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3.
Signal Transduct Target Ther ; 6(1): 328, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471088

RESUMO

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.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Microambiente Celular/imunologia , Pulmão/imunologia , Receptores CXCR3/imunologia , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/patologia , Interferon-alfa/imunologia , Interleucina-6/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta , Masculino
4.
Zool Res ; 42(5): 633-636, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34423606

RESUMO

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)-1ß 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.


Assuntos
Anti-Hipertensivos/uso terapêutico , COVID-19/complicações , Captopril/uso terapêutico , Hipertensão/complicações , Pneumopatias/tratamento farmacológico , SARS-CoV-2 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Captopril/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/complicações , Inflamação/tratamento farmacológico , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Pneumopatias/etiologia , Pneumopatias/virologia , Camundongos , Replicação Viral/efeitos dos fármacos
5.
Cell Res ; 31(8): 847-860, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34112954

RESUMO

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.


Assuntos
Antivirais/metabolismo , COVID-19/patologia , Proteínas do Envelope de Coronavírus/metabolismo , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Antivirais/química , Antivirais/uso terapêutico , Apoptose , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/virologia , Proteínas do Envelope de Coronavírus/antagonistas & inibidores , Proteínas do Envelope de Coronavírus/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Meia-Vida , Humanos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese Sítio-Dirigida , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/patogenicidade , Baço/metabolismo , Baço/patologia , Carga Viral , Virulência
6.
Zool Res ; 42(3): 350-353, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-33998182

RESUMO

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has become an unprecedented global health emergency. At present, SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 research. Here, we showed that northern pig-tailed macaques ( Macaca leonina, NPMs) supported SARS-CoV-2 replication. Furthermore, compared with rhesus macaques, NPMs showed rapid viral clearance in lung tissues, nose swabs, throat swabs, and rectal swabs, which may be due to higher expression of interferon (IFN)-α in lung tissue. However, the rapid viral clearance was not associated with good outcome. In the second week post infection, NPMs developed persistent or even more severe inflammation and body injury compared with rhesus macaques. These results suggest that viral clearance may have no relationship with COVID-19 progression and SARS-CoV-2-infected NPMs could be considered as a critically ill animal model in COVID-19 research.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Macaca nemestrina , SARS-CoV-2/imunologia , Animais , Modelos Animais de Doenças , Interferon-alfa/análise , Interleucina-1beta/análise , Interleucina-6/análise , Pulmão/imunologia , Pulmão/virologia , Nariz/virologia , Faringe/virologia , RNA Viral/análise , Reto/virologia , SARS-CoV-2/genética
7.
Zool Res ; 42(3): 335-338, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-33998180

RESUMO

The global outbreak of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as of 8 May 2021, has surpassed 150 700 000 infections and 3 279 000 deaths worldwide. Evidence indicates that SARS-CoV-2 RNA can be detected on particulate matter (PM), and COVID-19 cases are correlated with levels of air pollutants. However, the mechanisms of PM involvement in the spread of SARS-CoV-2 remain poorly understood. Here, we found that PM exposure increased the expression level of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) in several epithelial cells and increased the adsorption of the SARS-CoV-2 spike protein. Instillation of PM in a hACE2 mouse model significantly increased the expression of ACE2 and Tmprss2 and viral replication in the lungs. Furthermore, PM exacerbated the pulmonary lesions caused by SARS-CoV-2 infection in the hACE2 mice. In conclusion, our study demonstrated that PM is an epidemiological factor of COVID-19, emphasizing the necessity of wearing anti-PM masks to cope with this global pandemic.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/induzido quimicamente , COVID-19/imunologia , Material Particulado/efeitos adversos , SARS-CoV-2 , Adsorção/efeitos dos fármacos , Animais , Suscetibilidade a Doenças/induzido quimicamente , Suscetibilidade a Doenças/imunologia , Células Epiteliais/metabolismo , Camundongos , Camundongos Endogâmicos , Material Particulado/química , RNA Viral/análise , SARS-CoV-2/genética , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus/efeitos dos fármacos
8.
Science ; 371(6536): 1374-1378, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33602867

RESUMO

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.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Animais , Antivirais/química , Antivirais/uso terapêutico , COVID-19/patologia , COVID-19/virologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CXCL10/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Interferon beta/metabolismo , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Transgênicos , Oligopeptídeos , Prolina/análogos & derivados , Inibidores de Proteases/química , Inibidores de Proteases/uso terapêutico , Inibidores de Proteases/toxicidade , Ratos , Ratos Sprague-Dawley , Carga Viral/efeitos dos fármacos , Replicação Viral
9.
Cell Res ; 31(1): 17-24, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262453

RESUMO

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.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Teicoplanina/análogos & derivados , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Células CACO-2 , Chlorocebus aethiops , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Ligação Proteica/efeitos dos fármacos , Teicoplanina/farmacocinética , Teicoplanina/farmacologia , Células Vero
10.
Zool Res ; 41(5): 503-516, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32772513

RESUMO

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.


Assuntos
Envelhecimento/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Macaca mulatta/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Fatores Etários , Envelhecimento/metabolismo , Animais , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Inflamação/imunologia , Inflamação/veterinária , Inflamação/virologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta/virologia , Doenças dos Macacos/imunologia , Doenças dos Macacos/virologia , Pandemias/veterinária , Pneumonia Viral/veterinária , Pneumonia Viral/virologia , SARS-CoV-2 , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/veterinária , Síndrome Respiratória Aguda Grave/virologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Carga Viral/imunologia , Carga Viral/veterinária , Replicação Viral/imunologia
11.
Arch Virol ; 164(5): 1353-1360, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30859472

RESUMO

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.


Assuntos
Desaminase APOBEC-3G/genética , Desaminase APOBEC-3G/metabolismo , HIV-2/genética , Replicação Viral/genética , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , China , Citosina Desaminase/genética , Células HEK293 , HIV-2/crescimento & desenvolvimento , Humanos , Macaca mulatta , Polimorfismo Genético/genética , Alinhamento de Sequência , Ubiquitinação
12.
Mol Immunol ; 101: 627-634, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30170890

RESUMO

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-ß 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-ß 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.


Assuntos
Aotidae/metabolismo , Proteínas de Transporte/metabolismo , Ciclofilina A/metabolismo , Macaca/metabolismo , NF-kappa B/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Transporte/química , Células HEK293 , Humanos , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Fosforilação , Domínios Proteicos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo , Transcrição Genética
13.
Sci China Life Sci ; 61(8): 954-965, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29705873

RESUMO

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.


Assuntos
HIV-1/imunologia , Vírus da Leucemia Murina/imunologia , Macaca/imunologia , Proteínas Mutantes Quiméricas/imunologia , Infecções por Retroviridae/imunologia , Animais , Gatos , Linhagem Celular , Ciclofilina A/genética , Ciclofilina A/imunologia , Ciclofilina A/metabolismo , Expressão Gênica/imunologia , Células HEK293 , HIV-1/fisiologia , Humanos , Vírus da Leucemia Murina/fisiologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Macaca/virologia , Camundongos , Proteínas Mutantes Quiméricas/genética , Proteínas Mutantes Quiméricas/metabolismo , Proteínas/genética , Proteínas/imunologia , Proteínas/metabolismo , Interferência de RNA/imunologia , Infecções por Retroviridae/virologia , Ubiquitina-Proteína Ligases
14.
Microbes Infect ; 19(4-5): 288-294, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28104465

RESUMO

Heroin use is associated with increased incidence of infectious diseases such as HIV-1 infection, as a result of immunosuppression to a certain extent. Host restriction factors are recently identified cellular proteins with potent antiviral activities. Whether heroin use impacts on the in vivo expression of restriction factors that result in facilitating HIV-1 replication is poorly understood. Here we recruited 432 intravenous drug users (IDUs) and 164 non-IDUs at high-risk behaviors. Based on serological tests, significantly higher prevalence of HIV-1 infection was observed among IDUs compared with non-IDUs. We included those IDUs and non-IDUs without HIV-1 infection, and found IDUs had significantly lower levels of TRIM5α, TRIM22, APOBEC3G, and IFN-α, -ß expression than did non-IDUs. We also directly examined plasma viral load in HIV-1 mono-infected IDUs and non-IDUs and found HIV-1 mono-infected IDUs had significantly higher plasma viral load than did non-IDUs. Moreover, intrinsically positive correlation between type I interferon and TRIM5α or TRIM22 was observed, however, which was dysregulated following heroin use. Collectively, heroin use benefits HIV-1 replication that may be partly due to suppression of host restriction factors and type I interferon expression.


Assuntos
HIV-1/crescimento & desenvolvimento , Heroína/farmacologia , Interferon-alfa/sangue , Interferon beta/sangue , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Desaminase APOBEC-3G/sangue , Adulto , Proteínas de Transporte/sangue , Feminino , Infecções por HIV/virologia , Dependência de Heroína/fisiopatologia , Humanos , Imunossupressão , Masculino , Antígenos de Histocompatibilidade Menor/sangue , Proteínas Repressoras/sangue , Proteínas com Motivo Tripartido/sangue , Ubiquitina-Proteína Ligases
15.
Arch Virol ; 161(11): 3019-27, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27491414

RESUMO

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.


Assuntos
Antivirais/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Fatores Imunológicos/metabolismo , Lipopolissacarídeos/metabolismo , Macrófagos/virologia , Transcrição Reversa/efeitos dos fármacos , Linhagem Celular , Humanos , Vesiculovirus/fisiologia
16.
Infect Dis Poverty ; 5(1): 73, 2016 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-27502491

RESUMO

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.


Assuntos
Usuários de Drogas/estatística & dados numéricos , Uso Comum de Agulhas e Seringas/estatística & dados numéricos , Adolescente , Adulto , Idoso , China , Estudos Transversais , Feminino , Redução do Dano , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Assunção de Riscos , Adulto Jovem
18.
Mol Neurobiol ; 53(6): 3873-3881, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26162319

RESUMO

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.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , DNA Mitocondrial/genética , Predisposição Genética para Doença , Infecções por HIV/genética , HIV-1/fisiologia , Haplótipos/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Estudos de Casos e Controles , China , Feminino , Variação Genética , Células HeLa , Humanos , Masculino , Análise de Componente Principal , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco , Abuso de Substâncias por Via Intravenosa/genética , Carga Viral/genética
19.
Virology ; 487: 222-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26550946

RESUMO

Because of the difficulty of obtaining Indian-origin rhesus macaques, Chinese-origin rhesus macaques (CR) and Vietnamese-origin cynomolgus macaques (CM) are now used frequently in HIV/AIDS research. Nonetheless, the effects of TRIM5α polymorphism on viral replication in both CR and CM are unclear. To address these questions, we recruited 70 unrelated CR and 40 unrelated CM and studied the effect of TRIM5α polymorphism on HIV-2ROD and SIVmac239 replication in PBMCs. We found that 3 polymorphisms, located in the B30.2 domain of CR TRIM5α formed a haplotype and affected HIV-2ROD replication. In addition, we found that the variant Y178H, located in the Coiled-coil domain of CM TRIM5α, affected TRIM5α-mediated HIV-2ROD restriction. Finally, two polymorphisms, located in the Coiled-coil domain, altered anti-SIVmac239 activity in CR. We concluded that, CM TRIM5α polymorphism could alter HIV-2ROD infection; however, a different domain of CR TRIM5α was responsible for restricting different virus replication.


Assuntos
Proteínas de Transporte/genética , HIV-2/crescimento & desenvolvimento , Leucócitos Mononucleares/virologia , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento , Dedos de Zinco/genética , Animais , China , Modelos Animais de Doenças , Genótipo , Macaca fascicularis , Macaca mulatta , Doenças dos Macacos/virologia , Polimorfismo de Nucleotídeo Único/genética , Vietnã , Replicação Viral
20.
J Med Virol ; 88(6): 987-95, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26519943

RESUMO

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, -ß 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, -ß 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, -ß, 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.


Assuntos
Coinfecção/genética , Infecções por HIV/genética , Hepatite C Crônica/genética , Hepatite C/genética , Interações Hospedeiro-Patógeno/genética , Interferon Tipo I/genética , Desaminase APOBEC-3G/genética , Adulto , Proteínas de Transporte/genética , Coinfecção/sangue , Coinfecção/virologia , Estudos Transversais , Descoberta de Drogas , Feminino , Regulação da Expressão Gênica , Genótipo , HIV/fisiologia , Infecções por HIV/complicações , Infecções por HIV/imunologia , Infecções por HIV/virologia , Hepacivirus/fisiologia , Hepatite C/complicações , Hepatite C/imunologia , Hepatite C/virologia , Hepatite C Crônica/complicações , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Humanos , Interferon Tipo I/imunologia , Interferon-alfa/genética , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/genética , Proteínas Repressoras/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases , Carga Viral
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