human immunodeficiency viruses
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mBio ◽  
2022 ◽  
Author(s):  
Geraldine Vilmen ◽  
Anna C. Smith ◽  
Hector Cervera Benet ◽  
Rajni Kant Shukla ◽  
Ross C. Larue ◽  
...  

Rhesus macaques are a critical animal model for preclinical testing of HIV-1 vaccine and prevention approaches. However, HIV-1 does not replicate in rhesus macaques, and thus, chimeric simian-human immunodeficiency viruses (SHIVs), which encode HIV-1 envelope glycoproteins (Envs), are used as surrogate challenge viruses to infect rhesus macaques for modeling HIV-1 infection.


2021 ◽  
Author(s):  
Fanny Momboisse ◽  
Giacomo Nardi ◽  
Philippe Colin ◽  
Melanie Hery ◽  
Nelia Cordeiro ◽  
...  

G protein-coupled receptors (GPCR) are present at the cell surface in different conformational and oligomeric states. However, how these states impact GPCRs biological function and therapeutic targeting remains incompletely known. Here, we investigated this issue in living cells for the CC chemokine receptor 5 (CCR5), a major receptor in inflammation and the principal entry co-receptor for Human Immunodeficiency Viruses (HIV-1). We used TIRF microscopy and an original statistical method to track and classify the motion of different receptors subpopulations. We showed a diversity of ligand-free forms of CCR5 at the cell surface constituted of various oligomeric states and exhibiting transient Brownian and restricted motions. These forms were stabilized differently by distinct ligands. In particular, agonist stimulation restricted the mobility of CCR5 and led to its clustering, a feature depending on b-arrestin, while inverse agonist stimulation exhibited the opposite effect. These results suggest a link between receptor activation and immobilization. Applied to HIV-1 envelope glycoproteins gp120, our quantitative analysis revealed agonist-like properties of gp120s. Distinct gp120s influenced CCR5 dynamics differently, suggesting that they stabilize different CCR5 conformations. Then, using a dimerization-compromized mutant, we showed that dimerization (i) impacts CCR5 precoupling to G proteins, (ii) is a pre-requisite for the immobilization and clustering of receptors upon activation, and (iii) regulates receptor endocytosis, thereby impacting the fate of activated receptors. This study demonstrates that tracking the dynamic behavior of a GPCR is an efficient way to link GPCR conformations to their functions, therefore improving the development of drugs targeting specific receptor conformations.


2021 ◽  
pp. 096228022110605
Author(s):  
Xiaorui Wang ◽  
Guoyou Qin ◽  
Xinyuan Song ◽  
Yanlin Tang

Censored quantile regression has elicited extensive research interest in recent years. One class of methods is based on an informative subset of a sample, selected via the propensity score. Propensity score can either be estimated using parametric methods, which poses the risk of misspecification or obtained using nonparametric approaches, which suffer from “curse of dimensionality.” In this study, we propose a new estimation method based on multiply robust propensity score for censored quantile regression. This method only requires one of the multiple candidate models for propensity score to be correctly specified, and thus, it provides a certain level of resistance to the misspecification of parametric models. Large sample properties, such as the consistency and asymptotic normality of the proposed estimator, are thoroughly investigated. Extensive simulation studies are conducted to assess the performance of the proposed estimator. The proposed method is also applied to a study on human immunodeficiency viruses.


Immuno ◽  
2021 ◽  
Vol 1 (4) ◽  
pp. 468-498
Author(s):  
Pedro A. Reyes-Castillo ◽  
Raquel González-Vázquez ◽  
Edgar Torres-Maravilla ◽  
Mario Tello ◽  
Luis G. Bermúdez-Humarán ◽  
...  

Viral infections represent a major health problem worldwide. Due to the wide variety of etiological agents and their increasing resistance to anti-virals and antibiotics treatments, new strategies for effective therapies need to be developed. Scientific evidence suggests that probiotics may have prophylactic and therapeutic effects in viral diseases. Indeed, these microorganisms interact harmoniously with the intestinal microbiota and protect the integrity of the intestinal barrier as well as modulate the host immune system. Currently, clinical trials with probiotics have been documented in respiratory tract infections, infections caused by human immunodeficiency viruses, herpes, human papillomavirus and hepatic encephalopathy. However, the benefits documented so far are difficult to extrapolate, due to the strain-dependent effect. In addition, the dose of the microorganism used as well as host characteristics are other parameters that should be consider when advocating the use of probiotics to treat viral infections. This review addresses the scientific evidence of the efficacy of probiotics in clinical strains perspective in viral infectious diseases in the last 10 years.


Author(s):  
Ghazwan Butrous

December. 1st 2021 is "World AIDS Day" reminding us that HIV infection is still widespread and that many of its long-term effects can be deadly. One of these complications is its effect on the pulmonary vascular beds, leading to an increase in the pulmonary pressure, causing the clinical manifestation of "pulmonary hypertension". Unfortunately, we are still far from fully understanding the prevalence, mechanics, and pathobiology of "HIV pulmonary hypertension", especially in Africa and other developing countries where HIV is still common. In addition, the impact of other factors like co-infection and illicit drugs can add and modify the effect on the pulmonary vascular bed, complicating the pathological and clinical effects of HIV. Thus, "World AIDS Day" can be an impetus to pursue further research in this area.


Author(s):  
Silvana Larrea-Schiavon ◽  
Celia Hubert ◽  
René Leyva-Flores ◽  
Jacqueline M. Sánchez-Domínguez ◽  
Juan Pablo Ramírez-Hinojosa ◽  
...  

2021 ◽  
Vol 17 (10) ◽  
pp. e1009609
Author(s):  
Michaël M. Martin ◽  
Roy Matkovic ◽  
Pauline Larrous ◽  
Marina Morel ◽  
Angélique Lasserre ◽  
...  

Human Immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) succeed to evade host immune defenses by using their viral auxiliary proteins to antagonize host restriction factors. HIV-2/SIVsmm Vpx is known for degrading SAMHD1, a factor impeding the reverse transcription. More recently, Vpx was also shown to counteract HUSH, a complex constituted of TASOR, MPP8 and periphilin, which blocks viral expression from the integrated viral DNA. In a classical ubiquitin ligase hijacking model, Vpx bridges the DCAF1 ubiquitin ligase substrate adaptor to SAMHD1, for subsequent ubiquitination and degradation. Here, we investigated whether the same mechanism is at stake for Vpx-mediated HUSH degradation. While we confirm that Vpx bridges SAMHD1 to DCAF1, we show that TASOR can interact with DCAF1 in the absence of Vpx. Nonetheless, this association was stabilized in the presence of Vpx, suggesting the existence of a ternary complex. The N-terminal PARP-like domain of TASOR is involved in DCAF1 binding, but not in Vpx binding. We also characterized a series of HIV-2 Vpx point mutants impaired in TASOR degradation, while still degrading SAMHD1. Vpx mutants ability to degrade TASOR correlated with their capacity to enhance HIV-1 minigenome expression as expected. Strikingly, several Vpx mutants impaired for TASOR degradation, but not for SAMHD1 degradation, had a reduced binding affinity for DCAF1, but not for TASOR. In macrophages, Vpx R34A-R42A and Vpx R42A-Q47A-V48A, strongly impaired in DCAF1, but not in TASOR binding, could not degrade TASOR, while being efficient in degrading SAMHD1. Altogether, our results highlight the central role of a robust Vpx-DCAF1 association to trigger TASOR degradation. We then propose a model in which Vpx interacts with both TASOR and DCAF1 to stabilize a TASOR-DCAF1 complex. Furthermore, our work identifies Vpx mutants enabling the study of HUSH restriction independently from SAMHD1 restriction in primary myeloid cells.


Author(s):  
Stanislav Bondarenko ◽  
Per Kjærsgaard-Andersen ◽  
Valentyna Maltseva ◽  
Ahmed Badnaoui

Nowadays total hip arthroplasty (THA) is one of the most successful surgical procedures in the world and the number of procedures performed is growing every year. However, its success largely depends on the absence of postoperative complications. Among the risk factors affecting the occurrence of postoperative complications are smoking, alcohol abuse, drug abuse, human immunodeficiency viruses (HIV), obesity, anemia, diabetes mellitus, malnutrition, rheumatoid arthritis, cardiovascular diseases, renal failure and dialysis, depression and anxiety. In the presented manuscript, such factors as HIV, smoking and alcohol abuse were considered. In smokers, bone regeneration slows down due to impaired bone metabolism and a slowdown in vascular recovery. Alcohol abuse affects human immunity, inhibiting T-helper cells, and also causing blood coagulation disorders. Alcohol abuse increases the risk of hospital complications, surgery related complications and general medical complications. Smoking can increase the risk of septiccomplications (lower respiratory tract infection, sepsis, urinary tract infection), myocardial infarction, risk of aseptic loosening of implants. Mortality was also higher in smokers compared to nonsmokers. HIV increases bone fragility, debilitation, rate of cardiovascular diseases and decreases the number of CD4+ cells in the blood, which directly affects the risk of periprosthetic joint infections and revision. All three factors increase the patient's lengthof stay in the hospital after THA. Currently, recommendations have been developed for preventive measures that need to be taken to reduce the risk of postoperative complications by performing primary THA. According to the recommendations, quitting smoking and drinking alcohol 4 weeks before THA will significantly reduce the risk of postoperative complications. For HIV-positive patients, antiretroviral therapy and subsequent assessing the viral load arerequired prior to THA. Preoperative care in this category of patients, undergoing primary THA, can reduce the risk of complications.


Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 953
Author(s):  
Chuan Xu ◽  
Annie Wang ◽  
Ke Geng ◽  
William Honnen ◽  
Xuening Wang ◽  
...  

Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2), the causative agent of coronavirus disease 19 (COVID-19), enters cells through attachment to the human angiotensin converting enzyme 2 (hACE2) via the receptor-binding domain (RBD) in the surface/spike (S) protein. Several pseudotyped viruses expressing SARS-CoV-2 S proteins are available, but many of these can only infect hACE2-overexpressing cell lines. Here, we report the use of a simple, two-plasmid, pseudotyped virus system comprising a SARS-CoV-2 spike-expressing plasmid and an HIV vector with or without vpr to investigate the SARS-CoV-2 entry event in various cell lines. When an HIV vector without vpr was used, pseudotyped SARS-CoV-2 viruses produced in the presence of fetal bovine serum (FBS) were able to infect only engineered hACE2-overexpressing cell lines, whereas viruses produced under serum-free conditions were able to infect a broader range of cells, including cells without hACE2 overexpression. When an HIV vector containing vpr was used, pseudotyped viruses were able to infect a broad spectrum of cell types regardless of whether viruses were produced in the presence or absence of FBS. Infection sensitivities of various cell types did not correlate with mRNA abundance of hACE2, TMPRSS2, or TMPRSS4. Pseudotyped SARS-CoV-2 viruses and replication-competent SARS-CoV-2 virus were equally sensitive to neutralization by an anti-spike RBD antibody in cells with high abundance of hACE2. However, the anti-spike RBD antibody did not block pseudotyped viral entry into cell lines with low abundance of hACE2. We further found that CD147 was involved in viral entry in A549 cells with low abundance of hACE2. Thus, our assay is useful for drug and antibody screening as well as for investigating cellular receptors, including hACE2, CD147, and tyrosine-protein kinase receptor UFO (AXL), for the SARS-CoV-2 entry event in various cell lines.


2021 ◽  
Author(s):  
Michaël M Martin ◽  
Roy Matkovic ◽  
Pauline Larrous ◽  
Marina Morel ◽  
Angélique Lasserre ◽  
...  

Human Immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) succeed to evade host immune defenses by using their viral auxiliary proteins to antagonize host restriction factors. HIV-2/SIVsmm Vpx is known for degrading SAMHD1, a factor impeding the reverse transcription. More recently, Vpx was also shown to counteract HUSH, a complex constituted of TASOR, MPP8 and periphilin, which blocks viral expression from the integrated viral DNA. In a classical ubiquitin ligase hijacking model, Vpx bridges the DCAF1 ubiquitin ligase substrate adaptor to SAMHD1, for subsequent ubiquitination and degradation. Here, we investigated whether the same mechanism is at stake for Vpx-mediated HUSH degradation. While we confirm that Vpx bridges SAMHD1 to DCAF1, we show that TASOR can interact with DCAF1 in the absence of Vpx. Nonetheless, this association was stabilized in the presence of Vpx, suggesting the existence of a ternary complex. The N-terminal PARP-like domain of TASOR is involved in DCAF1 binding, but not in Vpx binding. We also characterized a series of HIV-2 Vpx point mutants impaired in TASOR degradation, while still degrading SAMHD1. Vpx mutants ability to degrade TASOR correlated with their capacity to enhance HIV-1 minigenome expression as expected. Strikingly, several Vpx mutants impaired for TASOR degradation, but not for SAMHD1 degradation, had a reduced binding affinity for DCAF1, but not for TASOR. In macrophages, Vpx R34A-R42A and Vpx R42A-Q47A-V48A, strongly impaired in DCAF1, but not in TASOR binding, could not degrade TASOR, while being efficient in degrading SAMHD1. Altogether, our results highlight the central role of a robust Vpx-DCAF1 association to trigger TASOR degradation. We then propose a model in which Vpx interacts with both TASOR and DCAF1 to stabilize a TASOR-DCAF1 complex. Furthermore, our work identifies Vpx mutants enabling the study of HUSH restriction independently from SAMHD1 restriction in primary myeloid cells.


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