Publications by authors named "Zining Zhang"

52 Publications

IP-10 Promotes Latent HIV Infection in Resting Memory CD4 T Cells LIMK-Cofilin Pathway.

Front Immunol 2021 10;12:656663. Epub 2021 Aug 10.

NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.

A major barrier to HIV eradication is the persistence of viral reservoirs. Resting CD4 T cells are thought to be one of the major viral reservoirs, However, the underlying mechanism regulating HIV infection and the establishment of viral reservoir in T cells remain poorly understood. We have investigated the role of IP-10 in the establishment of HIV reservoirs in CD4 T cells, and found that in HIV-infected individuals, plasma IP-10 was elevated, and positively correlated with HIV viral load and viral reservoir size. In addition, we found that binding of IP-10 to CXCR3 enhanced HIV latent infection of resting CD4 T cells Mechanistically, IP-10 stimulation promoted cofilin activity and actin dynamics, facilitating HIV entry and DNA integration. Moreover, treatment of resting CD4 T cells with a LIM kinase inhibitor R10015 blocked cofilin phosphorylation and abrogated IP-10-mediated enhancement of HIV latent infection. These results suggest that IP-10 is a critical factor involved in HIV latent infection, and that therapeutic targeting of IP-10 may be a potential strategy for inhibiting HIV latent infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.656663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383741PMC
September 2021

The characterization, expression and activity analysis of three superoxide dismutases in Eriocheir hepuensis under azadirachtin stress.

Fish Shellfish Immunol 2021 Oct 18;117:228-239. Epub 2021 Aug 18.

Beibu Gulf University, Qinzhou, Guangxi, 530005, PR China; School of Marine Sciences, State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, Guangxi, 530005, PR China. Electronic address:

Superoxide dismutase (SOD) can effectively eliminate of excess ROS, which causes oxidative damage to lipids, proteins, and DNA. In this study, we cloned the CuZn-SOD, cMn-SOD1, and cMn-SOD2 genes in Eriocheir hepuensis, and found that the coding sequence (CDS) lengths were 627 bp, 861 bp and 1062 bp, which encoded 208, 286, and 353 amino acids, respectively. Phylogenetic analysis indicated that all SOD genes were evolutionarily conserved, while cMn-SOD2 had an extra gap (67 amino acids) in the conserved domain compared with cMn-SOD1 without huge changes in the tertiary structure of the conserved domain, suggesting that cMn-SOD2 may be a duplicate of cMn-SOD1. qRT-PCR showed that the three SOD genes were widely expressed in all the tested tissues, CuZn-SOD and cMn-SOD1 were mostly expressed in the hepatopancreas, while cMn-SOD2 was mostly expressed in thoracic ganglia. Under azadirachtin stress, the oxidation index of surviving individuals, including the T-AOC, SOD activity, and MDA contents increased in the early stage and then remained steady except for a decrease in MDA contents in the later stage. qRT-PCR showed that the three SOD genes displayed the same trends as SOD activity in surviving individuals, and the highest expressions of CuZn-SOD in the hepatopancreas, heart, and gill were 14.16, 1.41, and 30.87 times that of the corresponding control group, respectively. The changes were 1.35, 5.77 and 3.33 fold for cMn-SOD1 and 1.62, 1.71 and 1.79 fold for cMn-SOD2, respectively. However, the activity and expression of SOD genes in dead individuals were lower than that observed in surviving individuals. These results reveal that SOD plays a significant role in the defence against azadirachtin-induced oxidative stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fsi.2021.08.010DOI Listing
October 2021

The accumulation of plasma acylcarnitines are associated with poor immune recovery in HIV-infected individuals.

BMC Infect Dis 2021 Aug 12;21(1):808. Epub 2021 Aug 12.

NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.

Background: Antiretroviral therapy (ART) can reduce opportunistic infections and mortality rates among individuals infected with human immunodeficiency virus (HIV); however, some HIV-infected individuals exhibit poor immune recovery after ART. Hence, we explored the association between metabolome profiles and immune recovery in HIV-infected individuals following ART.

Methods: An untargeted metabolomics approach was used to analyze plasma samples from 18 HIV-negative individuals and 20 HIV-infected individuals, including 10 immunological non-responders (INR, CD4 T cell rise < 100 cells/μl) and 10 immunological responders (IR, CD4 T cell rise > 300 cells/μl) after 2 years of ART. These individuals were followed for the next 6 years and viral loads and CD4 T cell count were measured regularly. Orthogonal projection on latent structures discriminant analysis (OPLS-DA), ANOVA, correlation, receiver operating characteristic (ROC), and survival analyses were used for selection of discriminant metabolites.

Results: Eighteen lipid metabolites were identified which could distinguish among control, INR, and IR groups. Among them, myristoylcarnitine (MC), palmitoylcarnitine (PC), stearoylcarnitine (SC), and oleoylcarnitine (OC) were significantly elevated in INR plasma samples compared with those from the IR and control groups and were negatively associated with CD4 T cell count. Additionally, ROC analysis using a combination of MC, PC, SC, and OC had high sensitivity and specificity for differentiating INR from IR (AUC = 0.94). Finally, survival analysis for the combination of MC, PC, SC, and OC demonstrated that it could predict CD4 T cell count in patients undergoing long-term ART.

Conclusions: High levels of lipid metabolites, MC, PC, SC, and OC are associated with poor immune recovery in patients receiving ART and these data provide potential new insights into immune recovery mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12879-021-06525-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362229PMC
August 2021

Rapid Clinical Progression and Its Correlates Among Acute HIV Infected Men Who Have Sex With Men in China: Findings From a 5-Year Multicenter Prospective Cohort Study.

Front Immunol 2021 22;12:712802. Epub 2021 Jul 22.

NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.

Background: In the "treat all" era, there are few data on the nature of HIV clinical progression in middle-income countries. The aim of the current study was to prospectively analyze the clinical progression of HIV and its indicators among men in China with acute HIV who have sex with men.

Methods: From 2009-2014 a total of 400 men with acute HIV infection (AHI) were identified among 7,893 men who have sex with men periodic pooled nucleic acid amplification testing, and they were assigned to an AHI prospective cohort in Beijing and Shenyang, China. Rapid progression was defined as two consecutive CD4 T cell counts < 350/µL within 3-24 months post-infection. Kaplan-Meier and Cox-regression analyses were conducted to identify predictors of rapid progression.

Results: Among 400 men with AHI 46.5% were rapid progressors, 35.1% reached rapid progressor status by 12 months post-infection, and 63.9% reached rapid progressor status by 24 months. Rapid progression was associated with herpes simplex-2 virus coinfection (adjusted hazard ratio [aHR] 1.7, 95% confidence interval [CI] 1.2-2.3], depression (aHR 1.9, 95% CI 1.5-2.6), baseline CD4 T cell count < 500/μL (aHR 3.5, 95% CI 2.4-5.1), higher baseline HIV viral load (aHR 1.6, 95% CI 1.2-2.3), acute symptoms lasting ≥ 2 weeks (aHR 1.6, 95% CI 1.1-2.2), higher body mass index (aHR 0.9, 95% CI 0.9-1.0), higher HIV viral load (aHR 1.7, 95% CI 1.4-2.1), set point viral load at 3 months (aHR 2.0, 95% CI 1.6-2.5), each 100-cell/μL decrease in CD4 T cell count at 3 months (aHR 2.2, 95% CI 1.9-2.5), and baseline routine blood tests including white blood cell count < 5.32, hemoglobin ≥ 151, mean corpuscular hemoglobin ≥ 30.5, hemoglobin concentration ≥ 342, mean platelet count ≥ 342, lymphocytes ≥ 1.98, and mixed cell count ≥ 0.4 (all < 0.05).

Conclusion: Almost half of the patients underwent rapid clinical progression within 2 years after HIV infection. A treat-all policy is necessary and should be strengthened globally. Rapid progression was correlated with herpes simplex-2 virus coinfection, depression, low CD4 T cell counts, and high set point viral load in acute infection stage. Rapid progression can be identified simple indicators such as body mass index and routine blood test parameters in low and middle-income countries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.712802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339583PMC
July 2021

CD27CD38 B cells accumulated in early HIV infection exhibit transitional profile and promote HIV disease progression.

Cell Rep 2021 Jul;36(2):109344

NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, China; National Clinical Research Center for Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Street, Hangzhou 310003, China. Electronic address:

Although peripheral B cell dysfunction in early HIV infection is established, how B cell subsets are altered by HIV infection is poorly understood. While investigating B cell subsets among individuals recently infected with HIV, we observe an accumulation of CD27CD38 B cells and find that these cells can directly facilitate HIV infection of primary CD4 T cells in vitro. Comprehensive analyses of the phenotype, function, and transcriptome of the CD27CD38 B cell subset is conducted compared with memory and naive B cells. We find that the CD27CD38 B cells exhibit a transitional B cell phenotype and an extremely high turnover rate. Importantly, individuals with higher proportions of CD27CD38 B cells during early HIV infection tend to become rapid progressors in the chronic infection stage. In this study, we identify a peripheral transitional B cell subset that accumulates during early HIV infection and may contribute to disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.109344DOI Listing
July 2021

Stearoyl-CoA Desaturase 1 Potentiates Hypoxic plus Nutrient-Deprived Pancreatic Cancer Cell Ferroptosis Resistance.

Oxid Med Cell Longev 2021 1;2021:6629804. Epub 2021 Apr 1.

Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, China 212001.

Hypoxia and nutrient starvation (H/NS) microenvironment, a notable characteristic of pancreatic carcinoma, plays a critical role in cell death resistance and tumor recurrence. However, its role in ferroptosis remains to be classified. Here, we found that H/NS contributed to the pancreatic cancer cell ferroptosis resistance depending on the altered intracellular lipid compositions. Mechanistically, H/NS induced the upregulation of stearoyl-CoA desaturase 1 (SCD1), which promoted monounsaturated fatty acids (MUFAs) synthesis and protected against lipid peroxidation. Surprisingly, SCD1 showed a strong correlation with antiferroptosis gene expression. Moreover, short-hairpin RNA-based knockdown of SCD1 enhanced erastin-induced ferroptosis under H/NS. Finally, our results demonstrate the synergistic effect of erastin and A939572, a special SCD1 inhibitor, in dictating pancreatic carcinoma subcutaneous ferroptotic death. Taken together, our findings reveal a new role of the H/NS microenvironment against ferroptosis and suggest a potential therapeutic strategy for overcoming ferroptosis resistance in pancreatic cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/6629804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032529PMC
May 2021

The inhibitory receptor Tim-3 fails to suppress IFN-γ production via the NFAT pathway in NK-cell, unlike that in CD4 T cells.

BMC Immunol 2021 04 9;22(1):25. Epub 2021 Apr 9.

NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Affiliated Hospital of China Medical University, No 155, Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China.

Background: T cell immunoglobulin and mucin domain-containing-3 (Tim-3) is a negative regulator expressed on T cells, and is also expressed on natural killer (NK) cells. The function of Tim-3 chiefly restricts IFNγ-production in T cells, however, the impact of Tim-3 on NK cell function has not been clearly elucidated.

Results: In this study, we demonstrated down-regulation of Tim-3 expression on NK cells while Tim-3 is upregulated on CD4 T cells during HIV infection. Functional assays indicated that Tim-3 mediates suppression of CD107a degranulation in NK cells and CD4 T cells, while it fails to inhibit the production of IFN-γ by NK cells. Analyses of downstream pathways using an antibody to block Tim-3 function demonstrated that Tim-3 can inhibit ERK and NFκB p65 signaling; however, it failed to suppress the NFAT pathway. Further, we found that the NFAT activity in NK cells was much higher than that in CD4 T cells, indicating that NFAT pathway is important for promotion of IFN-γ production by NK cells.

Conclusions: Thus, our data show that the expression of Tim-3 on NK cells is insufficient to inhibit IFN-γ production. Collectively, our findings demonstrate a potential mechanism of Tim-3 regulation of NK cells and a target for HIV infection immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12865-021-00417-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034152PMC
April 2021

Biological mechanisms of growth performance and meat quality in porcine muscle tissue.

Anim Biotechnol 2021 Mar 11:1-9. Epub 2021 Mar 11.

Yunnan Key Laboratory of Animal Nutrition and Feed Science, Yunnan Agricultural University, Kunming, China.

Growth performance and meat quality are important traits for pig production. The aim of the present study was to investigate the molecular mechanisms underlying growth performance and meat quality, and to identify novel target molecules for predicting the growth performance and meat quality. The differentially expressed genes (DEGs) in Diannan small ears pigs (DSP) and Landrace pigs (LP) were assessed by RNA-sequencing analyzing technology. A total of 339 DEGs were obtained between DSP and LP. 146 DEGs were upregulated in LP compared with DSP and 193 DEGs were upregulated in DSP compared with LP. The DEGs were significantly enriched in 26 GO and 3 KEGG pathways. The protein-protein interaction (PPI) network with 201 nodes and 382 edges was constructed and 5 modules were extracted from the entire network. The identified upregulated expression of genes involved in glycolysis and myogenesis as well as extracellular matrix may be associated with fast body and muscle deposition rates in LP. Increased expression of genes involved in PPAR signaling pathway and fatty acid metabolism as well as oxidative phosphate processes could be related to the intramuscular fat deposition and meat quality in DSP. The present study may provide an improved understanding of the growth performance and meat quality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10495398.2021.1886939DOI Listing
March 2021

Natural killer cell counts in primary HIV infection predicts disease progression and immune restoration after treatment.

Virology 2020 11 1;550:89-98. Epub 2020 Sep 1.

NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China; National Clinical Research Center for Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China; Key Laboratory of AIDS Immunology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, 110001, China. Electronic address:

The relationship between NK cell counts during primary infection and disease progression or immune restoration after antiretroviral treatment (ART) was explored. We followed 462 individuals with HIV infection and measured their NK, CD4 T, CD8 T cell counts and viral loads. Our data showed that individuals with high NK cell counts had much lower viral loads and higher CD4 T cell counts. NK cell counts during primary infection were negatively correlated with viral set-point and viral loads at one-year-infection point, and positively correlated with CD4 T cell counts at one-year-infection and one-year-ART point. Moreover, the NK cell counts during primary infection can predict HIV disease progression and immune restoration after ART. In conclusion, NK cell counts during primary infection represents a potential predictive biomarker to predict HIV disease prognosis in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virol.2020.08.007DOI Listing
November 2020

Rapid HIV Progression Is Associated with Extensive Ongoing Somatic Hypermutation.

J Immunol 2020 08 26;205(3):587-594. Epub 2020 Jun 26.

Key Laboratory of AIDS Immunology of National Health Commission (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, China;

The Ab response to HIV is of great interest, particularly in the context of a protective vaccine and broadly neutralizing Abs, but research is typically geared toward elite controllers because of their ability to successfully control the virus. In this study, we studied the evolution of the Ab repertoire over the first year of HIV infection in people classified as rapid progressors (RP) compared with typical progressors. HIV RPs are an important yet understudied group of HIV patients classified by a rapid decline in CD4 counts and accelerated development of AIDS. We found that the global IgG somatic hypermutation load negatively correlated with disease progression, possibly because of exaggerated isotype switching of unmutated sequences in patients with low CD4 counts. We measured Ab sequence evolution over time using longitudinal samples taken during the early stages of infection and 1 year postinfection. Within clonal lineages spanning both timepoints, visit 2-derived sequences harbored considerably more mutations than their visit 1 relatives. Despite extensive ongoing somatic hypermutation, the initially strong signs of Ag selection pressure observed in visit 1-derived sequences decayed by visit 2. These data suggest that excessive immune activation in RPs leads to a hyperactive B cell response that fails to confer protection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1901161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372316PMC
August 2020

The combination of CXCL9, CXCL10 and CXCL11 levels during primary HIV infection predicts HIV disease progression.

J Transl Med 2019 12 13;17(1):417. Epub 2019 Dec 13.

NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, 110001, Liaoning, China.

Background: Chemokines are small chemotactic cytokines involved in inflammation, cell migration, and immune regulation in both physiological and pathological contexts. Here, we investigated the profile of chemokines during primary HIV infection (PHI).

Methods: Fifty-four participants with blood samples before and during HIV infection and clinical information available were selected from an HIV-negative man who have sex with men (MSM) prospective cohort. Thirty chemokines and 10 cytokines were measured pre- and post-HIV infection in the same individuals using a Bio-Plex Pro™ Human Chemokine Panel.

Results: Levels of 18 chemokines/cytokines changed significantly during PHI relative to pre-HIV infection levels; 14 were up-regulated and 4 down-regulated. Among them, CXCL9, CXCL10, and CXCL11 were the most prominently raised. Levels of CXCL9 and CXCL10 were much higher in the high-set point group (log viral load (lgVL) ≥ 4.5) than those in the low-set point group (lgVL < 4.5) and levels of CXCL9, CXCL10, and CXCL11 were higher in the low-CD4 T-cell count group (CD4 T-cell count ≥ 500). A formula to predict HIV disease progression using a combination panel comprising CXCL9, CXCL10, and CXCL11 was developed, where risk score = 0.007 × CXCL9 + 0.004 × CXCL10 - 0.033 × CXCL11 - 1.724, with risk score values higher than the cutoff threshold (0.5211) indicating more rapid HIV disease progression.

Conclusions: A panel of plasma CXCL9, CXCL10, and CXCL11 measured during primary HIV-1 infection could predict long-term HIV disease prognosis in an MSM group and has potential as a novel biomarker in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-019-02172-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909626PMC
December 2019

CD56 CD16 NK cells from HIV-infected individuals negatively regulate IFN-γ production by autologous CD8 T cells.

J Leukoc Biol 2019 12 4;106(6):1313-1323. Epub 2019 Sep 4.

NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.

The percentage of human CD56 CD16 NK cells increases during chronic infection with human HIV; however, the biologic role of CD56 CD16 NK cells in HIV infection is unclear. Our results demonstrate that the percentage of CD56 CD16 NK cells producing IL-10 and TGF-β was higher than CD56 CD16 NK cells. CD56 CD16 NK cells could inhibit IFN-γ production by autologous CD8 T cells, and this inhibition could be partially reversed by anti-IL-10, anti-TGF-β, or anti-PD-L1 mAbs. CD56 CD16 NK cells are potential targets for the development of novel immune therapies against HIV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/JLB.3A0819-171RRDOI Listing
December 2019

Elevated CD54 Expression Renders CD4+ T Cells Susceptible to Natural Killer Cell-Mediated Killing.

J Infect Dis 2019 11;220(12):1892-1903

NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine.

Background: Natural killer (NK) cells are an important type of effector cell in the innate immune response, and also have a role in regulation of the adaptive immune response. Several studies have indicated that NK cells may influence CD4+ T cells during HIV infection.

Methods: In total, 51 HIV-infected individuals and 15 healthy controls participated in this study. We performed the flow cytometry assays and real-time PCR for the phenotypic analysis and the functional assays of NK cell-mediated deletion of CD4+ T cells, phosphorylation of nuclear factor-κB (NF-κB/p65) and the intervention of metformin.

Results: Here we detected high CD54 expression on CD4+ T cells in HIV-infected individuals, and demonstrate that upregulated CD54 is associated with disease progression in individuals infected with HIV. We also show that CD54 expression leads to the deletion of CD4+ T cells by NK cells in vitro, and that this is modulated by NF-κB/p65 signaling. Further, we demonstrate that metformin can suppress CD54 expression on CD4+ T cells by inhibiting NF-κB/p65 phosphorylation.

Conclusions: Our data suggest that further studies to evaluate the potential role of metformin as adjunctive therapy to reconstitute immune function in HIV-infected individuals are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiz413DOI Listing
November 2019

Predictive effects of body mass index on immune reconstitution among HIV-infected HAART users in China.

BMC Infect Dis 2019 May 2;19(1):373. Epub 2019 May 2.

NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, No 155, Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China.

Background: Body mass index (BMI) may contribute somewhat to drug metabolism, and thus affecting the efficacy of highly active antiretroviral therapy (HAART). This study aimed to determine the frequencies of underweight, normal and overweight/obesity at pre-HAART in a large cohort of HIV-infected Chinese patients, and investigate the prospective effects of BMI on immune reconstitution after HAART initiation.

Methods: A longitudinal cohort study was performed to analyze the effects of BMI on immune reconstitution in HIV-infected patients treated with HAART. Multiple linear regression was used to evaluate the relationship between baseline BMI and increased CD4+ T lymphocyte levels at 12 and 30 months after initiating HAART. In addition, Cox proportional hazard model was used to assess the relationship between BMI and time to achieve immunologic reconstitution (CD4+ T lymphocytes>500cells/μL) during the follow-up period.

Results: Among the 1612 enrolled patients, 283 (17.6%) were overweight/obese (BMI ≥ 25 kg/m), 173 (10.7%) were underweight (BMI < 18.5 kg/m) and the remaining were normal weight. Prior to HAART initiating, overweight HIV-infected patients were mostly males, older ages, exhibited higher CD4+ T lymphocytes and lower viral loads (p < 0.01 for all). Patients with higher baseline BMI had an independently positive effect on 30-month CD4+ T lymphocyte recovery (p = 0.028), but not 12-month CD4+ T lymphocyte gain (p = 0.104). In addition, a Cox proportional hazard model with baseline BMI as an independent variable indicated that BMI was correlated with an increased likelihood of achieving immunologic reconstitution over time (hazard ratios [HR] 1.03; 95% confidence intervals [CI] 1.01-1.06; p = 0.011), after adjusting for baseline age, gender, CD4+ T lymphocytes, CD4/CD8 ratio, viral load and WHO stage.

Conclusions: Higher baseline BMI could predict better immune reconstitution in HIV-infected patients after HAART initiating.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12879-019-3991-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498689PMC
May 2019

High polymorphism rates in well-known T cell epitopes restricted by protective HLA alleles during HIV infection are associated with rapid disease progression in early-infected MSM in China.

Med Microbiol Immunol 2019 Apr 8;208(2):239-251. Epub 2019 Mar 8.

NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, No 155, Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China.

T cell epitopes restricted by several protective HLA alleles, such as B*57, B*5801, B*27, B*51 and B*13, have been very well defined over the past two decades. We investigated 32 well-known T cell epitopes restricted by protective HLA molecules among 54 Chinese men who have sex with men (MSM) at the early stage of HIV-1 infection. Subjects in our cohort carrying protective HLA types did not exhibit slow CD4 T cell count decline (P = 0.489) or low viral load set points (P = 0.500). Variations occurred in 96.88% (31/32) of the known wild-type epitopes (rate 1.85-100%), and the variation rates of the strains of two CRF01_AE lineages were significantly higher than those of non-CRF01_AE strains (76.82% vs. 48.96%, P = 0.004; 71.27% vs. 8.96%, P = 0.025). Subjects infected with CRF01_AE exhibited relatively rapid disease progression (P = 0.035). Therefore, the lack of wild-type protective T cell epitopes restricted by classic protective HLA alleles in CRF01_AE HIV-1 strains may be one of the reasons why rapid disease progression is observed in Chinese MSM with HIV-1 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00430-019-00585-xDOI Listing
April 2019

Cofilin hyperactivation in HIV infection and targeting the cofilin pathway using an anti-αβ integrin antibody.

Sci Adv 2019 01 9;5(1):eaat7911. Epub 2019 Jan 9.

National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA.

A functional HIV cure requires immune reconstitution for lasting viremia control. A major immune dysfunction persisting in HIV infection is the impairment of T helper cell migration and homing to lymphoid tissues such as GALTs (gut-associated lymphoid tissues). ART (antiretroviral therapy) does not fully restore T cell motility for tissue repopulation. The molecular mechanism dictating this persistent T cell dysfunction is not understood. Cofilin is an actin-depolymerizing factor that regulates actin dynamics for T cell migration. Here, we demonstrate that blood CD4 T cells from HIV-infected patients ( = 193), with or without ART, exhibit significantly lower levels of cofilin phosphorylation (hyperactivation) than those from healthy controls ( = 100; ratio, 1.1:2.3; < 0.001); cofilin hyperactivation is also associated with poor CD4 T cell recovery following ART. These results suggest an HIV-mediated systemic dysregulation of T cell motility that cannot be repaired solely by ART. We further demonstrate that stimulating blood CD4 T cells with an anti-human αβ integrin antibody can trigger signal transduction and modulate the cofilin pathway, partially restoring T cell motility in vitro However, we also observed that severe T cell motility defect caused by high degrees of cofilin hyperactivation was not repairable by the anti-integrin antibody, demonstrating a mechanistic hindrance to restore immune functions in vivo. Our study suggests that cofilin is a key molecule that may need to be therapeutically targeted early for T cell tissue repopulation, immune reconstitution, and immune control of viremia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aat7911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326757PMC
January 2019

Crosstalk in competing endogenous RNA networks reveals new circular RNAs involved in the pathogenesis of early HIV infection.

J Transl Med 2018 11 29;16(1):332. Epub 2018 Nov 29.

NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, No 155, Nanjing North Street, Heping District, Shenyang, 110001, Liaoning, China.

Background: The events in early HIV infection (EHI) are important determinants of disease severity and progression rate to AIDS, but the mechanisms of pathogenesis in EHI have not been fully understood. Circular RNAs (circRNAs) have been verified as "microRNA sponges" that regulate gene expression through competing endogenous RNA (ceRNA) networks, but circRNA expression profiles and their contribution to EHI pathogenesis are still unclear.

Methods: Two different libraries were constructed with RNA from human peripheral blood mononuclear cells from 3 HARRT-naive EHI patients and 3 healthy controls (HCs). The complete transcriptomes were sequenced with RNA sequencing (RNA-Seq) and miRNA sequencing (miRNA-Seq). The differentially expressed (DE) RNAs were validated with RT-qPCR. The circRNA profile and circRNA-associated-ceRNA network in EHI were analyzed with the integrated data of RNA-Seq and miRNA-Seq. Gene ontology (GO) analysis was used to annotate the circRNAs involved in the circRNA-associated-ceRNA networks.

Results: A total of 1365 circRNAs, 30 miRNAs, and 2049 mRNAs were differentially expressed between HARRT-naive EHI patients and HCs. A ceRNA network was constructed with 516 DE circRNAs and 903 DE mRNAs that shared miR response elements with 21 DE miRNAs. GO analysis demonstrated the multiple roles of the circRNAs enriched in EHI with circRNA-associated-ceRNA networks, such as immune response, inflammatory response and defense responses to virus, 67 circRNAs were revealed to be potentially involved in HIV-1 replication through regulating the expression of CCNK, CDKN1A and IL-15.

Conclusions: This study, for the first time, revealed a large circRNA profile and complex pathogenesis roles of circRNAs in EHI. A group of enriched circRNAs and associated circRNA-associated-ceRNA networks might contribute to HIV replication regulation and provide novel potential targets for both the pathogenesis of EHI and antiviral therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-018-1706-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264784PMC
November 2018

Expression of the Inhibitory Receptor TIGIT Is Up-Regulated Specifically on NK Cells With CD226 Activating Receptor From HIV-Infected Individuals.

Front Immunol 2018 10;9:2341. Epub 2018 Oct 10.

Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, China.

Natural killer (NK) cells are important for maintenance of innate immune system stability and serve as a first line of defense against tumors and virus infections; they can act either directly or indirectly and are regulated via co-operation between inhibitory and stimulatory surface receptors. The recently reported inhibitory receptor, TIGIT, can be expressed on the NK cell surface; however, the expression level and function of TIGIT on NK cells during HIV infection is unknown. In this study, for the first time, we investigated the expression and function of TIGIT in NK cells from HIV-infected individuals. Our data demonstrate that the level of TIGIT is higher on NK cells from patients infected with human immunodeficiency virus (HIV) compared with HIV-negative healthy controls. TIGIT expression is inversely correlated with CD4 T cell counts and positively correlated with plasma viral loads. Additionally, levels of the TIGIT ligand, CD155, were higher on CD4 T cells from HIV-infected individuals compared with those from healthy controls; however, there was no difference in the level of the activating receptor, CD226, which recognizes the same ligands as TIGIT. Furthermore, TIGIT was found to specifically up-regulated on CD226 NK cells in HIV-infected individuals, and either rIL-10, or rIL-12 + rIL-15, could induce TIGIT expression on these cells. In addition, high TIGIT expression inhibited the production of interferon-gamma (IFN-γ) by NK cells, while TIGIT inhibition restored IFN-γ production. Overall, these results highlight the important role of TIGIT in NK cell function and suggest a potential new avenue for the development of therapeutic strategies toward a functional cure for HIV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.02341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192288PMC
October 2019

The Early Antibody-Dependent Cell-Mediated Cytotoxicity Response Is Associated With Lower Viral Set Point in Individuals With Primary HIV Infection.

Front Immunol 2018 9;9:2322. Epub 2018 Oct 9.

Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.

Antibody-dependent cell-mediated cytotoxicity (ADCC) is an immune response largely mediated by natural killer (NK) cells that can lyse target cells and combat tumors and viral infections. However, the role of ADCC in response to primary HIV infection is poorly understood. In the present study, we explored the ADCC response and evaluated its characteristics in 85 HIV-infected individuals, including 42 with primary infections. Our results showed that ADCC occurs during acute infection, and the earliest ADCC response to a single peptide was detected at 52 days. Primary HIV-infected individuals exhibiting ADCC responses had lower viral set points than those with no ADCC response, and functional analyses demonstrated that the ADCC response could significantly inhibit viral infection during primary HIV infection. HIV epitopes that provoked the ADCC response were determined and three relatively conserved epitopes (HNVWATYACVPTDPNPQE, TSVIKQACPKISFDPIPI, and VVSTQLLLNGSLAEEEII) from the surface of the three-dimensional structure of the HIV Env protein were identified. Overall, our data indicate that ADCC responses may be significant for the control of HIV from an early stage during infection. These findings merit further investigation and will facilitate improvements in vaccines or therapeutic interventions against HIV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.02322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189277PMC
October 2019

Configuration Synthesis and Performance Analysis of Finger Soft Actuator.

Appl Bionics Biomech 2018 14;2018:4264560. Epub 2018 Aug 14.

School of Mechanical Engineering and Automation, Beihang University, Beijing 100191, China.

Compared with the traditional rigid finger actuator, the soft actuator has the advantages of light weight and good compliance. This type of finger actuator can be used for data acquisition or finger rehabilitation training, and it has broad application prospects. The motion differences between the soft actuator and finger may cause extrusion deformation at the binding point, and the binding forces along nonfunctional direction may reduce drive efficiency. In order to reduce the negative deformation of soft structure and improve comfort, the configuration synthesis and performance analysis of the finger soft actuator were conducted for the present work. The configuration synthesis method for soft actuator was proposed based on the analysis of the physiological structure of the finger, and the soft actuator can make the human-machine closed-loop structure including joints ( = 1, 2, 3) meet the requirement of DOF (degrees of freedom). Then the typical feasible configurations were enumerated. The different typical configurations were analyzed and compared based on the establishment of mathematical models and simulation analysis. Results show that the configuration design method is feasible. This study offers a theoretical basis for designing the configuration of finger soft actuator.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/4264560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109997PMC
August 2018

Rapid CD4+ T-cell decline is associated with coreceptor switch among MSM primarily infected with HIV-1 CRF01_AE in Northeast China.

AIDS 2019 01;33(1):13-22

Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University.

Objective: CRF01_AE is the most prevalent HIV-1 subtype among MSM in China. However, the characteristics and underlying mechanism of the accelerated CD4 T-cell decline in CRF01_AE-infected MSM remain incompletely understood.

Design: A long-term prospective follow-up study was conducted with 1388 MSM at risk of HIV-1 infection in Northeast China. MSM with primary HIV-1 CRF01_AE infection were identified and followed for 3-6 years to explore the determinants of rapid CD4 T-cell decline.

Methods: Tropism was determined in primary infection by both single genome amplification-based genotypic prediction using four different algorithms and phenotypic determination using clinical isolates. Serial isolates were used to determine phenotype of coreceptor switch. Human leukocyte antigen genotypes and T-cell activation markers were determined.

Results: Fifty-nine MSM primarily infected with HIV-1 CRF01_AE were discovered and recruited for the follow-up study. CCR5-utilizing (R5) viruses accounted for up to 98% of HIV-1 CRF01_AE infections in Northeast China. Survival analysis indicated 39.5% of the patients underwent coreceptor switch within 3 years after infection. After adjustment for other potential risk factors, linear mixed-effect models demonstrated patients experienced R5 to CXCR4-utilizing/dual-tropic (X4/DM) coreceptor switch within 3 years after infection underwent a faster CD4 T-cell decline compared to those without coreceptor switch.

Conclusions: Primary HIV-1 CRF01_AE infection among MSM in Northeast China is characterized by R5 viral infection and early R5 to X4/DM coreceptor switch, which is associated with rapid CD4 T-cell decline. The findings highlight the importance of immediate treatment among the CRF01_AE-infected MSM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAD.0000000000001981DOI Listing
January 2019

Plasma metabolic changes in Chinese HIV-infected patients receiving lopinavir/ritonavir based treatment: Implications for HIV precision therapy.

Cytokine 2018 10 16;110:204-212. Epub 2018 May 16.

Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang 110001, PR China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, PR China. Electronic address:

Objectives: The goal of this study is to profile the metabolic changes in the plasma of HIV patients receiving lopinavir/ritonavir (LPV/r)-based highly active antiretroviral therapy (HAART) relative to their treatment-naïve phase, aimed to identify precision therapy for HIV for improving prognosis and predicting dyslipidemia caused by LPV/r.

Methods: 38 longitudinal plasma samples were collected from 19 HIV-infected patients both before and after antiretroviral therapy, and 18 samples from healthy individuals were used as controls. Untargeted metabolomics profiling of these plasma samples was performed using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS).

Results: A total of 331 compounds of known identity were detected among these metabolites, a 67-metabolite signature mainly mapping to tryptophan, histidine, acyl carnitine, ketone bodies and fatty acid metabolism distinguished HIV patients from healthy controls. The levels of 19 out of the 67 altered metabolites including histidine, kynurenine, and 3-hydroxybutyrate (BHBA), recovered after LPV/r-based antiretroviral therapy, and histidine was positively correlated with the presence of CD4 + T lymphocytes. Furthermore, using receiver operating characteristic (ROC) analyses, we discovered that butyrylcarnitine in combination with myristic acid from plasma in treatment-naïve patients could predict dyslipidemia caused by LPV/r with 87% accuracy.

Conclusions: Metabolites alterations in treatment-naïve HIV patients may indicate an inflammatory, oxidative state and mitochondrial dysfunction that is permissive for disease progression. Histidine may provide a specific protective function for HIV patients. Besides, elevated fatty acids levels including butyrylcarnitine and myristic acid after infection may indicate patients at risk of suffering from dyslipidemia after LPV/r-based HAART.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cyto.2018.05.001DOI Listing
October 2018

Alteration of CCR6CD95CD4 naïve T cells in HIV-1 infected patients: Implication for clinical practice.

Cell Immunol 2018 05 10;327:47-53. Epub 2018 Feb 10.

Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang 110001, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Street, Hangzhou 310003, China. Electronic address:

The profound deficiency of Th17 cells contributes to HIV disease progression. The mechanisms of their perturbation remain unclear. Recently, CCR6CD95CD4 naïve T cells (CCR6CD95CD4 T), identified as pre-committed Th17 precursors, were recognized as a subpopulation of CD4 T cells with stem cell properties. Following phenotypical identification, we evaluated their level in patients during chronic HIV infection and following antiretroviral therapy (ART) using flow cytometry. The levels of CCR6CD95CD4 T were decreased during chronic HIV infection and correlated with CD4 T cell counts. Immunological responders harbored higher frequency of CCR6CD95CD4 T, which was associated with CD4/CD8 T cell ratio. Immunological non-responders with lower frequency of CCR6CD95CD4 T failed to exhibit a correlation between CCR6CD95CD4 T and CCR6CD95CD4 T, and displayed elevated ratio of CCR6CD95CD4 T/T. The number of CCR6CD95CD4 T was increased following early ART. These findings shed light on the importance of targeting pre-committed Th17 precursors that enhance immune reconstitution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cellimm.2018.02.004DOI Listing
May 2018

IL-10 NK and TGF-β NK cells play negative regulatory roles in HIV infection.

BMC Infect Dis 2018 02 13;18(1):80. Epub 2018 Feb 13.

Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, No. 155, Nanjingbei Street, Heping District, Shenyang, Liaoning Province, 110001, China.

Background: Natural killer (NK) cells play cytotoxic roles by targeting tumor cells or virus infected cells, they also play regulatory roles by secreting cytokines and chemokines. Transforming growth factor (TGF)-β and interleukin (IL)-10 are important immunosuppressive cytokines potentially related to the immune dysregulation that occurs in the infection of human immunodeficiency virus (HIV). NK cells are an important source of TGF-β and a main early producer of IL-10 in response to viral infection. Here, we evaluated the percentages of IL-10 and TGF-β NK cells in HIV-infected patients relative to healthy controls (HCs).

Methods: Study participants (n = 63) included 31 antiretroviral treatment (ART)-naïve HIV-infected patients, 17 ART-treated HIV-infected patients, and 15 HIV-negative HCs. Expression of IL-10 or TGF-β in NK cells was examined by flow cytometry, and the influences of recombinant IL-10 (rIL-10) or recombinant TGF-β (rTGF-β) on NK cell function were investigated in vitro.

Results: Compared with HCs, ART-naïve HIV-infected patients had increased percentages of IL-10 (2.0% vs. 0.4%, p = 0.015) and TGF-β (4.5% vs. 2.1%, p = 0.022) NK cells, and ART-treated patients also had a higher percentage of IL-10 NK cells (2.5% vs. 0.4%, p = 0.002). The percentages of IL-10 and TGF-β NK cells were positively correlated (r = 0.388; p = 0.010). The results of in vitro experiments demonstrated that rIL-10 and rTGF-β inhibited NK cell CD107a expression (p = 0.037 and p = 0.024, respectively), IFN-γ secretion (p = 0.006, p = 0.016, respectively), and granzyme B release after stimulation (p = 0.014, p = 0.040, respectively).

Conclusions: Our data suggest that the percentages of IL-10 or TGF-β NK cells are increased in HIV-infected patients, and that rIL-10 and/or rTGF-β can inhibit NK cell functions in vitro, providing a potential therapeutic target for strategies aimed at combating HIV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12879-018-2991-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812185PMC
February 2018

NKG2CNKG2A Natural Killer Cells are Associated with a Lower Viral Set Point and may Predict Disease Progression in Individuals with Primary HIV Infection.

Front Immunol 2017 20;8:1176. Epub 2017 Sep 20.

Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, China.

Natural killer (NK) cells are the first line of defense against pathogens of the immune system and also play an important role in resistance against HIV. The activating receptor NKG2C and the inhibitory receptor NKG2A co-modulate the function of NK cells by recognizing the same ligand, HLA-E. However, the role of NKG2A and NKG2C on viral set point and the prediction of HIV disease progression have been rarely reported. In this study, we determined the expression of NKG2C or NKG2A on the surface of NK cells from 22 individuals with primary HIV infection (PHI) stage and 23 HIV-negative normal control (NC) subjects. The CD4 T cell count and plasma level of HIV RNA in the infected individuals were longitudinally followed-up for about 720 days. The proportion of NKG2CNKG2A NK cells was higher in subjects from the low set point group and was negatively correlated with the viral load. In addition, strong anti-HIV activities were observed in NKG2C NK cells from the HIV-positive donors. Furthermore, a proportion of NKG2CNKG2A NK cells >35.45%, and a ratio of NKG2C/NKG2A >1.7 were predictive for higher CD4 T cell counts 720 days after infection. Collectively, the experimental results allow us to draw the conclusion that NKG2C NK cells might exert an antiviral effect and that the proportion of NKG2CNKG2A NK cells, and the ratio of NKG2C/NKG2A, are potential biomarkers for predicting HIV disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.01176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611385PMC
September 2017

The investigation of CD4+T-cell functions in primary HIV infection with antiretroviral therapy.

Medicine (Baltimore) 2017 Jul;96(28):e7430

Department of Laboratory Medicine, Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, The First Hospital, China Medical University, Shenyang, China.

Human immunodeficiency virus (HIV) infection leads to reduced CD4T-cell counts and immune dysfunction. Initiation of antiretroviral therapy (ART) in HIV primary infection has been recommended to achieve an optimal clinical outcome, but a comprehensive study on restoration of CD4T-cell function in primary HIV-infected individuals with ART still needs to be eluciated. We investigated longitudinal changes in the CD4T-cell counts, phenotypes, and functions in HIV-infected individuals with early ART (initiated within 6 months after HIV infection) or later ART (initiated more than 12 months after HIV infection). Patients from early ART and later ART groups had received ART for at least 1 year. Individuals with early ART had more CD4T cells, a faster rate of CD4T-cell recovery than those receiving later ART; the levels of CD4T-cell activation and senescence were lower in early ART compared to those with later ART (P = .031; P = .016), but the activation was higher than normal controls (NC) (P = .001); thymic emigrant function was more upregulated in early ART than in later ART (P = .015), but still lower than NC (P = .027); proliferative capacity and interferon-γ secretion of CD4T cells were significantly decreased in primary infection (P < .001; P = .029), and early ART restored these CD4T-cell functions, there is no difference with NC, later ART could partially restore the functions of CD4T cells, but it remained lower than that of NC (P = .005; P = .019). Early ART could better improve CD4T-cell function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000007430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515751PMC
July 2017

Elevated interferon-γ-induced protein 10 and its receptor CXCR3 impair NK cell function during HIV infection.

J Leukoc Biol 2017 07 2;102(1):163-170. Epub 2017 May 2.

Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, China;

As the first line of defense in the human immune system, NK cells play essential roles in prevention of tumorigenesis and viral infection. It is known that NK cells have impaired function in HIV infection; however, it remains unclear why this occurs. IP-10 is a chemokine and inflammatory factor that is associated with such diseases as tuberculosis, hepatitis B virus, and pancreatic cancer. The aim of this study was to evaluate IP-10 levels and CXCR3 expression in NK cells that were affected by HIV and to elucidate whether NK cell function could be affected by IP-10. Our results demonstrate that IP-10 levels and expression of CXCR3 in NK cells was significantly higher in HIV-infected participants compared with noninfected participants. Moreover, the ability of NK cells to secrete IFN-γ and, specifically, to lyse K562, was suppressed with exposure to high levels of IP-10. This study also showed that CXCR3 NK cell function decreased dramatically when treated with IP-10, which indicates that CXCR3 NK cells were the main targets of IP-10. Furthermore, IP-10 or CXCR3 blocking could restore NK cell function. These data suggest that elevated IP-10 levels may impair NK cell function during HIV infection and that IP-10/CXCR3 blocking may be a novel therapeutic strategy in the control and functional cure of HIV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1189/jlb.5A1016-444RDOI Listing
July 2017

FOXO3, IRF4, and xIAP Are Correlated with Immune Activation in HIV-1-Infected Men Who Have Sex with Men During Early HIV Infection.

AIDS Res Hum Retroviruses 2017 02 22;33(2):172-180. Epub 2016 Dec 22.

1 Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University , Shenyang, China .

Forkhead box O (FOXO)1, FOXO3, interferon regulatory factor (IRF)4, X-linked inhibitor of apoptosis protein (xIAP), and E74-like factor (ELF)4 have been described as important regulators of T cell functions and differentiation. However, whether these molecules are associated with HIV-1 disease progression is still unknown. In this study, we showed that the levels of FOXO3, IRF4, and xIAP mRNA in rapid progressors (RPs) were significantly higher than in HIV-negative healthy controls (HCs). Moreover, FOXO3 expression was positively correlated with HIV-1 viral load and CD4 T cell activation. Remarkably, increased CD4 and CD8 T cell activation was apparent in RPs compared with typical progressors and HCs. In addition, a profile of higher apoptosis, more CD8 T cells, and fewer CD4 and CD8 Naive T cells were observed in early HIV infection patients with low CD4 T cell counts. Furthermore, in vitro, IRF4 and xIAP expression was enhanced in peripheral blood mononuclear cells from healthy people following T cell receptor stimulation. T cell activation was decreased by treatment with siRNA inhibiting FOXO3, IRF4, and xIAP. Our results show that significantly increased levels of FOXO3, IRF4, and xIAP mRNA in Chinese HIV-1-infected patients were related to T cell immune activation, implicating them as potential targets for developing new therapeutic avenues to slow down HIV-1 disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/AID.2015.0316DOI Listing
February 2017

Biophysical comparison of ATP synthesis mechanisms shows a kinetic advantage for the rotary process.

Proc Natl Acad Sci U S A 2016 10 19;113(40):11220-11225. Epub 2016 Sep 19.

Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260;

The ATP synthase (F-ATPase) is a highly complex rotary machine that synthesizes ATP, powered by a proton electrochemical gradient. Why did evolution select such an elaborate mechanism over arguably simpler alternating-access processes that can be reversed to perform ATP synthesis? We studied a systematic enumeration of alternative mechanisms, using numerical and theoretical means. When the alternative models are optimized subject to fundamental thermodynamic constraints, they fail to match the kinetic ability of the rotary mechanism over a wide range of conditions, particularly under low-energy conditions. We used a physically interpretable, closed-form solution for the steady-state rate for an arbitrary chemical cycle, which clarifies kinetic effects of complex free-energy landscapes. Our analysis also yields insights into the debated "kinetic equivalence" of ATP synthesis driven by transmembrane pH and potential difference. Overall, our study suggests that the complexity of the F-ATPase may have resulted from positive selection for its kinetic advantage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1608533113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056049PMC
October 2016

Thymic Function Is Most Severely Impaired in Chronic HIV-1 Infection, but Individuals With Faster Disease Progression During Early HIV-1 Infection Expressed Lower Levels of RTEs.

J Acquir Immune Defic Syndr 2015 Dec;70(5):472-8

*Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, China; †Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China; and ‡Department of Clinical Laboratory, Dongying People's Hospital, Dongying, China.

In HIV disease course, the decline of peripheral CD4 T-cell count correlates with rapid disease progression. The supply of peripheral naive T cells by the thymus requires precursor T-cell proliferation within the thymus. In the setting of HIV-1 infection, when both naive and memory T cells are progressively depleted, the contribution of thymic dysfunction in CD4 depletion needs to be studied. Previous research has shown that thymic function may also be impaired in HIV-1 infection. However, it is inconclusive regarding whether this impairment occurred at the early time or during the chronic phase. In addition, the relationship between thymic dysfunction and disease progression remains unknown. In this study, we examined the thymic function in 65 HIV-infected individuals. Among them, 17 were in acute phase, 15 were in early chronic phase, 15 were in chronic phase with no ART (antiretroviral therapy), and 18 were on ART. We also included 11 uninfected individuals as controls. We measured the peripheral blood levels of T-cell receptor rearrangement excision circles and PTK7 and CD31 expressions for the frequency of circulating recent thymic emigrants. We observed that the 2 indicators of thymic function, sj/β-TREC and PTK7, seemed to be lower in the chronic infection group than those in the acute and early chronic groups. Both indicators returned to the normal level after ART. However, after 1-year follow-up of patients with early HIV-1 infection, rapid progressors (n = 4) had lower PTK7 and CD31 expressions than chronic progressors (n = 6).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000000801DOI Listing
December 2015
-->