Landscape of gut mucosal immune cells showed gap of follicular or memory B cells into plasma cells in immunological non-responders.

BACKGROUND: The gut is an important site for human immunodeficiency virus (HIV) infection and immune responses. The role of gut mucosal immune cells in immune restoration in patients infected with HIV undergoing antiretroviral therapy remains unclear. METHODS: Ileocytes, including 54 475 immune cells, were obtained from colonoscopic biopsies of five HIV-negative controls, nine immunological responders (IRs), and three immunological non-responders (INRs) and were analyzed using single-cell RNA sequencing. Immunohistochemical assays were performed for validation. The 16S rRNA gene was amplified using PCR in faecal samples to analyze faecal microbiota. Flow cytometry was used to analyze CD4+ T-cell counts and the activation of T cells. RESULTS: This study presents a global transcriptomic profile of the gut mucosal immune cells in patients infected with HIV. Compared with the IRs, the INRs exhibited a lower proportion of gut plasma cells, especially the IGKC+IgA+ plasma cell subpopulation. IGKC+IgA+ plasma cells were negatively associated with enriched f. Prevotellaceae the INRs and negatively correlated with the overactivation of T cells, but they were positively correlated with CD4+ T-cell counts. The INRs exhibited a higher proportion of B cells than the IRs. Follicular and memory B cells were significantly higher in the INRs. Reduced potential was observed in the differentiation of follicular or memory B cells into gut plasma cells in INRs. In addition, the receptor-ligand pairs CD74_MIF and CD74_COPA of memory B/ follicular helper T cells were significantly reduced in the INRs, which may hinder the differentiation of memory and follicular B cells into plasma cells. CONCLUSIONS: Our study shows that plasma cells are dysregulated in INRs and provides an extensive resource for deciphering the immune pathogenesis of HIV in INRs. KEY POINTS: An investigation was carried out at the single-cell-level to analyze gut mucosal immune cells alterations in PLWH after ART. B cells were significantly increased and plasma cells were significantly decreased in the INRs compared to the IRs and NCs. There are gaps in the transition from gut follicular or memory B cellsinto plasma cells in INRs.

Retrospective Study on Genetic Diversity and Drug Resistance among People Living with HIV at an AIDS Clinic in Beijing.

(1) Background: The objective of this study was to investigate the prevalence of genetic diversity and drug resistance mutations among people living with HIV (PLWH) attending clinics in Beijing. (2) Methods: A retrospective analysis was conducted on PLWH admitted to the Fifth Medical Center of People's Liberation Army (PLA) General Hospital between 1 March 2013 and 31 July 2020. The participants were analyzed for pretreatment drug resistance (PDR) and acquired drug resistance (ADR). Nested polymerase chain reaction (PCR) was utilized to amplify the pol gene from plasma RNA samples obtained from the participants. Genotypic and HIV drug resistance were determined using the Stanford University HIV Drug Resistance Database. Univariate and multifactorial logistic analyses were used to assess the risk factors for PDR. (3) Results: The overall prevalence rates of PDR and ADR were 12.9% and 27.8%, respectively. Individuals treated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) exhibited the highest prevalence of mutations. Specific mutation sites, such as V179D for NNRTIs and M184V and K65R for nucleoside reverse transcriptase inhibitors (NRTIs), were identified as prevalent mutations. Individuals treated with efavirenz (EFV) and nevirapine (NVP) were found to be susceptible to developing resistance. The multifactorial regression analyses indicated that the factors of circulating recombination form (CRF) genotype CRF07-BC and a high viral load were associated with an increased risk of PDR. CRF01-AE and CRF07-BC were the most prevalent HIV genotypes in our study. (4) Conclusions: The distribution of HIV genotypes in Beijing is complex. There is a need for baseline screening for HIV drug resistance among ART-naive individuals, as well as timely testing for drug resistance among ART-experienced individuals.

Effect of SARS-CoV-2 Breakthrough Infection on HIV Reservoirs and T-Cell Immune Recovery in 3-Dose Vaccinated People Living with HIV.

People living with human immunodeficiency virus (PLWH) are a vulnerable population with a higher risk of severe coronavirus disease 2019 (COVID-19); therefore, vaccination is recommended as a priority. Data on viral reservoirs and immunologic outcomes for PLWH breakthrough infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently limited. In this study, we investigated the effects of SARS-CoV-2 breakthrough infection on hematological parameters, human immunodeficiency virus (HIV) reservoir size, and T-cell recovery in PLWH receiving antiretroviral therapy (ART) after SARS-CoV-2 booster vaccination. The results indicated that during breakthrough infection, booster vaccination with homologous and heterologous vaccines was safe in PLWH after receiving two doses of inactivated vaccination. The absolute CD4 counts decreased in the heterologous group, whereas the CD8 counts decreased in the homologous booster group after breakthrough infection in PLWH. Breakthrough infection increased HIV reservoirs and was associated with increased T-cell activation in PLWH who received virally suppressed ART and a 3-dose vaccination. According to our data, the breakthrough infection of SARS-CoV-2 may put PLWH at a greater risk for increased HIV reservoirs, even if these individuals were virally suppressed with ART after 3-dose SARS-CoV-2 vaccination.

Characteristics of blood immune cell profile and their correlation with disease progression in patients infected with HIV-1.

BACKGROUND: Antiretroviral therapy (ART) can reduce viral load in individuals infected with human immunodeficiency virus (HIV); however, some HIV-infected individuals still cannot achieve optimal immune recovery even after ART. Hence, we described the profile of peripheral immune cells and explored the association with disease progression in patients infected with HIV-1. METHODS: Mass cytometry analysis was used to characterize the circulating immune cells of 20 treatment-naïve (TNs), 20 immunological non-responders (INRs), 20 immunological responders (IRs), and 10 healthy controls (HCs). Correlation analysis was conducted between cell subpopulation percentages and indicators including HIV-1 cell-associated (CA)-RNA, DNA, CD4+ T cell count, and CD4/CD8 ratio. RESULTS: Global activation, immunosenescence, and exhaustion phenotypes were observed in myeloid cells and T cells from individuals with HIV-1 infection. We also found that specific subsets or clusters of myeloid, CD4+ T, and CD8+ T cells were significantly lost or increased in TN individuals, which could be partially restored after receiving ART. The percentages of several subpopulations correlated with HIV-1 CA-RNA, DNA, CD4+ T cell count, and CD4/CD8 ratio, suggesting that changes in immune cell composition were associated with therapeutic efficacy. CONCLUSION: These data provide a complete profile of immune cell subpopulations or clusters that are associated with disease progression during chronic HIV-1 infection, which will improve understanding regarding the mechanism of incomplete immune recovery in INRs.

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.

Abnormal blood microbiota profiles are associated with inflammation and immune restoration in HIV/AIDS individuals.

IMPORTANCE: The characteristics of blood microbiota in HIV-infected individuals and their relevance to disease progression are still unknown, despite alterations in gut microbiota diversity and composition in HIV-infected individuals. Here, we present evidence of increased blood microbiota diversity in HIV-infected individuals, which may result from gut microbiota translocation. Also, we identify a group of microbes, Porphyromonas gingivalis, Prevotella sp. CAG:5226, Eubacterium sp. CAG:251, Phascolarctobacterium succinatutens, Anaerobutyricum hallii, Prevotella sp. AM34-19LB, and Phocaeicola plebeius, which are linked to poor immunological recovery. This work provides a scientific foundation toward therapeutic strategies targeting blood microbiota for immune recovery of HIV infection.

Elevated glutamate impedes anti-HIV-1 CD8 + T cell responses in HIV-1-infected individuals on antiretroviral therapy.

CD8 + T cells are essential for long-lasting HIV-1 control and have been harnessed to develop therapeutic and preventive approaches for people living with HIV-1 (PLWH). HIV-1 infection induces marked metabolic alterations. However, it is unclear whether these changes affect the anti-HIV function of CD8 + T cells. Here, we show that PLWH exhibit higher levels of plasma glutamate than healthy controls. In PLWH, glutamate levels positively correlate with HIV-1 reservoir and negatively correlate with the anti-HIV function of CD8 + T cells. Single-cell metabolic modeling reveals glutamate metabolism is surprisingly robust in virtual memory CD8 + T cells (TVM). We further confirmed that glutamate inhibits TVM cells function via the mTORC1 pathway in vitro. Our findings reveal an association between metabolic plasticity and CD8 + T cell-mediated HIV control, suggesting that glutamate metabolism can be exploited as a therapeutic target for the reversion of anti-HIV CD8 + T cell function in PLWH.

Pyroptotic MAITs link microbial translocation with severity of alcohol-associated liver disease.

BACKGROUND: Mucosal-associated invariant T cells (MAITs) are markedly reduced in patients with alcohol-associated liver disease (ALD); however, the potential mechanism underlying MAITs' loss remains elusive. Hence, we aimed to explore what induced MAITs' loss and its clinical significance. METHODS: The characteristics of pyroptotic MAITs were evaluated in a cohort of patients with ALD, including 41 patients with alcohol-associated liver cirrhosis (ALC) and 21 patients with ALC complicated with severe alcoholic hepatitis (ALC + SAH). RESULTS: In patients with ALD, blood MAITs were significantly decreased, hyperactivated, and displayed enhanced cell death through pyroptosis. The frequencies of pyroptotic MAITs increased with disease severity in patients with ALC and patients with ALC + SAH. These frequencies were negatively associated with the frequencies of MAITs and positively correlated with the levels of MAITs' activation, plasma levels of intestinal fatty acid-binding protein (a marker of intestinal enterocyte damage), soluble CD14, lipopolysaccharide-binding protein, and peptidoglycan recognition proteins (surrogate markers of microbial translocation). Pyroptotic MAITs were also found in the liver of patients with ALD. Interestingly, MAITs underwent further activation and pyroptosis in vitro under stimulation by Escherichia coli or direct bilirubin. Notably, blocking IL-18 signaling reduced the activation and frequencies of pyroptotic MAITs. CONCLUSIONS: The loss of MAITs in patients with ALD is, at least in part, due to cell death from pyroptosis and is associated with the severity of ALD. Such increased pyroptosis may be affected by dysregulated inflammatory responses to intestinal microbial translocation or direct bilirubin.

The Imbalance Between Intestinal Th17 and Treg Cells Is Associated with an Incomplete Immune Reconstitution During Long-Term Antiretroviral Therapy in Patients with HIV.

Studies assessing the gut mucosal immune balance in HIV-infected patients using intestinal samples are scarce. In this study, we used intestinal mucosal specimens from the ileocecal region of seven immunological nonresponders (INRs), nine immunological responders (IRs), and six HIV-negative controls. We investigated T helper 17 (Th17) and T regulatory (Treg) cell counts and their ratio, zonula occludens-1 (ZO-1), intestinal fatty acid-binding protein (I-FABP), tumor necrosis factor-α, CD4+ T cell counts, HIV DNA, and cell-associated HIV RNA. The results showed that INRs had lower Th17 and higher Treg cell counts than IR, resulting in a significant difference in the Th17/Treg ratio between IRs and INRs. In addition, INRs had lower ZO-1 and higher I-FABP levels than IRs. The Th17/Treg ratio was positively associated with ZO-1 and negatively associated with I-FABP levels. There was a positive correlation between Th17/Treg ratio and CD4+ T cell counts and a negative correlation between the Th17/Treg ratio and HIV DNA in the intestine. Our study suggests that the imbalance of Th17/Treg in the intestine is a characteristic of incomplete immune reconstitution to antiretroviral therapy and is associated with intestinal damage.

Dynamics of SARS-CoV-2 Antibody Responses up to 9 Months Post-Vaccination in Individuals with Previous SARS-CoV-2 Infection Receiving Inactivated Vaccines.

Humoral immunity confers protection against COVID-19. The longevity of antibody responses after receiving an inactivated vaccine in individuals with previous SARS-CoV-2 infection is unclear. Plasma samples were collected from 58 individuals with previous SARS-CoV-2 infection and 25 healthy donors (HDs) who had been vaccinated with an inactivated vaccine. The neutralizing antibodies (NAbs) and S1 domain-specific antibodies against the SARS-CoV-2 wild-type and Omicron strains and nucleoside protein (NP)-specific antibodies were measured using a chemiluminescent immunoassay. Statistical analysis was performed using clinical variables and antibodies at different timepoints after SARS-CoV-2 vaccination. NAbs targeting the wild-type or Omicron strain were detected in individuals with previous SARS-CoV-2 infection at 12 months after infection (wild-type: 81%, geometric mean (GM): 20.3 AU/mL; Omicron: 44%, GM: 9.4 AU/mL), and vaccination provided further enhancement of these antibody levels (wild-type: 98%, GM: 53.3 AU/mL; Omicron: 75%, GM: 27.8 AU/mL, at 3 months after vaccination), which were significantly higher than those in HDs receiving a third dose of inactivated vaccine (wild-type: 85%, GM: 33.6 AU/mL; Omicron: 45%, GM: 11.5 AU/mL). The level of NAbs in individuals with previous infection plateaued 6 months after vaccination, but the NAb levels in HDs declined continuously. NAb levels in individuals with previous infection at 3 months post-vaccination were strongly correlated with those at 6 months post-vaccination, and weakly correlated with those before vaccination. NAb levels declined substantially in most individuals, and the rate of antibody decay was negatively correlated with the neutrophil-to-lymphocyte ratio in the blood at discharge. These results suggest that the inactivated vaccine induced robust and durable NAb responses in individuals with previous infection up to 9 months after vaccination.

Metabolic interventions improve HBV envelope-specific T-cell responses in patients with chronic hepatitis B.

BACKGROUND: Restoration of HBV-specific T cell immunity is a promising approach for the functional cure of chronic Hepatitis B (CHB), necessitating the development of valid assays to boost and monitor HBV-specific T cell responses in patients with CHB. METHODS: We analyzed hepatitis B virus (HBV) core- and envelope (env)-specific T cell responses using in vitro expanded peripheral blood mononuclear cells (PBMCs) from patients with CHB exhibiting different immunological phases, including immune tolerance (IT), immune activation (IA), inactive carrier (IC), and HBeAg-negative hepatitis (ENEG). Additionally, we evaluated the effects of metabolic interventions, including mitochondria-targeted antioxidants (MTA), polyphenolic compounds, and ACAT inhibitors (iACAT), on HBV-specific T-cell functionality. RESULTS: We found that HBV core- and env-specific T cell responses were finely coordinated and more profound in IC and ENEG than in the IT and IA stages. HBV env-specific T cells were more dysfunctional but prone to respond to metabolic interventions using MTA, iACAT, and polyphenolic compounds than HBV core-specific T-cells. The responsiveness of HBV env-specific T cells to metabolic interventions can be predicted by the eosinophil (EO) count and the coefficient of variation of red blood cell distribution width (RDW-CV). CONCLUSION: These findings may provide valuable information for metabolically invigorating HBV-specific T-cells to treat CHB.

Incidence and risk factors of hypertriglyceridemia in males with human immunodeficiency virus who are treated with combination antiretroviral therapy: a retrospective cohort study.

BACKGROUND: Hypertriglyceridemia is associated with subclinical atherosclerosis and vascular inflammation even when low-density lipoprotein cholesterol levels are normal. However, few cohort studies on hypertriglyceridemia have been conducted in males with higher susceptibility to human immunodeficiency virus (HIV)-related deterioration of arterial structure and function. Our objective was to investigate the incidence of hypertriglyceridemia during treatment with combination antiretroviral therapy (cART) in males with HIV and explore its related risk factors. METHODS: In this retrospective study, we included 309 males living with HIV (median age 31 years [interquartile range 26-42.5]) who initiated cART treatment in our hospital from January 2013 to December 2018. We collected follow-up data on serum triglycerides and other related information as of June 31, 2021. A Cox proportional hazards regression model was used to analyze the related risk factors. RESULTS: In 666.7 person-years, hypertriglyceridemia occurred in 140 patients (triglyceride ≥2.3 mmol/L [200 mg/dL]), and the incidence rate was 21.0 per 100 person-years (Patients who took the lamivudine [3TC] + tenofovir disoproxil fumarate [TDF] + efavirenz [EFV] regimen accounted for 77.0% of the total patients.). Multiple Cox regression analysis showed that baseline CD4/CD8 ratio < 0.20 (hazard ratio [HR], 2.705 [95% confidence interval (CI): 1.381-5.296]; P = 0.004}, body mass index (BMI) ≥ 24.0 kg/m2 (HR, 1.768 [95% CI: 1.225-2.552]; P = 0.002), borderline high triglyceride at baseline (HR, 3.457 [95% CI: 2.162-5.527]; P < 0.001), and 3TC + zidovudine (AZT) + EFV regimen (HR, 2.702 [95% CI: 1.593-4.581]; P < 0.001), or 3TC + TDF + lopinavir/ritonavir (LPV/r) regimen (HR, 4.349 [95% CI: 2.664-7.102]; P < 0.001) were independent risk factors for hypertriglyceridemia. CONCLUSION: During the course of cART treatment, the incidence of hypertriglyceridemia in males with HIV was high. The main risk factors influencing its occurrence are a low baseline CD4/CD8 ratio, overweight and obesity, and the use of AZT or LPV/r in the cART regimen.

Decreased granzyme-B expression in CD11c+CD8+ T cells associated with disease progression in patients with HBV-related hepatocellular carcinoma.

Introduction: CD11c+CD8+ T cells are an unconventional CD8+ T cell subset that exerts antiviral activity in infectious diseases. However, its characteristics in hepatocellular carcinoma (HCC) have not been elucidated. Methods: Twenty-six patients with hepatitis B virus (HBV)-related HCC and 25 healthy controls (HC) were enrolled. The frequency and phenotype of CD11c+CD8+ T cells in peripheral blood and tumors in situ were detected by flow cytometry and immunohistochemistry. Results: Both the HCC group and HC group had similar frequency and phenotype characteristics of CD11c+CD8+ T cells in the periphery. CD11c+CD8+ T cells were mainly composed of effector T cells, most of which were CD45RA+CCR7-. Compared with CD11c-CD8+ T cells, CD11c+CD8+ T cells had a higher proportion of CD38 and HLA-DR double positive, and expressed high levels of granzyme-B (GB) and degranulation marker CD107a, and produced high levels of interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ). However, the ability of degranulation and TNF-α production of CD11c+CD8+ T cells in patients with HCC were significantly lower than that in healthy controls. The GB expression level of peripheral CD11c+CD8+ T cells in patients with advanced stage of HCC was significantly lower than that in patients with early stage of HCC, and the GB expression level of liver-infiltrating CD11c+CD8+ T cells in tumor tissues was lower than that in non-tumor tissues. More importantly, the GB expression level of peripheral CD11c+CD8+ T cells was negatively correlated with tumor volume. Conclusions: These findings indicate that CD11c+CD8+ T cells may have potential anti-tumor activity and that GB+CD11c+CD8+ T cells are associated with disease progression in patients with HBV-related HCC.

Distinct inflammation-related proteins associated with T cell immune recovery during chronic HIV-1 infection.

Chronic inflammation and T cell dysregulation persist in individuals infected with human immunodeficiency virus type 1 (HIV-1), even after successful antiretroviral treatment. The mechanism involved is not fully understood. Here, we used Olink proteomics to comprehensively analyze the aberrant inflammation-related proteins (IRPs) in chronic HIV-1-infected individuals, including in 24 treatment-naïve individuals, 33 immunological responders, and 38 immunological non-responders. T cell dysfunction was evaluated as T cell exhaustion, activation, and differentiation using flow cytometry. We identified a cluster of IRPs (cluster 7), including CXCL11, CXCL9, TNF, CXCL10, and IL18, which was closely associated with T cell dysregulation during chronic HIV-1 infection. Interestingly, IRPs in cluster 5, including ST1A1, CASP8, SIRT2, AXIN1, STAMBP, CD40, and IL7, were negatively correlated with the HIV-1 reservoir size. We also identified a combination of CDCP1, CXCL11, CST5, SLAMF1, TRANCE, and CD5, which may be useful for distinguishing immunological responders and immunological non-responders. In conclusion, the distinct inflammatory milieu is closely associated with immune restoration of T cells, and our results provide insight into immune dysregulation during chronic HIV-1 infection.

Serum globulin levels are associated with HIV reservoir size and immune restoration during long-term ART.

OBJECTIVES: The objectives of this study were to analyze the relationship between serum globulin levels and immune restoration and HIV reservoir size during long-term antiretroviral therapy (ART). METHODS: We enrolled 13 patients living with HIV who had been receiving ART for 5 years. We measured levels of serum globulin, cell-associated (CA) HIV DNA and RNA, and p24 antibody at 0, 1, 3, and 5 years of ART. CD38 and human leukocyte antigen - DR isotype (HLA-DR) were used as activation markers for T-cell activation. Serum concentrations of the inflammatory cytokines interferon gamma-inducible protein (IP)-10 and soluble CD163 (sCD163) were detected by enzyme-linked immunosorbent assay. We analyzed the relationship between serum globulin levels, HIV reservoir size, immune restoration, T-cell immune activation, and inflammatory levels during long-term ART. RESULTS: Our data showed that serum globulin levels in people living with HIV were higher than in healthy controls and significantly decreased during the first year of ART. Serum globulin levels during long-term ART were positively correlated with CA HIV DNA, CA HIV RNA, p24 antibody levels, and CD8+ T-cell counts and negatively correlated with CD4+ T-cell counts and CD4/CD8 ratios. Moreover, serum globulin levels were positively correlated with CD4+ and CD8+ T-cell activation and the concentrations of inflammatory biomarkers IP-10 and sCD163 during long-term ART. CONCLUSIONS: Our findings suggest that serum globulin levels may be associated with HIV reservoir size and immune restoration during long-term ART.

Reduction of natural killer cells is associated with poor outcomes in patients with hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND AND AIMS: Natural killer (NK) cells are critical innate effectors that respond to viral infections and contribute to immunopathology. Here, we aimed to investigate the role of NK cells in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) and elucidate the underlying mechanism by examining their phenotypic and functional profiles. METHODS: We included patients with HBV-ACLF (n = 37) and chronic hepatitis B (n = 19), and healthy controls (n = 13) in our study. We examined the phenotype and function of different subsets of peripheral NK cells using flow cytometry and RNA-sequencing analysis, and screened liver NK cells using immunohistochemistry. We detected inflammatory cytokines using a Luminex assay. In addition, we analyzed the relationships between these parameters and disease severity. RESULTS: Peripheral NK cells were decreased and characterized by high expression of caspase-3, Ki67, CXCR3, NKG2D, NKp46, CD107a, and GM-CSF, and typified by higher cell migration and immune response by RNA-sequencing analysis in patients with HBV-ACLF than in those with chronic hepatitis B. Accumulations of CXCL-10 and NK cells were found in the liver, and excessive production of CXCL-10 in the peripheral blood contributed to the apoptosis of NK cells in vitro. The decrease in NK cells was associated with the level of HBV DNA and disease severity and had good prognostic performance in predicting the outcome of patients with HBV-ACLF through AUROC analysis. CONCLUSION: NK cells were significantly decreased and showed dysfunction of phenotypic and functional profiles across distinct subsets in the peripheral blood of patients with ACLF. Crosstalk between CXCL-10 and NK cells may mediate the unbalanced distribution of NK cells. Understanding the dysfunction and decrease in NK cells may provide new insights into ACLF pathogenesis.

Soluble Receptor for Advanced Glycation End Product Is Involved in the Inflammatory Response of Human Adenovirus-Infected Patients.

Human adenovirus (HAdV) infection causes excessive inflammation associated with severe tissue injury, such as pneumonia. The molecules involved in the underlying inflammatory mechanisms remain to be elucidated. Receptor for advanced glycation end product (RAGE) is mainly expressed on immune cells and lung tissues, and it is a key factor in the initiation and development of inflammation. RAGE can be cleaved by metalloprotease 9 (MMP9) to release the extracellular segment, which is named soluble RAGE (sRAGE), into the intercellular space, where it can bind to RAGE ligands and block RAGE activation and subsequent inflammation. In our study, we enrolled HAdV-infected patients and their contacts to examine the relationship between sRAGE and inflammation induced by HAdV infection. The results showed that HAdV infection stimulated inflammatory cytokine secretion, increased such as high mobility group box 1 (HMGB1) levels, and suppressed sRAGE expression. sRAGE levels were significantly different between patients with or without pneumonia. We also found that MMP9 was significantly lower in patients with pneumonia, and it was positively correlated with sRAGE levels over 7 days after disease onset. The mitogen-activated protein kinase (MAPK) pathway is an important immune activation signaling pathway that is regulated by RAGE. We observed the activation of the MAPK pathway in the peripheral blood mononuclear cells (PBMCs) of patients. Negative correlations between sRAGE and phosphorylated JNK and p38 were observed. These results suggest that sRAGE is involved in HAdV-induced inflammatory responses, and might be a potential therapeutic target to alleviate the HAdV-induced excessive inflammation.

CCL5-Secreting Virtual Memory CD8+ T Cells Inversely Associate With Viral Reservoir Size in HIV-1-Infected Individuals on Antiretroviral Therapy.

Recent studies highlighted that CD8+ T cells are necessary for restraining reservoir in HIV-1-infected individuals who undergo antiretroviral therapy (ART), whereas the underlying cellular and molecular mechanisms remain largely unknown. Here, we enrolled 60 virologically suppressed HIV-1-infected individuals, to assess the correlations of the effector molecules and phenotypic subsets of CD8+ T cells with HIV-1 DNA and cell-associated unspliced RNA (CA usRNA). We found that the levels of HIV-1 DNA and usRNA correlated positively with the percentage of CCL4+CCL5- CD8+ central memory cells (TCM) while negatively with CCL4-CCL5+ CD8+ terminally differentiated effector memory cells (TEMRA). Moreover, a virtual memory CD8+ T cell (TVM) subset was enriched in CCL4-CCL5+ TEMRA cells and phenotypically distinctive from CCL4+ TCM subset, supported by single-cell RNA-Seq data. Specifically, TVM cells showed superior cytotoxicity potentially driven by T-bet and RUNX3, while CCL4+ TCM subset displayed a suppressive phenotype dominated by JUNB and CREM. In viral inhibition assays, TVM cells inhibited HIV-1 reactivation more effectively than non-TVM CD8+ T cells, which was dependent on CCL5 secretion. Our study highlights CCL5-secreting TVM cells subset as a potential determinant of HIV-1 reservoir size. This might be helpful to design CD8+ T cell-based therapeutic strategies for cure of the disease.

Activation-induced pyroptosis contributes to the loss of MAIT cells in chronic HIV-1 infected patients.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells are systemically depleted in human immunodeficiency virus type 1 (HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy (cART). This study aimed to identify the mechanism underlying MAIT cell depletion. METHODS: In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. RESULTS: Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D (GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12 (IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro. CONCLUSIONS: Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients, which could potentiate disease progression and poor immune reconstitution.

HIV Infection Predisposes to Increased Chances of HBV Infection: Current Understanding of the Mechanisms Favoring HBV Infection at Each Clinical Stage of HIV Infection.

Human immunodeficiency virus (HIV) selectively targets and destroys the infection-fighting CD4+ T-lymphocytes of the human immune system, and has a life cycle that encompasses binding to certain cells, fusion to that cell, reverse transcription of its genome, integration of its genome into the host cell DNA, replication of the HIV genome, assembly of the HIV virion, and budding and subsequent release of free HIV virions. Once a host is infected with HIV, the host's ability to competently orchestrate effective and efficient immune responses against various microorganisms, such as viral infections, is significantly disrupted. Without modern antiretroviral therapy (ART), HIV is likely to gradually destroy the cellular immune system, and thus the initial HIV infection will inexorably evolve into acquired immunodeficiency syndrome (AIDS). Generally, HIV infection in a patient has an acute phase, a chronic phase, and an AIDS phase. During these three clinical stages, patients are found with relatively specific levels of viral RNA, develop rather distinctive immune conditions, and display unique clinical manifestations. Convergent research evidence has shown that hepatitis B virus (HBV) co-infection, a common cause of chronic liver disease, is fairly common in HIV-infected individuals. HBV invasion of the liver can be facilitated by HIV infection at each clinical stage of the infection due to a number of contributing factors, including having identical transmission routes, immunological suppression, gut microbiota dysbiosis, poor vaccination immune response to hepatitis B immunization, and drug hepatotoxicity. However, there remains a paucity of research investigation which critically describes the influence of the different HIV clinical stages and their consequences which tend to favor HBV entrenchment in the liver. Herein, we review advances in the understanding of the mechanisms favoring HBV infection at each clinical stage of HIV infection, thus paving the way toward development of potential strategies to reduce the prevalence of HBV co-infection in the HIV-infected population.