4T cell counts were measured by flow cytometry. Correlation between CD(+)4T cell count and peripheral lymphocyte count were analyzed by spearman coefficient. AUCROC were used to evaluate the performance of lymphocyte count as a surrogate for CD(+)4T cell count. RESULTS: The lymphocyte count and CD(+)4T cell count of these 2 013 patients were (1 600 ± 670) × 10(6)/L and (244 ± 148) × 10(6)/L respectively. CD(+)4T cell count were positively correlated with lymphocyte count (r = 0.482, P < 0.000 1). AUCROC of lymphocyte count as a surrogate for CD(+)4T cell counts of <100×10(6)/L, <200×10(6)/L and <350×10(6)/L were 0.790 (95%CI 0.761-0.818, P < 0.000 1), 0.733 (95%CI 0.710-0.755, P < 0.000 1) and 0.732 (95%CI 0.706-0.758, P < 0.000 1) respectively. CONCLUSION: Lymphocyte count could be considerad as a potential surrogate marker for CD(+)4T cell count in HIV/AIDS patients not having access to T cell subset test by flowcytometry.

Prospective echocardiographic assessment of cardiac structure and function in Chinese persons living with HIV.

BACKGROUND: Persons living with human immunodeficiency virus (HIV) are at increased risk of developing cardiovascular disease. Few studies have focused on echocardiographic abnormalities in this population. METHODS: China AIDS Clinical Trial 0810 is a prospective, multicenter cohort study of persons living with HIV (PLWH). We performed an echocardiography substudy of 325 PLWH. We examined the prevalence of left ventricular systolic dysfunction (LVSD), diastolic dysfunction (DD), pulmonary arterial hypertension (PAH), and increased left ventricular mass (ILVM) in antiretroviral therapy (ART)-naive PLWH at baseline and week 48 after initiation of ART. RESULTS: Compared with age- and sex-matched healthy controls, PLWH had a higher prevalence of DD (16.5% vs 7.2%, P < .027) and a marginally significant higher prevalence of LVSD (7.3% vs 2.1%, P = .056). The increase in the prevalence of DD from baseline to week 48 in PLWH was marginally significant (P = .056). No significant difference was observed in the prevalence of LVSD, PAH, or ILVM at baseline and week 48 in PLWH. In logistic regression analysis of all participants, age was significantly associated with LVSD; HIV infection, age, and hypertension were associated with DD whereas HIV infection and hypertension were associated with ILVM at baseline. Logistic regression analysis of PLWH showed that only age was significantly associated with LVSD and DD. CONCLUSIONS: The prevalence of echocardiographic abnormalities was significantly higher in ART-naive PLWH than in controls. HIV infection was significantly associated with cardiac abnormalities. No significant change in echocardiographic abnormalities was observed after 48 weeks of ART. Longer-term prospective studies are warranted.

[Clinical characteristics of 297 newly diagnosed Chinese HIV/AIDS patients].

OBJECTIVE: To determine the clinical characteristics of HIV infected patients in China in order to improve early recognition and diagnosis of AIDS. METHODS: A total of 297 newly diagnosed HIV/AIDS patients were enrolled in Peking Union Medical College Hospital (PUMCH) from January 2001 to December 2012, including 19 patients of primary phase, 115 of asymptomatic phase and 163 of AIDS phase. Clinical characteristics of these patients were retrospectively analyzed. RESULTS: Two hundred and nineteen out of 297 patients reported clinical symptoms with variety. The main systemic symptoms included fever (100 cases, 33.7%), weight loss (50 cases, 16.8%) and fatigue (38 cases, 12.8%). Organ involvement included mucocutaneous (67 cases, 22.6%), respiratory (62 cases, 20.9%), gastrointestinal (40 cases, 13.5%) systems. Patients in AIDS phase were more symptomatic. Seventy-three out of 173 (42.2%)patients have been referred by 2 healthcare providers at least before the diagnosis of HIV infection was confirmed. Initial diagnoses were made in Departments of Infectious Diseases (36.9%), Gastroenterology (16.4%), and Emergency (13.7%). Opportunistic infections accounted for most AIDS defining conditions (ADC), including pneumocystis jiroveci pneumonia (PCP) (36 cases, 22.1%), cytomegalovirus infection (25 cases, 15.3%) and tuberculosis (22 cases, 13.5%). Median peripheral CD(+)4 T lymphocyte count in patients with ADC were 36 cells/µl. CONCLUSIONS: Common clinical presentations of HIV/AIDS included fever, weight loss, diarrhea, short of breath and mucocutaneous lesions. Opportunistic infections mainly affected respiratory and gastrointestinal system, with PCP the most common one. The diagnosis of HIV infection was delayed in most cases, suggesting that more efforts are required especially in universal education of clinicians and accurate viral detection.

Design, synthesis and antifreeze properties of biomimetic peptoid oligomers.

Ice crystals can cause great damage. The utilization of antifreeze agents is an efficient method to prevent or reduce ice crystal formation and growth. Synthetic antifreeze agents are toxic and have low efficiency, and natural antifreeze proteins suffer from high cost and low stability. Here, we have designed and synthesized a series of peptoid oligomers by mimicking the antifreeze protein structure, and the structure-property relationship was also studied. The reported peptoids here have excellent antifreeze properties and are nontoxic to cells. These novel peptoid materials have great potential to replace current commonly used antifreeze agents, such as dimethyl sulfoxide, and become a new generation of antifreeze agents applied in cryopreservation.

[The influence of long-term nucleotide reverse transcriptase inhibitors on lipids metabolism in HIV/AIDS patients].

OBJECTIVE: To evaluate the influence of long-term nucleotide reverse transcriptase inhibitors (NRTIs) on lipids metabolism in HIV/AIDS patients and correlating clinical factors. METHODS: A total of 118 HIV/AIDS patients were divided into 3 groups: untreated group (40 patients), highly active antiretroviral therapy (HAART) for 1 - 2 years group (37 patients) and HAART over 5 years group (41 patients), with 20 healthy individuals as the control group. Clinical lipodystrophy (LD) was defined as concordance between patient's report of change and physical examination. Fat mass (FM) was measured by dual-energy X-ray absorptiometry (DXA). RESULTS: There was no significant difference in the incidence of LD between HAART for 1 - 2 years group and HAART over 5 years group (51.2% vs 40.5%, P = 0.345). The prevalence of LD was 2.4 folds with stavudine (d4T) treatment compared with zidovudine (AZT)-containing regimens (61.6% vs 23.5%, P = 0.001). Based on DXA measurements, FM of total body and limbs were significantly lower in the HAART over 5 years group than that in the control group, the untreated group and the HAART for 1 - 2 years group (P < 0.05). Trunk FM was significantly lower in the HAART over 5 years group than the untreated group and the HAART for 1 - 2 years group (P < 0.05). FM of total body and trunk were significantly lower in patients without LD in the HAART over 5 years group than patients without LD in the HAART for 1 - 2 years group (P < 0.05). FM was correlated positively with body weight and BMI. Limbs FM was correlated negatively with peripheral blood triglyceride concentration. CONCLUSIONS: HIV/AIDS patients with NRTIs therapy have high prevalence of LD, which mainly occurs 1 - 2 years after therapy, and increases with d4T treatment compared with AZT-containing regimens. There was no significant difference in the incidence of LD between the HAART for 1 - 2 years group and the HAART over 5 years group. FM was significantly decreased after long-term HAART in the patients with or without LD. DXA can evaluate LD objectively and guide further clinical treatment.

[Influence of long-term highly active antiretroviral therapy on bone mineral density in HIV/AIDS patients].

OBJECTIVE: To evaluate the influence of highly active antiretroviral therapy (HAART) on bone mineral density (BMD) in HIV/AIDS patients and correlating clinical factors. METHODS: 149 HIV patients were divided into 3 groups:untreated group with 41 patients, HAART for 1-2 years group with 60 patients, HAART over 5 years group with 48 patients; 20 healthy individuals included as a control group. BMD-T score and BMD-Z score were measured by dual-energy X-ray absorptiometry (DXA). RESULTS: BMD-Z score of right hip was significantly lower in HAART over 5 years group (0.16 ± 0.82) than untreated group (0.61 ± 1.09) (P = 0.039). BMD-Z score of right femoral neck was significantly lower in HAART over 5 years group (-0.002 ± 0.87) than untreated group (0.55 ± 1.08) (P = 0.012). BMD-Z score of HAART for 1-2 years group was not significantly decreased. BMD-Z score of right hip and right femoral neck were correlated negatively with HAART duration. The incidence of osteopenia/osteoporosis in HAART for 1 - 2 years group (31.7%) and HAART over 5 years group (31.3%) were significantly higher than untreated group (12.2%) (P < 0.05). Body weight was revealed as a risk factor of osteopenia/osteoporosis. CONCLUSION: BMD of right hip and right femur neck were significantly lower in HAART over 5 years group. The incidence of osteopenia/osteoporosis were significantly higher in patients receiving HAART. BMD were correlated negatively with HAART duration. Patients in long-term HAART combined with risk factors such as old age or lower body weight should be checked by DXA regularly.

Association between ERCC1 Gene Polymorphism (rs11615) and Colorectal Cancer Susceptibility: A Meta-Analysis of Medical Image Fusion and Safety Applications.

Colorectal cancer (CRC) is a malignant tumor of the colorectal mucosa epithelial tissue transformed. The fusion of data for medical imaging has become a central issue in such biomedical applications as image-guided surgery and radiotherapy. Currently, CRC has been one of the most threatening tumors affecting people's health worldwide. The excision repair cross-complementation group 1 (ERCC1) is a key enzyme for nucleotide excision repair (NER). Emerging epidemiological studies have indicated that the presence of colorectal cancer (CRC) may be relevant to the ERCC1 rs11615 genetic polymorphism. However, the results of ERCC1 rs11615 on CRC in these studies are controversial. We searched PubMed, Web of Science, Embase, CNKI, and CBM databases for the effects of ERCC1 rs11615 variant on CRC development. There was no meta-analysis focused on the diagnosis of colorectal cancer with ERCC1 rs11615 variant. We creatively carried out a meta-analysis of nine case-control studies and used Stata (version 12.0) software to integrate the pooled odds ratios (ORs) corresponding to a 95% confidence interval (CI) of overall and subgroup analysis. Our results suggest that a significant correlation was observed between rs11615 and the susceptibility of CRC OR 95% CI = 1.13 (1.04-1.23) under an allele genetic model and OR 95% CI = 1.14 (1.01-1.30) under a dominant genetic model for overall CRC. Significant statistical difference was also noted in Asians rather than Caucasians based on the ethnicity subgroups. These results suggested that there is a certain association between rs11615 and the susceptibility of colorectal cancer in the Asian populations.

Understanding via Exploration: Discovery of Interpretable Features With Deep Reinforcement Learning.

Understanding the environments through interactions has been one of the most important human intellectual activities in mastering unknown systems. Deep reinforcement learning (DRL) has already been known to achieve effective control through human-like exploration and exploitation in many applications. However, the opaque nature of deep neural network (DNN) often hides critical information about feature relevance to control, which is essential for understanding the target systems. In this article, a novel online feature selection framework, namely, the dual-world-based attentive feature selection (D-AFS), is first proposed to identify the contribution of the inputs over the whole control process. Rather than the one world used in most DRL, D-AFS has both the real world and its virtual peer with twisted features. The newly introduced attention-based evaluation (AR) module performs the dynamic mapping from the real world to the virtual world. The existing DRL algorithms, with slight modification, can learn in the dual world. By analyzing the DRL's response in the two worlds, D-AFS can quantitatively identify respective features' importance toward control. A set of experiments is performed on four classical control systems in OpenAI Gym. Results show that D-AFS can generate the same or even better feature combinations than the solutions provided by human experts and seven recent feature selection baselines. In all cases, the selected feature representations are closely correlated with the ones used by underlying system dynamic models.

Therapeutic effect of (5R)-5-hydroxytriptolide (LLDT-8) in SIV infected rhesus monkeys.

BACKGROUNDS: Human immunodeficiency virus (HIV) infections induce robust, generalized inflammatory responses and lead to pathological systemic immune activation. This abnormal immune status persists despite successful antiretroviral therapy (ART). Immune modulating strategies in conjunction with ART were tried to reduce abnormal immune activation. Previously, we demonstrated that Tripterygium Wilfordii Hook F has been shown immunosuppressive activity in HIV patients. (5R)-5-hydroxytriptolide (LLDT-8), a new analog of triptolide, and the most active ingredient of Tripterygium Wilfordii Hook F, has been shown to have lower cytotoxicity. However, the role of LLDT-8 in HIV or simian immunodeficiency virus (SIV) needs to be explored. METHODS: Six male adult Chinese rhesus monkeys were enrolled in our study. All of them were healthy and negative for SIV, and chronically SIVmac239 infected macaques were treated with LLDT-8 combined with ART (n = 4) or ART only (n = 2) after 14 weeks of infection. ART was determined at week 33, and LLDT-8 was continued until week 48. T cell immune activation and inflammation were compared during the period, and viral rebound time and reservoir were supervised after stopping ART. RESULTS: The RNA level of the two groups continued to decline after initiating ART, RNA of 4 rhesus monkeys declined to the lower limit of detection at week 20. LLDT-8 administration combined with ART did not affect T cell activation and plasma levels of IL-6 and CRP. The viral load of all the macaques in both groups was rebounded 2 weeks after ART discontinuation. Furthermore, no significant decrease of SIV DNA was observed in the LLDT-8 treatment group. CONCLUSIONS: LLDT-8 administration during chronic SIV infection had no effect on T cell activation and plasma levels; Furthermore, LLDT-8 may not contribute to suppression of viral rebound and reservoir. These results suggest that LLDT-8 is unlikely to reduce immune activation and viral persistence without additional interventions.

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.

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.

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.

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.