Severe acute respiratory syndrome coronavirus 2 virus-like particles induce dendritic cell maturation and modulate T cell immunity.

Dendritic cells (DCs) are professional antigen-presenting cells that play an important role in both innate and acquired immune responses against pathogens. However, the role of DCs in coronavirus disease 2019 (COVID-19) is unclear. Virus-like particles (VLPs) that structurally mimic the original virus are one of the candidates COVID-19 vaccines. In the present study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) VLPs were used as an alternative to live virus to evaluate the interaction of the virus with DCs. The results revealed that SARS-CoV-2 VLPs induced DC maturation by augmenting cell surface molecule expression (CD80, CD86, and major histocompatibility complex class II (MHC-II)) and inflammatory cytokine production (tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-12p70) in DCs via the mitogen-activated protein kinase and nuclear factor-κB signaling pathways. In addition, mature DCs induced by SARS-CoV-2 VLPs promoted T cell proliferation, which was dependent on VLPs concentration. Our results suggest that SARS-CoV-2 VLPs regulate the immune response by interacting with DCs. These findings will improve the understanding of SARS-CoV-2 pathogenesis and SARS-CoV-2 vaccine development.

Prevalence of Different Genotypes of HIV-1 in Injection Drug Users in China: A Systematic Review and Meta-Analysis.

BACKGROUND: Since 1981, an increasing trend in HIV has been observed for transmission via injection drug users (IDUs), sexual transmission and mother-to-child transmission. The IDUs are blamed for early increases in HIV-positive cases in China. OBJECTIVE: HIV genotypes of IDUs were comprehensively analysed to trace the source and relationships of the AIDS epidemic in China. METHODS: Relevant databases written in English and Chinese were searched. Overall, 7,149 publications were identified in six databases. After screening 7,104 articles according to the inclusion and exclusion criteria, 45 studies consisting of 2,765 cases were finally identified. A meta-analysis was conducted using R MATLAB software, RevMan and SPSS. Subgroup analyses focused on time frame, region, and location of different genotypes of IDUs in China. RESULTS: There were five dominant HIV-1 genotypes among the 2,765 IDU cases. The proportions of CRF07_BC, CRF01_AE, CRF08_BC, subtype B/B', and subtype C were 45.18% (95% CI: 33.55-57.08%), 16.00% (95% CI: 9.39-23.82%), 13.43% (95% CI: 7.32-20.84%), 3.58% (95% CI: 1.52-6.24%), and 0.90% (95% CI: 0.04-2.43%), respectively. HIV genotypes transmitted among IDUs in China are primarily CRF07-BC, followed by CRF01-AE and CRF08-BC. Across the different time frames and regions, CRF07_BC was the most prevalent HIV-1 genotype among IDUs, while CRF08_BC was the most prevalent genotype in the southwest region. CONCLUSION: Our study reveals that CRF07-BC was the dominant prevalent strain among IDUs from 1991 to 2015 in China, while CRF08-BC was the dominant prevalent strain among IDUs in southwestern China. This systematic review and meta-analysis shows evidence of the comprehensive prevalence of different genotypes, data and characteristics of HIV among IDUs in China.

Immunogenicity and protective efficacy of multistage vaccine candidates (Mtb8.4-HspX and HspX-Mtb8.4) against Mycobacterium tuberculosis infection in mice.

In this study, Mtb8.4 and HspX, which are expressed at proliferating and dormant stages of Mycobacterium tuberculosis (M. tuberculosis), respectively, were chosen to construct two fusion proteins, Mtb8.4-HspX (8.4H) and HspX-Mtb8.4 (H8.4), and we investigated whether the antigen dose and protein sequential order could impact the immunogenicity and protective efficacy of these fusion protein vaccines against M. tuberculosis. C57BL/6 mice were vaccinated with new constructions containing a fusion protein with adjuvant of N, N'-dimethyl-N, N'-dioctadecylammonium bromide (DDA) or a mixed adjuvant composed of DDA, polyribocytidylic acid and gelatin (DPG), and the antigen specific immune responses and protective efficacy against M. tuberculosis H37Rv were evaluated. The results showed that both antigens, Mtb8.4-HspX and HspX-Mtb8.4, could elicit strong human T cell responses. With the existing of DDA adjuvant, HspX-Mtb8.4 induced significantly higher secretion level of IFN-γ and TNF-α in spleen cells than Mtb8.4-HspX (p<0.05). In its protective efficacy study, the isolated bacterial Colony Form Unit (CFU) in H8.4-DPG group was significantly reduced compared to 8.4H-DPG group (p<0.05). Furthermore, with the stimulation of Mtb8.4 in vitro, the secretion of IFN-γ and TNF-α from mice immunized with 20µg of H8.4 exhibited relative higher level than the group immunized by 7µg of H8.4 (p<0.05), whereas, IL-2 secreting showed contrary result. The data suggest that the antigen sequential order and dose selection should be considered when a tuberculosis protein vaccine is to be constructed and its immune strategy is to be planned.

Pandemic Influenza A (H1N1) Virus Infection Increases Apoptosis and HIV-1 Replication in HIV-1 Infected Jurkat Cells.

Influenza virus infection has a significant impact on public health, since it is a major cause of morbidity and mortality. It is not well-known whether influenza virus infection affects cell death and human immunodeficiency virus (HIV)-1 replication in HIV-1-infected patients. Using a lymphoma cell line, Jurkat, we examined the in vitro effects of pandemic influenza A (H1N1) virus (pH1N1) infection on cell death and HIV-1 RNA production in infected cells. We found that pH1N1 infection increased apoptotic cell death through Fas and Bax-mediated pathways in HIV-1-infected Jurkat cells. Infection with pH1N1 virus could promote HIV-1 RNA production by activating host transcription factors including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB), nuclear factor of activated T-cells (NFAT) and activator protein 1 (AP-1) through mitogen-activated protein kinases (MAPK) pathways and T-cell antigen receptor (TCR)-related pathways. The replication of HIV-1 latent infection could be reactivated by pH1N1 infection through TCR and apoptotic pathways. These data indicate that HIV-1 replication can be activated by pH1N1 virus in HIV-1-infected cells resulting in induction of cell death through apoptotic pathways.

Bicarbonate versus lactate solutions for acute peritoneal dialysis.

BACKGROUND: The high mortality rate among critically ill patients with acute kidney injury (AKI) remains an unsolved problem in intensive care medicine, despite the use of renal replacement therapy (RRT). Increasing evidence from clinical studies in adults and children suggests that the new peritoneal dialysis (PD) fluids may allow for better long-term preservation of peritoneal morphology and function. Formation of glucose degradation products (GDPs) can be reduced and even avoided with the use of newer "biocompatible" solutions. However, it is still unclear if there are any differences in using conventional (lactate) solutions compared with low GDP (bicarbonate) solutions for acute PD. OBJECTIVES: To look at the benefits and harms of bicarbonate versus lactate solutions in acute PD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1966), EMBASE (from 1980), Latin American and Caribbean Health Sciences Literature Database LILACS (from 1982), and reference lists of articles.Date of last search: 6 May 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing bicarbonate to lactate solution for acute PD. DATA COLLECTION AND ANALYSIS: Two authors independently assess the methodological quality of studies. One author abstracted data onto a standard form, and a second author checked data extraction. We used the random-effects model and expressed the results as relative risk (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included one study (20 patients) in this review. In shock patients, bicarbonate did not differ from lactate with respect to mortality (RR 0.50, 95% CI 0.06 to 3.91); however there were significant differences in blood lactate (MD -1.60 mmol/L, 95% CI -2.04 to -1.16), serum bicarbonate (MD 5.00 mmol/L, 95% CI 3.26 to 6.74) and blood pH (MD 0.12, 95% CI 0.06 to 0.18). In non-shock patients there was a significance difference in blood lactate (MD -0.60 mmol/L, 95% CI -0.85 to -0.35) but not in serum bicarbonate (MD 1.10 mmol/L, 95% CI -0.27 to 2.47) or blood pH (MD -0.02, 95% CI -0.02 to -0.06). Other outcomes could not be analysed because of the limited data available. AUTHORS' CONCLUSIONS: There is no strong evidence that any clinical advantage for patients requiring acute PD for AKI when comparing conventional (lactate) with low GDP dialysis solutions (bicarbonate).

Novel pandemic influenza A (H1N1) virus infection modulates apoptotic pathways that impact its replication in A549 cells.

It is not well-known whether apoptosis signaling affects influenza virus infection and reproduction in human lung epithelial cells. Using A549 cell line, we studied the relationship of some apoptosis-associated molecules with novel pandemic influenza A (H1N1) virus, A/California/04/2009. Infected cells displayed upregulated Fas ligand, activated FADD and caspase-8, and downregulated FLIP in the extrinsic apoptotic pathway. p53 expression increased and Bcl-XL expression decreased in the intrinsic pathway. Expression of pre-apoptotic molecules (FasL, FADD, and p53) increased virus replication, while inhibition of activity of FADD, caspase-8 and caspase-3, and expression of anti-apoptotic proteins (FLIP and Bcl-XL) decreased virus replication. p38, ERK and JNK from MAPK pathways were activated in infected cells, and inhibition with their inhibitors diminished virus replication. In the p38 superfamily, p38α expression increased viral RNA production, while expression of p38ß and p38γ decreased. These data indicated that influenza virus induces apoptotic signaling pathways, which benefit virus replication.

Some mechanisms of FLIP expression in inhibition of HIV-1 replication in Jurkat cells, CD4+ T cells and PBMCs.

HIV-1 infection and replication are affected by host factors. Recent studies demonstrate that molecules from apoptotic pathways regulate HIV-1 replication. Therefore, studies on effects of host factors that maintain host cell survival and influence HIV-1 replication are critical to understanding the mechanisms of HIV-1 replicative cycle. Using the susceptible Jurkat cell line, CD4(+) T cells, and peripheral blood mononuclear cells (PBMCs), we studied the role of FLIP, an inhibitor of caspase-8, in HIV-1 production. Full length cellular FLIP (cFLIP) inhibited HIV-1 replication in these cells. cFLIP upregulated the expression of viral restriction factors, such as TRIM5, Apobec3G, and Bst2/tetherin, decreased nuclear factor 1C expression and inactivated ERK and p38 induced by HIV-1 in Jurkat cells. cFLIP blocked the trafficking of gp120 and Gag p24 capsid protein into lipid rafts with inhibition of Tsg101 and Alix in ESCRT signaling pathway. cFLIP also promoted Bst2/tetherin trafficking into lipid rafts. These results indicate that cFLIP may inhibit the HIV-1 replication cycle at multiple steps, including viral RNA release, transcription, traffic and assembly. We also found that cFLIP expression downregulated Fas expression and inactivated FADD in the Fas-mediated apoptotic pathway. The inactivated FADD also inhibited HIV-1 replication.

HIV-1 and HIV-2 infections induce autophagy in Jurkat and CD4+ T cells.

Autophagy plays important roles during innate and adaptive immune responses to pathogens, including virus infection. Viruses develop ways to subvert the pathway for their own benefit in order to escape restriction by autophagy, leading to increased viral replication and/or control over apoptosis of their host cells. The effects of HIV infection on the autophagic pathway in host cells have been little documented. Using the susceptible Jurkat cell line and CD4(+) T cells, we studied the relationship of HIV-1 and -2 infections with autophagy. We found that HIV infections significantly increase transcription of ULK1, a member of the autophagy-initiated complex. Two ubiquitin-like conjugation systems, the Atg12 conjugation system and the microtubule-associated protein L chain 3 (LC3) conjugation system that control the elongation of the autophore to form the autophagosome, were activated after HIV infection, with upregulation of Atg12-Atg5 complex and increased transcription of LC3, and formed more autophagosome in infected cells detected using an EM assay. We also found that HIV-1 induced more autophagic death in Jurkat cells relative to HIV-2, and the inhibition of autophagy with 3MA and Beclin-1 knockdown decreased HIV-1 replication significantly. The results indicate that HIV is able to induce the autophagic signaling pathway in HIV-infected host cells, which may be required for HIV infection-mediated apoptotic cell death.

Bicarbonate versus lactate solutions for acute peritoneal dialysis.

BACKGROUND: The high mortality rate among critically ill patients with acute kidney injury (AKI) remains an unsolved problem in intensive care medicine, despite the use of renal replacement therapy (RRT). Increasing evidence from clinical studies in adults and children suggests that the new peritoneal dialysis (PD) fluids may allow for better long-term preservation of peritoneal morphology and function. Formation of glucose degradation products (GDPs) can be reduced and even avoided with the use of newer "biocompatible" solutions. However, it is still unclear if there are any differences in using conventional (lactate) solutions compared with low GDP (bicarbonate) solutions for acute PD. OBJECTIVES: To look at the benefits and harms of bicarbonate versus lactate solutions in acute PD. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1966), EMBASE (from 1980), Latin American and Caribbean Health Sciences Literature Database LILACS (from 1982), and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing bicarbonate to lactate solution for acute PD. DATA COLLECTION AND ANALYSIS: Two authors independently assess the methodological quality of studies. One author abstracted data onto a standard form, and a second author checked data extraction. We used the random-effects model and expressed the results as relative risk (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included one study (20 patients) in this review. In shock patients, bicarbonate did not differ from lactate with respect to mortality (RR 0.50, 95% CI 0.06 to 3.91); however there were significant differences in blood lactate (MD -1.60 mmol/L, 95% CI -2.04 to -1.16), serum bicarbonate (MD 5.00 mmol/L, 95% CI 3.26 to 6.74) and blood pH (MD 0.12, 95% CI 0.06 to 0.18). In non-shock patients there was a significance difference in blood lactate (MD -0.60 mmol/L, 95% CI -0.85 to -0.35) but not in serum bicarbonate (MD 1.10 mmol/L, 95% CI -0.27 to 2.47) or blood pH (MD -0.02, 95% CI -0.02 to -0.06). Other outcomes could not be analysed because of the limited data available. AUTHORS' CONCLUSIONS: There is no strong evidence that any clinical advantage for patients requiring acute PD for AKI when comparing conventional (lactate) with low GDP dialysis solutions (bicarbonate).

Safety of irinotecan/cisplatin versus etoposide/cisplatin for patients with extensive-stage small-cell lung cancer: a metaanalysis.

PURPOSE: The objective of this study was to evaluate the safety of patients with extensive small-cell lung cancer treated with irinotecan/cisplatin (IP) versus etoposide/cisplatin (EP). PATIENTS AND METHODS: This is a metaanalysis of a randomized controlled trial. The main outcome measures for safety were grade 3/4 leukopenia, grade 3 anemia, grade 3/4 thrombocytopenia, grade 3/4 neutropenia, grade 3 vomiting/nausea, grade 3/4 diarrhea, and infection. RESULTS: Three randomized controlled trials totaling 535 patients were included. Metaanalysis results are as follows: fewer patients receiving IP experienced grade 3/4 leukopenia (response rate [RR], 0.44; 95% confidence interval [CI], 0.29-0.67), grade 3 anemia (RR, 0.65; 95% CI, 0.43-0.99), and grade 3/4 thrombocytopenia (RR, 0.23; 95% CI, 0.12-0.42), compared with patients receiving EP. But more patients experienced grade 3 vomiting or nausea (RR, 2.27; 95% CI, 1.37-3.37) and grade 3/4 diarrhea (RR, 21.66; 95% CI, 4.87-96.2). There was no significant difference between the 2 groups with regard to infection (RR, 0.75; 95% CI, 0.54-1.04). CONCLUSION: Current clinical studies might confirm that fewer patients receiving IP experienced grade 3/4 leukopenia, grade 3 anemia, grade 3/4 thrombocytopenia, and grade 3/4 neutropenia, compared with patients receiving EP, but more experienced grade 3 vomiting/nausea and grade 3/4 diarrhea. There was no significant difference between the group receiving IP and the group receiving EP with regard to infection. Although there is convincing evidence to confirm the results mentioned herein, they still need to be confirmed by large-sample, multicenter, randomized, controlled trials.