Search

SARS-CoV-2 binds to microplastics which facilitates viral host infection with enhanced inflammatory responses.

COVID-19 is an immune-mediated inflammatory disease caused by SARS-CoV-2 infection, the combination of anti-inflammatory and antiviral therapy is predicted to provide clinical benefits. We recently demonstrated that mast cells (MCs) are an essential mediator of SARS-CoV-2-initiated hyperinflammation. We also showed that spike protein-induced MC degranulation initiates alveolar epithelial inflammation for barrier disruption and suggested an off-label use of antihistamines as MC stabilizers to block degranulation and consequently suppress inflammation and prevent lung injury. In this study, we emphasized the essential role of MCs in SARS-CoV-2-induced lung lesions新冠肺炎（COVID-19）是由新型冠状病毒（SARS-CoV-2）感染导致的炎症相关疾病。抗病毒药物和抗炎药物联用有望在临床治疗取得有益的效果。我们最近证明，肥大细胞（Mast cell，MC）是SARS-CoV-2引发炎症的重要效应细胞。发现SARS-CoV-2刺突蛋白（Spike）通过诱导MC脱颗粒诱发肺泡上皮细胞炎症从而造成组织通透性破坏，并发现临床上治疗过敏性疾病的抗组胺药物可作为MC稳定剂，阻止Spike诱导的MC脱颗粒,进而抑制炎症发生和保护肺损伤。在该研究中，我们进一步阐述MC在SARS-CoV-2引发肺损伤中的作用，并评价抗组胺药物和抗病毒药物联用对病毒复制和炎症损伤的双重抑制效果。证明Spike诱导的MC脱颗粒可导致肺泡毛细血管损伤，而抗组胺药物预处理肺微血管内皮细胞，可防止细胞间紧密连接的破坏；特别重要一点，发现抗组胺药物HR1(histamine receptor)拮抗剂氯雷他定（Loratadine）和抗病毒药物瑞德西韦（Remdesivir）联用，可同时抑制SARS-CoV-2复制和缓解炎症造成的小鼠肺部损伤。该研究再次证明了MC在SARS-CoV-2诱导肺部炎症和导致肺损伤中的重要作用，并提出一种COVID-19抗病毒药物和抗炎药物联用治疗策略。.

Targeting the SARS-CoV-2 main protease Vaccines are an important tool in the fight against COVID-19, but developing antiviral drugs is also a high priority, especially with the rise of variants that may partially evade vaccines. The viral protein main protease is required for cleaving precursor polyproteins into functional viral proteins. This essential function makes it a key drug target. Qiao et al. designed 32 inhibitors based on either boceprevir or telaprevir, both of which are protease inhibitors approved to treat hepatitis C virus. Six compounds protected cells from viral infection with high potency, and two of these were selected for in vivo studies based on pharmokinetic experiments. Both showed strong antiviral activity in a mouse model. Science, this issue p. 1374, Designed SARS-CoV-2 Mpro (main protease) inhibitors display excellent antiviral activity both in vitro and in a transgenic mouse model., The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent responsible for the global coronavirus disease 2019 (COVID-19) pandemic. Numerous studies have demonstrated that cardiovascular disease may affect COVID-19 progression. In the present study, we investigated the effect of hypertension on viral replication and COVID-19 progression using a hypertensive mouse model infected with SARS-CoV-2. Results revealed that SARS-CoV-2 replication was delayed in hypertensive mouse lungs. In contrast, SARS-CoV-2 replication in hypertensive mice treated with the antihypertensive drug captopril demonstrated similar virus replication as SARS-CoV-2-infected normotensive mice. Furthermore, antihypertensive treatment alleviated lung inflammation induced by SARS-CoV-2 replication (interleukin (IL)-1β up-regulation and increased immune cell infiltration). No differences in lung inflammation were observed between the SARS-CoV-2-infected normotensive mice and hypertensive mice. Our findings suggest that captopril treatment may alleviate COVID-19 progression but not affect viral replication.严重急性呼吸系统综合症冠状病毒2型 (SARS-CoV-2) 是导致全球2019冠状病毒病 (COVID-19) 大流行的病原体。大量研究表明，心血管疾病可能会影响COVID-19的进展。在该研究中，我们使用感染了 SARS-CoV-2 的高血压小鼠模型研究了高血压对病毒复制和 COVID-19 进展的影响。结果显示，在高血压小鼠的肺中SARS-CoV-2的复制延迟。相比之下，用抗高血压药物卡托普利治疗的高血压小鼠的SARS-CoV-2 复制与感染了SARS-CoV-2 的正常血压小鼠的病毒复制相似。此外，抗高血压治疗减轻了由 SARS-CoV-2 复制引起的IL-1β上调和免疫细胞浸润增加。在感染 SARS-CoV-2 的血压正常小鼠和高血压小鼠之间没有观察到肺部炎症的差异。因此，我们的研究结果初步表明，卡托普利治疗可能会缓解COVID-19的进展，但不会影响病毒复制。.

Intravenous drug users (IDUs) are a high-risk group for HIV-1, hepatitis C virus (HCV), and hepatitis B virus (HBV) infections, which are the leading causes of death in IDUs. However, the plasma virome of IDUs and how it is influenced by above viral infections remain unclear. Using viral metagenomics, we determined the plasma virome of IDUs and its association with HIV-1, HCV, and/or HBV infections. Compared with healthy individuals, IDUs especially those with major viral infections had higher viral abundance and diversity.

As of June 2020, Coronavirus Disease 2019 (COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years, making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To examine the effect of age on death, we established a SARS-CoV-2 infection model in Chinese rhesus macaques ( Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b + and CD8 + cells in lungs at one-week post infection (wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b + cells, and persistent infiltration of CD8 + cells in the lungs at 2 wpi. In addition, peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.

Recombinant viral vectors represent an important platform for vaccine delivery. Our recent studies have demonstrated distinct innate immune profiles in responding to viral vectors of different families (e.g., adenovirus versus poxvirus): while human Ad5 vector is minimally innate immune stimulatory, the poxviral vector ALVAC induces strong innate response and stimulates type I interferon (IFN) and inflammasome activation. However, the impact of the innate immune signaling on vaccine-induced adaptive immunity in viral vector vaccination is less clear. Here, we show that Modified Vaccinia Ankara (MVA), another poxviral vector, stimulated a type I IFN response in innate immune cells through cGAS-STING. Using MVA-HIV vaccine as a model, we found that type I IFN signaling promoted the generation of humoral immunity in MVA-HIV vaccination in vivo. Following vaccination, type I IFN receptor-knockout (IFNAR1(–/–)) mice produced significantly lower levels of total and HIV gp120-specific antibodies compared to wild-type (WT) mice. Consistent with the antibody response, a type I IFN signaling deficiency also led to reduced levels of plasma cells and memory-like B cells compared to WT mice. Furthermore, analysis of vaccine-induced CD4 T cells showed that type I IFN signaling also promoted the generation of a vaccine-specific CD4 T-cell response and a T follicular helper (Tfh) response in mice. Together, our data indicate a role for type I IFN signaling in promoting humoral immunity in poxviral vector vaccination. The study suggests that modulating type I IFN and its associated innate immune pathways will likely affect vaccine efficacy. IMPORTANCE Viral vectors, including MVA, are an important antigen delivery platform and have been commonly used in vaccine development. Understanding the innate host-viral vector interactions and their impact on vaccine-induced immunity is critical but understudied. Using MVA-HIV vaccination of WT and IFNAR1(–/–) mice as a model, we report that type I IFN signaling promotes humoral immunity in MVA vaccination, including vaccine-induced antibody, B-cell, and Tfh responses. Our findings provide insights that not only add to our basic understanding of host-viral vector interactions but also will aid in improving vaccine design by potentially modulating type I IFN and its associated innate immune pathways in viral vector vaccination.

Understanding the pathological features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in an animal model is crucial for the treatment of coronavirus disease 2019 (COVID-19). Here, we compared immunopathological changes in young and old rhesus macaques (RMs) before and after SARS-CoV-2 infection at the tissue level. Quantitative analysis of multiplex immunofluorescence staining images of formalin-fixed paraffin-embedded (FFPE) sections showed that SARS-CoV-2 infection specifically induced elevated levels of apoptosis, autophagy, and nuclear factor kappa-B (NF-κB) activation of angiotensin-converting enzyme 2 (ACE2)+ cells, and increased interferon α (IFN-α)- and interleukin 6 (IL-6)-secreting cells and C-X-C motif chemokine receptor 3 (CXCR3)+ cells in lung tissue of old RMs. This pathological pattern, which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens, was significantly correlated with the systemic accumulation of CXCR3+ cells in lungs, spleens, and peripheral blood. Furthermore, the ratio of CXCR3+ to T-box protein expression in T cell (T-bet)+ (CXCR3+/T-bet+ ratio) in CD8+ cells may be used as a predictor of severe COVID-19. These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+ cells in predicting severe COVID-19.

Animal cells have multiple innate effector mechanisms that inhibit viral replication. For the pathogenic retrovirus human immunodeficiency virus 1 (HIV-1), there are widely expressed restriction factors, such as APOBEC3 proteins, tetherin/BST2, SAMHD1 and MX2, as well as TRIM5α. We previously found that the TRIM5α gene clearly affects SIVmac or HIV-2 replication, but the major determinant of the combinatorial effect caused by multiple host restriction factors is still not fully clear. APOBEC3G (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G), a host restriction factor that restricts HIV replication by causing cytosine deamination, can be targeted and degraded by the SIV/HIV-1/HIV-2 accessory protein Vif. Although rhesus macaques are widely used in HIV/AIDS research, little is known regarding the impact of APOBEC3G gene polymorphisms on viral Vif-mediated ubiquitin degradation in Chinese-origin rhesus macaques. In this study, we therefore genotyped APOBEC3G in 35 Chinese rhesus macaques. We identified a novel transcript and 27 APOBEC3G polymorphisms, including 20 non-synonymous variants and 7 synonymous mutation sites, of which 10 were novel. According to the predicted structure of the A3G protein, we predicted that the E88K and G212D mutations, both on the surface of the A3G protein, would have a significant effect on Vif-induced A3G degradation. However, an in vitro overexpression assay showed that these mutations did not influence HIV-2-Vif-mediated degradation of APOBEC3G. Unexpectedly, another polymorphism L71R, conferred resistance to Vif-mediated ubiquitin degradation, strongly suggesting that L71R might play an important role in antiviral defense mechanisms.

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. Here we showed that SARS-CoV-2-triggeed MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation alterred various signaling pathways in alveolar epithelial cells, particularly, led to the production of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.Graphical abstractIn BriefSARS-CoV-2 triggers an immediate mast cell (MC) degranulation, which initiates the alveolar epithelial inflammation and disrupts the tight junction. MC stabilizers that block degranulation reduce virus-induced lung inflammation and injury.HighlightsThe binding of RBD of Spike protein of SARS-CoV-2-to ACE2 receptor protein triggers an immediate MC degranulationMC degranulation induces transcriptomic changes include an upregulated inflammatory signaling and a downregulated cell-junction signalingMC degranulation leads to alveolar epithelial inflammation and disruption of tight junctionsMC stabilizer that inhibits degranulation reduces SARS-CoV-2-induced lung inflammation and injury in vivo

In the search for treatment schemes of COVID-19, we start by examining the general weakness of coronaviruses and then identify approved drugs attacking that weakness. The approach, if successful, should identify drugs with a specific mechanism that is at least as effective as the best drugs proposed and are ready for clinical trials. All coronaviruses translate their non-structural proteins (∼16) in concatenation, resulting in a very large super-protein. Homo-harringtonine (HHT), which has been approved for the treatment of leukemia, blocks protein elongation very effectively. Hence, HHT can repress the replication of many coronaviruses at the nano-molar concentration. In two mouse models, HHT clears SARS-CoV-2 in 3 days, especially by nasal dripping of 40 ug per day. We also use dogs to confirm the safety of HHT delivered by nebulization. The nebulization scheme could be ready for large-scale applications at the onset of the next epidemics. For the current COVID-19, a clinical trial has been approved by the Ditan hospital of Beijing but could not be implemented for want of patients. The protocol is available to qualified medical facilities.

The global emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic can only be solved with effective and widespread preventive and therapeutic strategies, and both are still insufficient. Here, we describe an ultrathin two-dimensional CuInP

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8–10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.

The research can be used to generate animal models of severe disease based on the hACE2 mice for development of treatment against severe COVID-19 and also quickly establish specific mouse models in response to other emergency situations in the future.

TRIMCyp generated by retrotransposition of a cyclophilin A inserting into TRIM5 locus, has been identified in owl monkey and most of Old World monkeys (OWM). Owl monkey TRIMCyp (omTRIMCyp) inhibits HIV-1 infection by direct interaction with viral capsid and indirect innate immune induction, whereas most of TRIMCyps from OWM cannot inhibit HIV-1, and the impact of which on immunoregulation is largely unknown. Here we reported that omTRIMCyp induces NF-κB, AP-1 and IFN-β activation in a dose-dependent manner, while TRIMCyp from northern pig-tailed macaque (npmTRIMCyp) does not activate NF-κB and moderately enhances AP-1 and IFN-β activities. The Cyclophilin A (CypA) domain plays an important role in omTRIMCyp-mediated NF-κB activation, and RBCC domains have a synergetic effect. We further indicated the mechanism by which npmTRIMCyp unable to activate NF-κB is that npmTRIMCyp hardly phosphorylates IκBα, different from omTRIMCyp which dramatically induces IκBα phosphorylation. Ubiquitination activity of omTRIMCyp was greater than npmTRIMCyp, although both could be ubiquitylated. Given that npmTRIMCyp neither interacts with viral capsid resulting in susceptibility to HIV-1 infection, nor activates NF-κB that is indispensable to HIV-1 provirus transcription, we proposed a model that npmTRIMCyp may play an important role in HIV-1 infected northern pig-tailed macaque with latency.

A practical and step-economic route to Favipiravir, an antiviral drug, was developed. Favipiravir was synthesized in only six steps from 3-aminopyrazine-2-carboxylic acid with an overall yield of about 22.3%. Key intermediates 3 and 6 were obtained in excellent purity via recrystallization from optimized solvents, which was beneficial to large-scale production. In the key synthetic reaction, 3,6-dichloropyrazine-2-carbonitrile (6) was reacted sequentially, in one pot, with KF and 30% H2O2 to give (after crystallization from 95% EtOH) favipiravir as colorless crystals, with a 60% yield for this final step of the synthesis.

HIV-1-infected macrophages are long-lived and act as human immunodeficiency virus 1 (HIV-1) virus reservoirs. Lipopolysaccharide (LPS) has been demonstrated to suppress HIV-1 replication in macrophages, but the mechanism is not clear. Previous research suggested that downregulation of CD4 and CCR5 as well as blockage of the interaction of HIV-1 with cells are major causes of inhibition of HIV-1 replication in macrophages by LPS. In order to study whether LPS blocks the post-entry event of HIV-1 replication, we developed a macrophage HIV-1 infection model by using VSV-G pseudotyped HIV-1-luciferase virus to infect THP-1 differentiated macrophage-like cells. We found that LPS can suppress HIV-1 replication at post-entry steps. Further study suggested that HIV-1 reverse transcription was blocked by LPS, but addition of exogenous deoxyribonucleosides led to only partial recovery of HIV-1 replication. However, the inhibition of pro-inflammatory pathway completely rescued HIV-1 replication. Thus, our study shows that LPS can suppress the events of HIV-1 replication post-entry, including reverse transcription, and this restriction is mediated by more than one mechanism.

TRIM5α restricts retroviruses in a species-specific manner. Cyclophilin A was independently retrotransposed into the TRIM5 loci in different species, leading to the generation of antiviral TRIM5-cyclophilin A (TRIMCyp) proteins. Previously, we found that assam macaques express a TRIMCyp chimera (amTRIMCyp), along with a TRIM5α allelic protein (amTRIM5α). Herein, we investigated the antiviral activity of amTRIMCyp and amTRIM5α individually, as well as their interaction and joint effects. amTRIMCyp showed a divergent restriction pattern from amTRIM5α. Although both proteins potently restricted the replication of HIV-1, only amTRIM5α inhibited N-MLV. Remarkably, cellular anti-HIV-1 activity increased when amTRIMCyp and amTRIM5α were coexpressed, indicating a synergistic block of HIV-1 replication. Consistently, PMBCs from heterozygous amTRIM5α/TRIMCyp showed stronger resistance to HIV-1 infection than those from amTRIM5α/TRIM5α homozygotes. The anti-HIV-1 synergistic effect was dependent on the amTRIMCyp-amTRIM5α interaction. In contrast, amTRIMCyp completely abrogated the anti-N-MLV activity mediated by amTRIM5α, showing a dominant-negative effect, indicating that the generation of amTRIMCyp was involved in the trade-off between divergent restriction activities. Our results provide a new paradigm to study functional trade-offs mediated by allelic proteins, a theoretical basis for utilizing animal models with various TRIM5 alleles, as well as novel HIV-1 gene therapy strategies.

Host restriction factors and type I interferon are important in limiting HIV and HCV infections, yet the role of HIV, HCV mono- and co-infection in regulating these antiviral genes expression is not clear. In this study, we measured the levels of TRIM5α, TRIM22, APOBEC3G, and IFN-α, -β mRNA expression in peripheral blood mononuclear cells of 43 HIV mono-infected, 70 HCV mono-infected and 64 HIV/HCV co-infected patients along with 98 healthy controls. We also quantified HIV and HCV viral loads in mono- and co-infected patients. The results showed that HCV, HIV mono- and co-infection differentially increased TRIM22, APOBEC3G, and IFN-α, -β mRNA expression while the mRNA expression of TRIMα was upregulated only by HCV-mono infection. HIV/HCV co-infection was associated with higher viral load, compared to either HIV or HCV mono-infection. Additionally, we showed TRIMα and TRIM22 positively correlated with IFN-α, -β, which could be dysregulated by HIV, HCV mono- and co-infection. Furthermore, we found TRIM22 negatively correlated with HCV viral load in mono-infected patients and APOBEC3G positively correlated with HCV viral load in co-infected patients. Collectively, our findings suggest the potential role of restriction factors in restricting HIV, HCV mono- and co-infection in vivo, which appears to be a therapeutic target for potential drug discovery.

Despite repeated exposures to HIV-1, some individuals remain uninfected, suggesting that genetic factors confer host resistance to HIV-1 acquisition. The chemokine receptors CCR5, CXCR4 and the principal ligand SDF1 of CXCR4 play an important role for the entry of HIV-1 to target cells. To explore the relationship between genetic variants and HIV-1 infection, 11 common SNPs in CCR5, CXCR4 and SDF1 were genotyped in 921 male intravenous drug users (IDUs), of which 263 individuals were HIV-1-exposed seropositive (HESP) and 658 were HIV-1-exposed seronegative (HESN). According to the situation of syringe-sharing, the whole cohort was divided into two subgroups: syringe-sharing (SS) and syringe-not-sharing (SNS). We found that in the SNS subgroup rs17540465 of SDF1 showed significant difference of allele and genotype frequencies between HESP IDUs and HESN IDUs, but not in the SS subgroup. HESP with SNS carried significantly less allele A compared with HESN with SNS, indicating a protective role of allele A against HIV-1 infection. Syringe-sharing IDUs are supposed to be exposed highly to HIV-1 infection risk due to the direct transfer of HIV-1 infected blood to another. For syringe-not-sharing IDUs, sexual contact may be the major route of HIV-1 transmission. Considering the different route of HIV-1 transfection between two subgroups, we speculate that SDF1 may contribute susceptibility to HIV-1 infection in the route of sexual intercourse.

The concerns raised from adenovirus 5 (Ad5)-based HIV vaccine clinical trials, where excess HIV infections were observed in some vaccine recipients, have highlighted the importance of understanding host responses to vaccine vectors and the HIV susceptibility of vector-specific CD4 T cells in HIV vaccination. Our recent study reported that human Ad5-specific CD4 T cells induced by Ad5 vaccination (RV156A trial) are susceptible to HIV. Here we further investigated the HIV susceptibility of vector-specific CD4 T cells induced by ALVAC, a canarypox viral vector tested in the Thai trial RV144, as compared to Ad5 vector-specific CD4 T cells in the HVTN204 trial. We showed that while Ad5 vector-specific CD4 T cells were readily susceptible to HIV, ALVAC-specific CD4 T cells in RV144 PBMC were substantially less susceptible to both R5 and X4 HIV in vitro. The lower HIV susceptibility of ALVAC-specific CD4 T cells was associated with the reduced surface expression of HIV entry co-receptors CCR5 and CXCR4 on these cells. Phenotypic analyses identified that ALVAC-specific CD4 T cells displayed a strong Th1 phenotype, producing higher levels of IFN-γ and CCL4 (MIP-1β) but little IL-17. Of interest, ALVAC and Ad5 vectors induced distinct profiles of vector-specific CD8 vs. CD4 T-cell proliferative responses in PBMC, with ALVAC preferentially inducing CD8 T-cell proliferation, while Ad5 vector induced CD4 T-cell proliferation. Depletion of ALVAC-, but not Ad5-, induced CD8 T cells in PBMC led to a modest increase in HIV infection of vector-specific CD4 T cells, suggesting a role of ALVAC-specific CD8 T cells in protecting ALVAC-specific CD4 T cells from HIV. Taken together, our data provide strong evidence for distinct HIV susceptibility of CD4 T cells induced by different vaccine vectors and highlight the importance of better evaluating anti-vector responses in HIV vaccination., Author summary Development of a safe and efficacious HIV vaccine is a critical global health priority. Recombinant viral vectors are an important platform for HIV vaccine delivery. Recent clinical trials testing candidate HIV vaccines based on Ad5 vectors failed and reported excess HIV infections in some vaccine recipients, underscoring the necessity to investigate HIV susceptibility of viral vector-specific CD4 T cells in HIV vaccination. By using PBMC samples from clinical trials that examined two important HIV vaccine vectors (canarypox viral vector ALVAC and human Ad5 vector), we here report that compared to Ad5 vector, the ALVAC-specific CD4 T cells are more resistant to HIV infection, providing evidence for distinct HIV susceptibility of CD4 T-cell populations induced by different HIV vaccine vectors. Our findings present new insights into our understanding of HIV vaccine-induced immunity and help improve the design and immune assessment of viral vectors for the development of HIV vaccines.

Viral vectors derived from different virus families, including poxvirus (canarypox virus vector ALVAC) and adenovirus (human Ad5 vector), have been widely used in vaccine development for a range of human diseases including HIV/AIDS. Less is known about the mechanisms underlying the host innate response to these vectors. Increasing evidence from clinical vaccine trials testing different viral vectors has suggested the importance of understanding basic elements of host–viral vector interactions. In this study, we investigated the innate interactions of APCs with two commonly used HIV vaccine vectors, ALVAC and Ad5, and identified AIM2 as an innate sensor for ALVAC, triggering strong inflammasome activation in both human and mouse APCs. Microarray and comprehensive gene-knockout analyses (CRISPR/Cas9) identified that ALVAC stimulated the cGAS/IFI16–STING–type I IFN pathway to prime AIM2, which was functionally required for ALVAC-induced inflammasome activation. We also provided evidence that, in contrast to ALVAC, the Ad5 vector itself was unable to induce inflammasome activation, which was related to its inability to stimulate the STING–type I IFN pathway and to provide inflammasome-priming signals. In preconditioned APCs, the Ad5 vector could stimulate inflammasome activation through an AIM2-independent mechanism. Therefore, our study identifies the AIM2 inflammasome and cGAS/IFI16–STING–type I IFN pathway as a novel mechanism for host innate immunity to the ALVAC vaccine vector.

TRIM5-cyclophilin A (TRIMCyp) fusion gene is an unusual TRIM5 locus. At present, this fusion phenomenon has been found in the representative species which contain owl monkey (Aotus trivirgatus) of Aotus genus that belongs to New World monkeys and Old World monkeys such as Northern pig-tailed macaque (M. leonina), Sunda pig-tailed macaque(M. nemestrina), Crab-eating macaque (M. fascicularis), Indian rhesus macaque (M. mulatta) and Assam macaque (M. assamensis), etc. But the fusion mode and transcription splicing pattern of TRIMCyp fusion gene are different between New World and Old World monkeys. The TRIMCyp fusion gene of New World monkeys is formed by inserting a CypA pseudogene cDNA sequence into the region between exon 7 and exon 8 of the TRIM5 locus through retrotransposition. However the TRIMCyp fusion gene of Old World monkeys results from the retrotransposition of a CypA pseudogene cDNA into 3' terminal or 3'-UTR of TRIM5 gene. The distributions, genotypes, expression and restricting activities against different retroviruses of TRIMCyp were different across species of primates. Moreover, most of the researches focused on the TRIMCyp fusion gene of owl monkey and pig-tailed macaque and found that they may play very important roles in restricting HIV-1 replication and determine the susceptibility to HIV-1 infection. It was reported that the TRIMCyp protein of owl monkey could inhibit HIV-1 infection in a similar way as TRIM5α, but TRIMCyp protein of pig-tailed monkey loss the restricting activity to HIV-1 infection. Here we reviewed the distributions, genotypes and restriction mechanism for inhibiting retroviruses replication of TRIMCyp fusion gene in primates.

Loss of immune control over opportunistic infections can occur at different stages of HIV-1 (HIV) disease, among which mucosal candidiasis caused by the fungal pathogen Candida albicans (C. albicans) is one of the early and common manifestations in HIV-infected human subjects. The underlying immunological basis is not well defined. We have previously shown that compared to cytomegalovirus (CMV)-specific CD4 cells, C. albicans-specific CD4 T cells are highly permissive to HIV in vitro. Here, based on an antiretroviral treatment (ART) naïve HIV infection cohort (RV21), we investigated longitudinally the impact of HIV on C. albicans- and CMV-specific CD4 T-cell immunity in vivo. We found a sequential dysfunction and preferential depletion for C. albicans-specific CD4 T cell response during progressive HIV infection. Compared to Th1 (IFN-γ, MIP-1β) functional subsets, the Th17 functional subsets (IL-17, IL-22) of C. albicans-specific CD4 T cells were more permissive to HIV in vitro and impaired earlier in HIV-infected subjects. Infection history analysis showed that C. albicans-specific CD4 T cells were more susceptible to HIV in vivo, harboring modestly but significantly higher levels of HIV DNA, than CMV-specific CD4 T cells. Longitudinal analysis of HIV-infected individuals with ongoing CD4 depletion demonstrated that C. albicans-specific CD4 T-cell response was preferentially and progressively depleted. Taken together, these data suggest a potential mechanism for earlier loss of immune control over mucosal candidiasis in HIV-infected patients and provide new insights into pathogen-specific immune failure in AIDS pathogenesis., Author Summary HIV infection is closely associated with enhanced host susceptibility to various opportunistic infections (OIs), among which mucosal candidiasis caused by the fungal pathogen Candida albicans (C. albicans) is an early and common manifestation. Even in the era of effective ART, mucosal candidiasis is still a clinically relevant presentation in HIV-infected patients. The underlying mechanisms are not well defined. CD4-mediated immunity is the major host defense mechanism against C. albicans. We here investigated a group of ART naïve, HIV-infected human subjects and examined longitudinally the impact of HIV on C. albicans-specific CD4 T-cell immunity as compared to CD4 T-cell immunity specific for CMV, another opportunistic pathogen that usually does not cause active disease in early HIV infection. We found that C. albicans-specific CD4 T cells were more susceptible to HIV in vivo and were preferentially depleted in progressive HIV-infected individuals as compared to CMV-specific CD4 T cells. Of importance, we also found that in these HIV-infected subjects C. albicans-specific CD4 T cell response manifested a sequential dysfunction with earlier impairment of Th17, but not Th1, functions. Our study suggests an immunological basis that helps explain the earlier and more common onsets of mucosal candidiasis in progressive HIV-infected patients.

HIV causes infection and progressive depletion of human CD4 T cells. Emerging data have shown that antigen-specific CD4 T-cell subsets manifest differential susceptibility to HIV, potentially leading to pathogen-specific immune failure and opportunistic infections. This concept was recently explored in context of vectors utilized in HIV vaccine trials, and the data suggest that adenovirus type 5(Ad5)-specific CD4 T cells elicited by Ad5-HIV vaccine may be particularly susceptible to HIV, potentially rendering Ad5 vaccine recipients susceptible to HIV acquisition. We here examined recent data regarding the HIV susceptibility of antigen-specific CD4 T cells induced during infection or HIV vaccination and discussed its potential impact on HIV acquisition risk posed by HIV vaccination.

Multilingual abstracts in the five official working languages of the United Nations. (PDF 458 kb)

Background Network analyses have been widely utilized to evaluate large datasets, but have not yet been used to explore factors associated with risk behaviours. In combination with traditional regression analysis, network analyses may provide useful information and highlight key factors for reducing needle sharing behaviours among people who inject drugs (PWID). Methods Sociodemographic data, and information on injection behaviour and sexual practices were collected from a cross-sectional survey that was conducted with PWID in five prefectures of Yunnan province, China. A combination of logistic regression and correlation network analyses were used to explore key factors for reducing needle-sharing behaviours among PWID. Results In a total of 1 049 PWID, 37.5 % had a history of needle or syringe sharing. The logistic analysis showed that Zhaotong, Qujing, Dehong, or Lincang residents, diazepam use, longer injection duration, needle reuse, and infection with HIV, viral hepatitis, tuberculosis and/or malaria were independently associated with needle sharing. The correlation network analyses showed that, compared to PWID who had never shared needles, PWID who did share needles would achieve harm reduction goals faster and more permanently. HIV serostatus and marital status were found to be closely associated with other risk factors. By combining regression analyses with network analyses, it was shown that PWID who are HIV seropositive will be an ideal target group for harm reduction programs. Conclusion Needle-sharing behaviours are common among PWID in Yunnan, and harm reduction programs may help PWID who are HIV seropositive reduce risk behaviours and prevent blood borne diseases. Electronic supplementary material The online version of this article (doi:10.1186/s40249-016-0169-y) contains supplementary material, which is available to authorized users.

Drug addiction is one of the most serious social problems in the world today and addicts are always at a high risk of acquiring HIV infection. Mitochondrial impairment has been reported in both drug addicts and in HIV patients undergoing treatment. In this study, we aimed to investigate whether mitochondrial DNA (mtDNA) haplogroup could affect the risk of drug addiction and HIV-1 infection in Chinese. We analyzed mtDNA sequence variations of 577 Chinese intravenous drug addicts (289 with HIV-1 infection and 288 without) and compared with 2 control populations (n = 362 and n = 850). We quantified the viral load in HIV-1-infected patients with and without haplogroup A status and investigated the potential effect of haplogroup A defining variants m.4824A > G and m.8794C > T on the cellular reactive oxygen species (ROS) levels by using an allotopic expression assay. mtDNA haplogroup A had a protective effect against drug addiction but appeared to confer an increased risk of HIV infection in addicts. HIV-1-infected addicts with haplogroup A had a trend for a higher viral load, although the mean viral load was similar between carriers of haplogroup A and those with other haplogroup. Hela cells overexpressing allele m.8794 T showed significantly decreased ROS levels as compared to cells with the allele m.8794C (P = 0.03). Our results suggested that mtDNA haplogroup A might protect against drug addiction but increase the risk of HIV-1 infection. The contradictory role of haplogroup A might be caused by an alteration in mitochondrial function due to a particular mtDNA ancestral variant.

The kinetics of Fe3O4 formation by air oxidation of slightly acidic suspension of Fe(OH)2 was studied. The effects of initial concentration of Fe(II), temperature, partial pressure of oxygen, air flow rate and stirring rate on the oxidation rate were investigated. The results show that Fe3O4 formation is composed of two-step reaction, the first step is the formation of Fe(OH) 2 + by oxidation of Fe(OH)+ complex ions, the second step is the formation of magnetite by dehydration and deprotonation of Fe(OH)+ and Fe(OH) 2 + . The oxidation reaction is zero-order with respect to the concentration of Fe(II) and around 0.5-order with respect to partial pressure of oxygen, and oxygen transfer process is rate-limiting step of oxidation reaction with apparent activation energy of 2.74 kJ · mol−1.

The origin of novel genes and their evolutionary fates are long-standing questions in evolutionary biology. These questions become more complicated for genes conserved across various lineages, such as TRIM5, an antiretroviral restriction factor and a retrovirus capsid sensor in immune signaling. TRIM5 has been subjected to numerous pathogenic challenges and undergone dynamic evolution, making it an excellent example for studying gene diversification. Previous studies among several species showed that TRIM5 gained genetic and functional novelty in a lineage-specific manner, either through gene duplication or a cyclophilin A retrotransposing into the TRIM5 locus, creating the gene fusion known as TRIM5-Cyclophilin A (TRIMCyp). To date, the general pattern of TRIM5 across the mammalian lineage remains elusive. In this study, we surveyed 36 mammalian genomes to verify a potentially novel TRIM5 pattern that uniquely seems to have occurred in tree shrews (Tupaia belangeri), and found that both gene duplication and retrotransposition worked jointly to form a specific TRIM5/TRIMCyp cluster not found among other mammals. Evolutionary analyses showed that tree shrew TRIMCyp (tsTRIMCyp) originated independently in comparison with previously reported TRIMCyps and underwent strong positive selection, whereas no signal of positive selection was detected for other tree shrew TRIM5 (tsTRIM5) genes. Functional assay results suggest a functional divergence between tsTRIMCyp and its closest paralog TRIM5-4, likely reflecting different fates under diverse evolutionary forces. These findings present a rare example of novel gene origination resulting from a combination of gene duplication, retrotransposition, and exon shuffling processes, providing a new paradigm to study genetic innovations and evolutionary fates of duplicated genes.