Delving deeper into the mechanisms fundamental to HIV-associated immunopathology using single-cell sequencing techniques: A scoping review of current literature.

Human immunodeficiency virus (HIV) infection has evolved into an established global pandemic over the past four decades; however, despite massive research investment globally, the precise underlying mechanisms which are fundamental to HIV-related pathogenesis remain unclear. Single cell ribonucleic acid (RNA) sequencing methods are increasingly being used for the identification of specific cell-type transcriptional changes in HIV infection. In this scoping review, we have considered information extracted from fourteen published HIV-associated single-cell RNA sequencing-related studies, hoping to throw light on the underlying mechanisms of HIV infection and pathogenesis, and to explore potential candidate biomarkers for HIV disease progression and antiviral treatment. Generally, HIV positive individuals tend to manifest disturbances of frequency of multiple cellular types, and specifically exhibit diminished levels of CD4+ T-cells and enriched numbers of CD8+ T-cells. Cell-specific transcriptional changes tend to be linked to cell permissiveness, hyperacute or acute HIV infection, viremia, and cell productivity. The transcriptomes of CD4+ T-cell and CD8+ T-cell subpopulations are also observed to change in HIV-positive diabetic individuals, spontaneous HIV controllers, individuals with high levels of HIV viremia, and those in an acute phase of HIV infection. The transcriptional changes seen in B cells, natural killer (NK) cells, and myeloid dendritic cells (mDCs) of HIV-infected individuals demonstrate that the humoral immune response, antiviral response, and immune response regulation, respectively, are all altered following HIV infection. Antiretroviral therapy (ART) plays a crucial role in achieving immune reconstitution, in improving immunological disruption, and in mitigating immune system imbalances in HIV-infected individuals, while not fully restoring inherent cellular transcription to levels seen in HIV-negative individuals. The preceding observations not only illustrate compelling advances in the understanding of HIV-associated immunopathogenesis, but also identify specific cell-type transcriptional changes that may serve as potential biomarkers for HIV disease monitoring and therapeutic targeting.

Interactions between HIV proteins and host restriction factors: implications for potential therapeutic intervention in HIV infection.

Different host proteins target different HIV proteins and antagonize their functions, depending on the stage of the HIV life cycle and the stage of infection. Concurrently, HIV proteins also target and antagonize various different host proteins to facilitate HIV replication within host cells. The preceding quite specific area of knowledge in HIV pathogenesis, however, remains insufficiently understood. We therefore propose, in this review article, to examine and discuss the HIV proteins that counteract those host restriction proteins which results directly in increased infectivity of HIV. We elaborate on HIV proteins that antagonize host cellular proteins to promote HIV replication, and thus HIV infection. We examine the functions and mechanisms via which Nef, Vif, Vpu, Env, Vpr, and Vpx counteract host proteins such as Ser5, PSGL-1, IFITMS, A3G, tetherin, GBP5, SAMHD1, STING, HUSH, REAF, and TET2 to increase HIV infectivity. Nef antagonizes three host proteins, viz., Ser5, PSGL1, and IFITIMs, while Vpx also antagonizes three host restriction factors, viz., SAMHD1, STING, and HUSH complex; therefore, these proteins may be potential candidates for therapeutic intervention in HIV infection. Tetherin is targeted by Vpu and Env, PSGL1 is targeted by Nef and Vpu, while Ser5 is targeted by Nef and Env proteins. Finally, conclusive remarks and future perspectives are also presented.

Mechanisms underlying the development of type 1 diabetes in ART-treated people living with HIV: an enigmatic puzzle.

The immunopathogenesis of HIV infection remains poorly understood. Despite the widespread use of effective modern antiretroviral therapy (ART), people living with HIV (PLWH) are known to develop several comorbidities, including type 1 diabetes (T1DM). However, the etiology and critical mechanisms accounting for the onset of T1DM in the preceding context remain unknown. This article proposes to address this topic in order to provide further understanding and future research directions.

Performance of metagenomic Next-Generation Sequencing and metagenomic Nanopore Sequencing for the diagnosis of tuberculosis in HIV-positive patients.

Background: Patients who were infected by the Human Immunodeficiency Virus (HIV) could have weakened immunity that is complicated by opportunistic infections, especially for Mycobacterium tuberculosis (MTB). Notably, the HIV-MTB co-infection will accelerate the course of disease progress and greatly increase the mortality of patients. Since the traditional diagnostic methods are time-consuming and have low sensitivity, we aim to investigate the performance of mNGS (metagenomic Next-Generation Sequencing) and mNPS (metagenomic NanoPore Sequencing) for the rapid diagnosis of tuberculosis in HIV-infected patients. Methods: The 122 HIV-infected patients were enrolled for the retrospective analysis. All of the patients underwent traditional microbiological tests, mNGS, and (or) mNPS tests. The clinical comprehensive diagnosis was used as the reference standard to compare the diagnostic performance of culture, mNGS, and mNPS on tuberculosis. We also investigate the diagnostic value of mNGS and mNPS on mixed-infection. Furthermore, the treatment adjustment directed by mNGS and mNPS was analyzed. Results: Compared with the composite reference standard, the culture showed 42.6% clinical sensitivity and 100% specificity, and the OMT(other microbiological testing) had 38.9% sensitivity and 100% specificity. The mNGS had 58.6% clinical sensitivity and 96.8% specificity, and the mNPS had 68.0% clinical sensitivity and 100% specificity. The proportion of mixed-infection cases (88.9%) in the TB group was higher than those in the non-TB group (54.8%) and the mNGS and mNPS are more competitive on mixed-infection diagnosis compared with the traditional methods. Furthermore, there are 63 patients (69.2%) and 36 patients (63.2%) achieved effective treatment after receiving the detection of mNPS and mNGS, respectively. Conclusion: Our study indicated that mNPS and mNGS have high sensitivity and specificity for TB diagnosis compared with the traditional methods, and mNPS seems to have better diagnostic performance than mNGS. Moreover, mNGS and mNPS showed apparent advantages in detecting mixed infection. The mNPS and mNGS-directed medication adjustment have effective treatment outcomes for HIV-infected patients who have lower immunity.

Prevalence and antimicrobial susceptibility pattern of Mycobacterium abscessus complex isolates in Chongqing, Southwest China.

Objectives: To investigate the prevalence of Mycobacterium abscessus complex (MABC), drug resistance characteristics, and the relationship between clarithromycin (CLA) susceptibility and MABC genotype in Chongqing, China. Methods: A total of 434 NTM patient isolates were collected between October 2018 and October 2019. Isolates confirmed to be non-tuberculous mycobacteria (NTM) were tested for minimal inhibitory concentrations of antimicrobial agents. In addition, rrl and erm(41) gene sequences were used to analyze the acquired macrolide resistance and inducible macrolide resistance. Results: Overall, 17 different NTM species were detected, of which M. abscessus (22.6 %, 91/403) was most prevalent. Amikacin, CLA, azithromycin and cefoxitin exhibited potent activities against MABC organisms, but no significant differences were observed in drug resistance rates between M. abscessus and M. massiliense (P > 0.05). On day 3 of culture, the acquired resistance rate against CLA was 7.4 % (9/121). Of 41 MABC isolates with inducible CLA resistant, 95.1 % (39/41) isolates belonged to the erm(41) T28 sequevar, while the remaining 4.9 % (2/41) possessed the M. massiliense genotype. All erm(41) C28 sequevar isolates were sensitive to CLA on day3 and day 14 of culture. Meanwhile, of the 5 erm(41) T28 isolates with acquired resistance, all possessed rrl 2058/2059 mutations, including 3 isolates with A2058C mutation and 2 isolates with A2059G mutation. While 2 of the 4 M. massiliense isolates with acquired resistance possessed the A2059G mutation, and one isolate possessed the A2058G mutation. Conclusion: Erm(41) and rrl gene could serve as useful markers for predicting macrolide susceptibility of MABC complex isolates.

Switch to fixed-dose ainuovirine, lamivudine, and tenofovir DF versus elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed people living with HIV-1: the 48-week results of the SPRINT trial, a multi-centre, randomised, double-blind, active-controlled, phase 3, non-inferiority trial.

Background: We compared the efficacy and safety profiles of ainuovirine (ANV), a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), with boosted elvitegravir (EVG), both coformulated with two nucleoside reverse transcriptase inhibitors (NRTIs), in people living with HIV-1 (PLWH) who had achieved virological suppression on previous NNRTI-based antiretroviral (ARV) regimen. Methods: This study was a multi-centre, randomised, double-blind, active-controlled, non-inferiority trial recruiting PLWH from 10 clinical centres across China. Main inclusion criteria included age of 18-65 years (inclusive), and stably staying on an ARV regimen combining an NNRTI with a two-drug NRTI backbone for at least 12 months. Eligible participants must have maintained plasma HIV-1 ribonucleic acid (RNA) titre below 50 copies per mL confirmed on two successive tests at an interval of at least one month prior to randomisation. Participants were randomly assigned to receive ANV 150 mg plus lamivudine (3TC) 300 mg, and tenofovir disoproxil fumarate (TDF) 300 mg (ANV/3TC/TDF), or cobicistat (Cobi) 150 mg boosted EVG plus emtricitabine (FTC) 200 mg, and tenofovir alafenamide (TAF) 10 mg. The primary efficacy endpoint was the proportion of participants with HIV-1 RNA titre at 50 copies per mL or above at week 48 using the US Food and Drug Administration snapshot algorithm, with a non-inferiority margin of 4 percentage points at a two-side 95% confidence level. This trial is active, but not recruiting, and is registered with Chinese Clinical Trial Registry (ChiCTR), number ChiCTR2100051605. Findings: Between October 2021 and February 2022, 923 patients were screened for eligibility, among whom 762 participants were randomized and had received at least one dose of ANV/3TC/TDF (n = 381) or EVG/Cobi/FTC/TAF (n = 381). At week 48, 7 (1.8%) participants on ANV/3TC/TDF and 6 (1.6%) participants on EVG/Cobi/FTC/TAF had plasma HIV-1 RNA titre at 50 copies per mL or above, including missing virological data within the time window (the Cochran-Mantel-Haenszel method, estimated treatment difference [ETD], 0.3%, 95% CI -1.6 to 2.1), establishing the non-inferiority of ANV/3TC/TDF to EVG/Cobi/FTC/TAF. The proportions of participants experiencing at least one treatment-emergent adverse events (AEs) were comparable between the two arms (97.6% versus 97.6%). A small proportion of participants discontinued study drug due to AEs (0.3% versus 0.3%). Serious AEs occurred in 11 (2.9%) participants on ANV/3TC/TDF and 9 (2.4%) participants on EVG/Cobi/FTC/TAF, respectively, none of which was considered related to study drug at the jurisdiction of the investigator. At week 48, participants on ANV/3TC/TDF showed a significantly less weight gain from baseline compared to those on EVG/Cobi/FTC/TAF (least square mean, 1.16 versus 2.05 kg, ETD -0.90 kg, 95% CI, -1.43 to -0.37). The changes in serum lipids from baseline also favoured ANV/3TC/TDF over EVG/Cobi/FTC/TAF. Interpretation: In virologically suppressed PLWH on previous NNRTI-based ARV regimen, switch to ANV/3TC/TDF resulted in less weight gain, and improved lipid metabolism while maintaining virological suppression non-inferior to that to EVG/Cobi/FTC/TAF. Funding: Jiangsu Aidea Pharmaceutical & the National "Thirteenth Five-year Period" Major Innovative Drugs Research and Development Key Project of the People's Republic of China Ministry of Science and Technology.

HIV-associated neurocognitive disorder: key implications of the microbiota-gut-brain axis.

HIV-associated neurocognitive disorder (HAND) is now recognized to be relatively common in people living with HIV (PLWH), and remains a common cause of cognitive impairment. Unfortunately, the fundamental pathogenic processes underlying this specific outcome of HIV infection have not as yet been fully elucidated. With increased interest in research related to the microbiota-gut-brain axis, the gut-brain axis has been shown to play critical roles in regulating central nervous system disorders such as Alzheimer's disease and Parkinson's disease. PLWH are characterized by a particular affliction, referred to as gut-associated dysbiosis syndrome, which provokes an alteration in microbial composition and diversity, and of their associated metabolite composition within the gut. Interestingly, the gut microbiota has also been recognized as a key element, which both positively and negatively influences human brain health, including the functioning and development of the central nervous system (CNS). In this review, based on published evidence, we critically discuss the relevant interactions between the microbiota-gut-brain axis and the pathogenesis of HAND in the context of HIV infection. It is likely that HAND manifestation in PLWH mainly results from (i) gut-associated dysbiosis syndrome and a leaky gut on the one hand and (ii) inflammation on the other hand. In other words, the preceding features of HIV infection negatively alter the composition of the gut microbiota (microbes and their associated metabolites) and promote proinflammatory immune responses which singularly or in tandem damage neurons and/or induce inadequate neuronal signaling. Thus, HAND is fairly prevalent in PLWH. This work aims to demonstrate that in the quest to prevent and possibly treat HAND, the gut microbiota may ultimately represent a therapeutically targetable "host factor."

Knockdown of PIK3R6 impedes the onset and advancement of clear cell renal cell carcinoma.

In this research, we investigated the role of PIK3R6, a regulatory subunit of PI3Kγ, known for its tumor-promoting properties, in clear cell renal cell carcinoma (CCRCC). Utilizing the UALCAN website, we found PIK3R6 upregulated in CCRCC, correlating with lower survival rates. We compared PIK3R6 expression in CCRCC tumor tissues and adjacent normal tissues using immunohistochemistry. Post RNA interference-induced knockdown of PIK3R6 in 786-O and ACHN cell lines, we performed CCK-8, colony formation, Edu staining, flow cytometry, wound healing, and transwell assays. Results showed that PIK3R6 silencing reduced cell proliferation, migration, and invasion, and induced G0/G1 phase arrest and apoptosis. Molecular analysis revealed decreased CDK4, Cyclin D1, N-cadherin, Vimentin, Bcl-2, p-PI3K and p-AKT, with increased cleaved caspase-3, Bax, and E-cadherin levels in CCRCC cells. Moreover, inhibiting PIK3R6 hindered tumor growth. These findings suggest a significant role for PIK3R6 in CCRCC cell proliferation and metastasis, presenting it as a potential therapeutic target.

An oncolytic virus delivering tumor-irrelevant bystander T cell epitopes induces anti-tumor immunity and potentiates cancer immunotherapy.

Tumor-specific T cells are crucial in anti-tumor immunity and act as targets for cancer immunotherapies. However, these cells are numerically scarce and functionally exhausted in the tumor microenvironment (TME), leading to inefficacious immunotherapies in most patients with cancer. By contrast, emerging evidence suggested that tumor-irrelevant bystander T (TBYS) cells are abundant and preserve functional memory properties in the TME. To leverage TBYS cells in the TME to eliminate tumor cells, we engineered oncolytic virus (OV) encoding TBYS epitopes (OV-BYTE) to redirect the antigen specificity of tumor cells to pre-existing TBYS cells, leading to effective tumor inhibition in multiple preclinical models. Mechanistically, OV-BYTE induced epitope spreading of tumor antigens to elicit more diverse tumor-specific T cell responses. Remarkably, the OV-BYTE strategy targeting human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory efficiently inhibited tumor progression in a human tumor cell-derived xenograft model, providing important insights into the improvement of cancer immunotherapies in a large population with a history of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination.

Transcriptomic crosstalk between viral and host factors drives aberrant homeostasis of T-cell proliferation and cell death in HIV-infected immunological non-responders.

BACKGROUND: Immunological non-responders (INRs) among people living with HIV have inherently higher mortality and morbidity rates. The underlying immunological mechanisms whereby failure of immune reconstitution occurs in INRs require elucidation. METHOD: HIV-1 DNA and HIV-1 cell-associated RNA (CA-HIV RNA) quantifications were conducted via RT-qPCR. Transcriptome sequencing (RNA-seq), bioinformatics, and biological verifications were performed to discern the crosstalk between host and viral factors. Flow cytometry was employed to analyze cellular activation, proliferation, and death. RESULTS: HIV-1 DNA and CA-HIV RNA levels were observed to be significantly higher in INRs compared to immunological responders (IRs). Evaluation of CD4/CD8 ratios showed a significantly negative correlation with HIV-1 DNA in IRs, but not in INRs. Bioinformatics analyses and biological verifications showed IRF7/INF-α regulated antiviral response was intensified in INRs. PBMCs of INRs expressed significantly more HIV integrase-mRNA (p31) than IRs. Resting (CD4+CD69- T-cells) and activated (CD4+CD69+ T-cells) HIV-1 reservoir harboring cells were significantly higher in INRs, with the co-occurrence of significantly higher cellular proliferation and cell death in CD4+ T-cells of INRs. CONCLUSION: In INRs, the systematic crosstalk between the HIV-1 reservoir and host cells tends to maintain a persistent antiviral response-associated inflammatory environment, which drives aberrant cellular activation, proliferation, and death of CD4+ T-cells.

Clinical characteristics and outcomes of newly diagnosed patients with human immunodeficiency virus-associated Burkitt lymphoma: the Central and Western China AIDS lymphoma league 002 study (CALL-002 study).

BACKGROUND: Despite the introduction of combined antiretroviral therapy, the clinical outcomes of HIV-associated Burkitt lymphoma (BL) remain poor. METHODS: To evaluate the clinical characteristics, prognostic factors, and outcomes of HIV-associated BL, we conducted a retrospective analysis of patients from multiple centers in China. RESULTS: The study included 41 patients from 8 medical centers. Among the included population, male patients accounted for 87.8%, with 75.6% in advanced stages. Notably, 46.3% of cases involved bone marrow, while 19.5% involved the central nervous system (CNS). The most commonly used chemotherapy regimen was DA-EPOCH ± R, accounting for 53.6% of cases. The overall response rates for patients receiving DA-EPOCH ± R and R-Hyper-CVAD were 59% and 58.2%, respectively. Interestingly, patients receiving regimens containing rituximab had similar complete remission rates (25% vs. 23.5%) and overall survival time (45.69 ± 11.58 vs. 47.79 ± 11.72 months, P = 0.907) compared to those without rituximab, but differed in progression rates (33.3% vs. 47.1%). For the entire cohort, the 1-year progression-free survival (PFS) and overall survival (OS) rates were 52% and 67%, respectively. CNS involvement was independent risk factors for survival, with 1-year PFS and OS rates of 0% and 38% for patients with CNS involvement, and PFS and OS rates of 66% and 75% for patients without CNS involvement. CONCLUSIONS: HIV-associated BL patients in China have poor prognosis and show limited response to current treatment regimens. The absence of CNS involvement significantly improves clinical outcomes. The use of rituximab is not significantly associated with improved outcomes but can reduce disease progression.

Willingness to take long-acting injectable pre-exposure prophylaxis among men who have sex with men who participated in the CROPrEP study: a cross-sectional online study.

INTRODUCTION: Evidence on the willingness of men who have sex with men (MSM) with oral pre-exposure prophylaxis (PrEP) experience, especially those with suboptimal adherence, to take long-acting injectable PrEP (LAI-PrEP) is critical to guide future LAI-PrEP implementation. OBJECTIVE: The objective was to assess the willingness of MSM with oral PrEP experience to take LAI-PrEP. METHODS: MSM who participated in the China Real-world Study of Oral PrEP (CROPrEP) were enrolled in this study. Information on the willingness of MSM to take LAI-PrEP and potential correlates was collected using a structured online questionnaire. The main outcomes were the willingness of MSM to take LAI-PrEP and its association with HIV-related behaviours, sexually transmitted infections, and oral PrEP history. Logistic regression was used to identify correlates of the willingness of MSM to take LAI-PrEP. RESULTS: A total of 612 former CROPrEP participants (FCPs) were included in this study. There were 315 (51.5%) daily oral PrEP (D-PrEP) users and 297 (48.5%) event-driven oral PrEP (ED-PrEP) users at the last follow-up. Most FCPs (77.8%) were willing to take free LAI-PrEP. FCPs with no less than two sexual male partners (aOR = 1.54, [95% CI: 1.04, 2.29], P = 0.031), those with male partners with unknown HIV statuses (aOR = 2.04, [95% CI: 1.31, 3.18], P = 0.002), those with recreational drug use (aOR = 1.58, [95% CI: 1.05, 2.40], P = 0.030), and those with HSV-2 positivity (aOR = 2.15, [95% CI: 1.30, 3.57], P = 0.003) were more willing to take LAI-PrEP, while ED-PrEP users (aOR = 0.66, [95% CI: 0.45, 0.98], P = 0.037) and FCPs with suboptimal oral PrEP adherence (aOR = 0.58, [95% CI: 0.36, 0.94], P = 0.026) were less willing to take LAI-PrEP. CONCLUSION: LAI-PrEP has good prospects for expanding PrEP coverage. However, FCPs with suboptimal oral PrEP adherence are less likely to take LAI-PrEP. Further intervention and implementation efforts are needed to improve the willingness of MSM to use LAI-PrEP, and sexual health should be considered during the discussion about PrEP initiation.

Influence of HIV infection on cognition and overall intelligence in HIV-infected individuals: advances and perspectives.

It is now well understood that HIV-positive individuals, even those under effective ART, tend to develop a spectrum of cognitive, motor, and/or mood conditions which are contemporarily referred to as HIV-associated neurocognitive disorder (HAND), and which is directly related to HIV-1 infection and HIV-1 replication in the central nervous system (CNS). As HAND is known to induce difficulties associated with attention, concentration, and memory, it is thus legitimate and pertinent to speculate upon the possibility that HIV infection may well influence human cognition and intelligence. We therefore propose herein to review the concept of intelligence, the concept of cells of intelligence, the influence of HIV on these particular cells, and the evidence pointing to differences in observed intelligence quotient (IQ) scores between HIV-positive and HIV-negative individuals. Additionally, cumulative research evidence continues to draw attention to the influence of the gut on human intelligence. Up to now, although it is known that HIV infection profoundly alters both the composition and diversity of the gut microbiota and the structural integrity of the gut, the influence of the gut on intelligence in the context of HIV infection remains poorly described. As such, we also provide herein a review of the different ways in which HIV may influence human intelligence via the gut-brain axis. Finally, we provide a discourse on perspectives related to HIV and human intelligence which may assist in generating more robust evidence with respect to this issue in future studies. Our aim is to provide insightful knowledge for the identification of novel areas of investigation, in order to reveal and explain some of the enigmas related to HIV infection.

The influence of inflammation on the characteristics of adipose-derived mesenchymal stem cells (ADMSCs) and tissue repair capability in a hepatic injury mouse model.

BACKGROUND: Mesenchymal stem cells (MSCs) are adult stem cells with self-renewal and multi-directional differentiation potential and possess the functions of immunomodulation, regulation of cell growth, and repair of damage. Over recent years, MSCs have been found to regulate the secretion of inflammatory factors and to exert regulatory effects on various lymphocytes in inflammatory states, and on the subsequent repair of tissue damage caused by inflammation. In the present study, we analyzed the effects of tissue inflammation on the characteristics of MSCs. METHODS: Human fat derived from the infrapatellar fat pad (IPFP) of knees with differing degrees of inflammation was extracted from specimens derived from total knee arthroplasties. HE and immunohistochemical staining was performed to directly observe the evidence and degree of inflammation in human infrapatellar fat pad tissue in order to classify MSCs cells, by their origin, into highly inflamed and lowly inflamed groups, and to study the effect of tissue inflammation on cell acquisition rates via cellular counting data. Flow cytometry assays were performed to investigate the effect of tissue inflammation on MSC surface marker expression. Trilineage differentiation, including osteogenesis, adipogenesis, and chondrogenesis, was performed to assess the effect of tissue inflammation on the ability of MSCs to undergo directed differentiation. The effect of tissue inflammation on the ability of MSCs to proliferate was investigated via clone formation studies. RNA-sequencing was performed to evaluate the transcriptomes of MSCs derived from different areas of inflammation. The effect of tissue inflammation on tissue repair capacity and safety of MSCs was investigated via a murine model of acute liver injury. RESULTS: The results of cell count data indicate that a high degree of tissue inflammation significantly decreases the acquisition rate of MSCs, and the proportion of CD34+ and CD146+ cells. The results of our trilineage differentiation assay show that a higher degree of inflammation decreases osteogenic differentiation and enhances adipogenic and chondrogenic differentiation of MSCs. However, these differences were not statistically significant. Clone formation assays indicate that the degree of tissue inflammation at the MSC source does not significantly affect the proliferative capacity of MSCs. The transcriptomes of MSCs remain relatively stable in fat pad tissues derived from both highly and lowly inflamed samples. The results of acute liver injury investigations in mice indicate that MSCs of high and low inflammatory tissue origin have no significant difference in their tissue repair capability. CONCLUSIONS: High tissue inflammation at the source of MSCs reduces the acquisition rate of MSCs and the percentage of CD34+ and CD146+ cells acquisition. However, source tissue inflammation may not significantly affect trilineage differentiation potential and proliferative capacity of MSCs. Also, MSCs obtained from differing source degrees of inflammation retain stable and similar transcriptomic profile and are both safe and efficacious for tissue repair/regeneration without detectable differences.

PSGL-1, a Strategic Biomarker for Pathological Conditions in HIV Infection: A Hypothesis Review.

P-selectin glycoprotein ligand-1 (PSGL-1) has been established to be a cell adhesion molecule that is involved in the cellular rolling mechanism and the extravasation cascade, enabling the recruitment of immune cells to sites of inflammation. In recent years, researchers have established that PSGL-1 also functions as an HIV restriction factor. PSGL-1 has been shown to inhibit the HIV reverse transcription process and inhibit the infectivity of HIV virions produced by cells expressing PSGL-1. Cumulative evidence gleaned from contemporary literature suggests that PSGL-1 expression negatively affects the functions of immune cells, particularly T-cells, which are critical participants in the defense against HIV infection. Indeed, some researchers have observed that PSGL-1 expression and signaling provokes T-cell exhaustion. Additionally, it has been established that PSGL-1 may also mediate virus capture and subsequent transfer to permissive cells. We therefore believe that, in addition to its beneficial roles, such as its function as a proinflammatory molecule and an HIV restriction factor, PSGL-1 expression during HIV infection may be disadvantageous and may potentially predict HIV disease progression. In this hypothesis review, we provide substantial discussions with respect to the possibility of using PSGL-1 to predict the potential development of particular pathological conditions commonly seen during HIV infection. Specifically, we speculate that PSGL-1 may possibly be a reliable biomarker for immunological status, inflammation/translocation, cell exhaustion, and the development of HIV-related cancers. Future investigations directed towards our hypotheses may help to evolve innovative strategies for the monitoring and/or treatment of HIV-infected individuals.

Development, assessment and validation of a novel prediction nomogram model for risk identification of tracheobronchial tuberculosis in patients with pulmonary tuberculosis.

OBJECTIVE: Tracheobronchial tuberculosis (TBTB), a specific subtype of pulmonary tuberculosis (PTB), can lead to bronchial stenosis or bronchial occlusion if not identified early. However, there is currently no available means for predicting the risk of associated TBTB in PTB patients. The objective of this study was to establish a risk prediction nomogram model for estimating the associated TBTB risk in every PTB patient. METHODS: A retrospective cohort study was conducted with 2153 PTB patients. Optimised characteristics were selected using least absolute shrinkage and selection operator regression. Multivariate logistic regression was applied to build a predictive nomogram model. Discrimination, calibration and clinical usefulness of the prediction model were assessed using C-statistics, receiver operator characteristic curves, calibration plots and decision analysis. The developed model was validated both internally and externally. RESULTS: Among all PTB patients who underwent bronchoscopies (n=2153), 40.36% (n=869) were diagnosed with TBTB. A nomogram model incorporating 11 predictors was developed and displayed good discrimination with a C-statistics of 0.782, a sensitivity of 0.661 and a specificity of 0.762 and good calibration with a calibration-in-the-large of 0.052 and a calibration slope of 0.957. Model's discrimination was favourable in both internal (C-statistics, 0.782) and external (C-statistics, 0.806) validation. External validation showed satisfactory accuracy (sensitivity, 0.690; specificity, 0.804) in independent cohort. Decision curve analysis showed that the model was clinically useful when intervention was decided on at the exacerbation possibility threshold of 2.3%-99.2%. A clinical impact curve demonstrated that our model predicted high-risk estimates and true positives. CONCLUSION: We developed a novel and convenient risk prediction nomogram model that enhances the risk assessment of associated TBTB in PTB patients. This nomogram can help identify high-risk PTB patients who may benefit from early bronchoscopy and aggressive treatment to prevent disease progression.

Severe intestinal barrier damage in HIV-infected immunological non-responders.

The intestinal epithelial barrier plays an important role during human immunodeficiency virus (HIV) disease progression. However, the extent to which the intestinal epithelial barrier is damaged in immunological non-responders (INRs) and immunological responders (IRs) is largely unknown. In this study, we investigated and compared the levels of intestinal gland damage and related molecules, including the tight junction protein claudin-1, apoptosis marker caspase-3, HIV DNA, CD4+ T cell count, and inflammation marker tumor necrosis factor-α (TNF-α) among the IRs (n = 10), INRs (n = 8), and healthy controls (HCs, n = 7). Intestinal damage was not completely restored in both INRs and IRs and was more serious in INRs than that in IRs. Moreover, intestinal damage was positively correlated with HIV DNA levels and negatively correlated with CD4+ T cell counts. These results provide insight into understanding the characteristics of intestinal epithelial barrier damage between IRs and INRs.

The Influence of Oral Terbinafine on Gut Fungal Microbiome Composition and Microbial Translocation in People Living with HIV Treated for Onychomycosis.

People living with HIV (PLWH) display altered gut epithelium that allows for the translocation of microbial products, contributing to systemic immune activation. Although there are numerous studies which examine the gut bacterial microbiome in PLWH, few studies describing the fungal microbiome, or the mycobiome, have been reported. Like the gut bacterial microbiome, the fungal microbiome and its by-products play a role in maintaining the body's homeostasis and modulating immune function. We conducted a prospective study to assess the effects of oral terbinafine, an antifungal agent widely used against onychomycosis, on gut permeability and microbiome composition in ART-treated PLWH (trial registration: ChiCTR2100043617). Twenty participants completed all follow-up visits. During terbinafine treatment, the levels of the intestinal fatty acid binding protein (I-FABP) significantly increased, and the levels of interleukin-6 (IL-6) significantly decreased, from baseline to week 12. Both markers subsequently returned to pre-treatment levels after terbinafine discontinuation. After terbinafine treatment, the abundance of fungi decreased significantly, while the abundance of the bacteria did not change. After terbinafine discontinuation, the abundance of fungi returned to the levels observed pre-treatment. Moreover, terbinafine treatment induced only minor changes in the composition of the gut bacterial and fungal microbiome. In summary, oral terbinafine decreases fungal microbiome abundance while only slightly influencing gut permeability and microbial translocation in ART-treated PLWH. This study's findings should be validated in larger and more diverse studies of ART-treated PLWH; our estimates of effect size can be used to inform optimal sample sizes for future studies.

Severe anemia, severe leukopenia, and severe thrombocytopenia of amphotericin B deoxycholate-based induction therapy in patients with HIV-associated talaromycosis: a subgroup analysis of a prospective multicenter cohort study.

BACKGROUND: This study's objective was to investigate the predictors for severe anemia, severe leukopenia, and severe thrombocytopenia when amphotericin B deoxycholate-based induction therapy is used in HIV-infected patients with talaromycosis. METHODS: A total of 170 HIV-infected patients with talaromycosis were enrolled from January 1st, 2019, to September 30th, 2020. RESULTS: Approximately 42.9%, 20.6%, and 10.6% of the enrolled patients developed severe anemia, severe leukopenia, and severe thrombocytopenia, respectively. Baseline hemoglobin level < 100 g/L (OR = 5.846, 95% CI: 2.765 ~ 12.363), serum creatinine level > 73.4 µmol/L (OR = 2.573, 95% CI: 1.157 ~ 5.723), AST/ALT ratio > 1.6 (OR = 2.479, 95% CI: 1.167 ~ 5.266), sodium level ≤ 136 mmol/liter (OR = 4.342, 95% CI: 1.747 ~ 10.789), and a dose of amphotericin B deoxycholate > 0.58 mg/kg/d (OR = 2.504, 95% CI:1.066 ~ 5.882) were observed to be independent risk factors associated with the development of severe anemia. Co-infection with tuberculosis (OR = 3.307, 95% CI: 1.050 ~ 10.420), and platelet level (per 10 × 109 /L) (OR = 0.952, 95% CI: 0.911 ~ 0.996) were shown to be independent risk factors associated with the development of severe leukopenia. Platelet level < 100 × 109 /L (OR = 2.935, 95% CI: 1.075 ~ 8.016) was identified as the independent risk factor associated with the development of severe thrombocytopenia. There was no difference in progression to severe anemia, severe leukopenia, and severe thrombocytopenia between the patients with or without fungal clearance at 2 weeks. 10 mg on the first day of amphotericin B deoxycholate was calculated to be independent risk factors associated with the development of severe anemia (OR = 2.621, 95% CI: 1.107 ~ 6.206). The group receiving a starting amphotericin B dose (10 mg, 20 mg, daily) exhibited the highest fungal clearance rate at 96.3%, which was significantly better than the group receiving a starting amphotericin B dose (5 mg, 10 mg, 20 mg, daily) (60.9%) and the group receiving a starting amphotericin B dose (5 mg, 15 mg, and 25 mg, daily) (62.9%). CONCLUSION: The preceding findings reveal risk factors for severe anemia, severe leukopenia, and severe thrombocytopenia. After treatment with Amphotericin B, these severe adverse events are likely unrelated to fungal clearance at 2 weeks. Starting amphotericin B deoxycholate at a dose of 10 mg on the first day may increase the risk of severe anemia but can lead to earlier fungal clearance. TRIAL REGISTRATION: ChiCTR1900021195. Registered 1 February 2019.