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Frontiers in Immunology 2021Neutrophils are important components of the innate immune system that mediate pathogen defense by multiple processes including phagocytosis, release of proteolytic... (Review)
Review
Neutrophils are important components of the innate immune system that mediate pathogen defense by multiple processes including phagocytosis, release of proteolytic enzymes, production of reactive oxygen species, and neutrophil extracellular trap formation. Abnormalities of neutrophil count and function have been described in the setting of HIV infection, with the majority of antiretroviral agents (ARVs), excluding zidovudine, having been reported to correct neutropenia. Questions still remain, however, about their impact on neutrophil function, particularly the possibility of persistent neutrophil activation, which could predispose people living with HIV to chronic inflammatory disorders, even in the presence of virally-suppressive treatment. In this context, the effects of protease inhibitors and integrase strand transfer inhibitors, in particular, on neutrophil function remain poorly understood and deserve further study. Besides mediating hemostatic functions, platelets are increasingly recognized as critical role players in the immune response against infection. In the setting of HIV, these cells have been found to harbor the virus, even in the presence of antiretroviral therapy (ART) potentially promoting viral dissemination. While HIV-infected individuals often present with thrombocytopenia, they have also been reported to have increased platelet activation, as measured by an upregulation of expression of CD62P (P-selectin), CD40 ligand, glycoprotein IV, and RANTES. Despite ART-mediated viral suppression, HIV-infected individuals reportedly have sustained platelet activation and dysfunction. This, in turn, contributes to persistent immune activation and an inflammatory vascular environment, seemingly involving neutrophil-platelet-endothelium interactions that increase the risk for development of comorbidities such as cardiovascular disease (CVD) that has become the leading cause of morbidity and mortality in HIV-infected individuals on treatment, clearly underscoring the importance of unraveling the possible etiologic roles of ARVs. In this context, abacavir and ritonavir-boosted lopinavir and darunavir have all been linked to an increased risk of CVD. This narrative review is therefore focused primarily on the role of neutrophils and platelets in HIV transmission and disease, as well as on the effect of HIV and the most common ARVs on the numbers and functions of these cells, including neutrophil-platelet-endothelial interactions.
Topics: Animals; Anti-HIV Agents; Blood Platelets; HIV; HIV Infections; Host-Pathogen Interactions; Humans; Neutrophil Activation; Neutrophils; Platelet Activation; Treatment Outcome
PubMed: 33777022
DOI: 10.3389/fimmu.2021.634386 -
ACS Nano May 2022The COVID-19 pandemic has been inflicted upon humanity by the SARS-CoV-2 virus, the latest insidious incarnation of the coronaviruses group. While in its wake intense... (Review)
Review
The COVID-19 pandemic has been inflicted upon humanity by the SARS-CoV-2 virus, the latest insidious incarnation of the coronaviruses group. While in its wake intense scientific research has produced breakthrough vaccines and cures, there still exists an immediate need to further understand the origin, mechanobiology and biochemistry, and destiny of this virus so that future pandemics arising from similar coronaviruses may be contained more effectively. In this Perspective, we discuss the various evidential findings of virus propagation and connect them to respective underpinning cellular biomechanical states leading to corresponding manifestations of the viral activity. We further propose avenues to tackle the virus, including from a "musical" vantage point, and contain its relentless strides that are currently afflicting the global populace.
Topics: Humans; COVID-19; Pandemics; SARS-CoV-2; Music; Antiviral Agents
PubMed: 35512182
DOI: 10.1021/acsnano.1c11491 -
The New England Journal of Medicine Sep 2022Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as... (Comparative Study)
Comparative Study
BACKGROUND
Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited.
METHODS
We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results.
RESULTS
Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar.
CONCLUSIONS
Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).
Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Cobicistat; Cohort Studies; Darunavir; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Infant, Newborn; Oxazines; Piperazines; Pregnancy; Premature Birth; Pyridones; Quinolones; Raltegravir Potassium; Rilpivirine; Ritonavir; United States
PubMed: 36053505
DOI: 10.1056/NEJMoa2200600 -
Clinical Pharmacokinetics Sep 2023The life expectancy of people living with HIV (PLWHIV) has significantly improved in recent decades, mostly due to antiretroviral (ARV) therapy. Aging can affect the...
BACKGROUND AND OBJECTIVE
The life expectancy of people living with HIV (PLWHIV) has significantly improved in recent decades, mostly due to antiretroviral (ARV) therapy. Aging can affect the pharmacokinetics of drugs and, as a consequence, increase the risk of drug interactions and toxicity that may impact treatment. The aim of this study was to carry out a systematic review of the literature on the effect of aging on ARV pharmacokinetics.
METHODS
Searches were performed in the BVS, EMBASE and PUBMED databases until November 2022. All studies available in English, Spanish and Portuguese investigating the pharmacokinetics of ARV approved by the US Food and Drug Administration (FDA) from 2005 to 2020 were selected. Peer-reviewed publications were included if they met all criteria: adults (≥ 18 years of age) living with or without HIV; report any pharmacokinetic parameter or plasma concentration of at least one of the following ARVs: tenofovir alafenamide fumarate (TAF); doravirine (DOR), rilpivirine (RIL) and etravirine (ETR); darunavir (DRV), tipranavir (TPV) and fostemsavir (FTR); dolutegravir (DTG), raltegravir (RAL), bictegravir (BIC) and elvitegravir (EVG); maraviroc (MVC); ibalizumab (IBA); cobicistat (COBI). Pharmacokinetic parameters were reported stratified per age group: young adults (aged 18-49 years) or older (age ≥ 50 years) and all studies were evaluated for quality. The review protocol was registered in the PROSPERO database (registration number CRD42021236432).
RESULTS
Among 97 studies included, 20 reported pharmacokinetic evaluation in older individuals (age ≥ 50 years). Twenty five percent of the articles were phase I randomized clinical trials with HIV-negative participants and non-compartmental pharmacokinetic analysis presenting the parameters area under the curve (AUC) and peak drug concentration (C). Seven age-stratified studies evaluated BIC, ETR, DRV, DTG, DOR and RAL. We found publications with discordant results for ETR and DTG pharmacokinetics in different age groups. DRV exposure was highly variable but modestly increased in aging PLWHIV. In contrast, no influence of age on BIC, DOR and RAL exposure was observed. A variability in pharmacokinetic parameters could be observed for the other ARVs (TAF and MVC) in different age groups.
CONCLUSION
Exposure to DRV increases modestly with age, while exposure to BIC, DOR and RAL appears to be unaffected by age. As the available evidence to confirm a potential effect of aging on ARV pharmacokinetics is limited, further studies are necessary.
Topics: Young Adult; Humans; Aged; Adolescent; Anti-HIV Agents; Tenofovir; Pharmaceutical Preparations; Anti-Retroviral Agents; HIV Infections; Raltegravir Potassium; Adenine; Darunavir
PubMed: 37561283
DOI: 10.1007/s40262-023-01291-x -
Chemical Communications (Cambridge,... Oct 2022We report our recent development of a conceptually new generation of exceptionally potent non-peptidic HIV-1 protease inhibitors that displayed excellent pharmacological... (Review)
Review
We report our recent development of a conceptually new generation of exceptionally potent non-peptidic HIV-1 protease inhibitors that displayed excellent pharmacological and drug-resistance profiles. Our X-ray structural studies of darunavir and other designed inhibitors from our laboratories led us to create a variety of inhibitors incorporating fused ring polycyclic ethers and aromatic heterocycles to promote hydrogen bonding interactions with the backbone atoms of HIV-1 protease as well as van der Waals interactions with residues in the S2 and S2' subsites. We have also incorporated specific functionalities to enhance van der Waals interactions in the S1 and S1' subsites. The combined effects of these structural templates are critical to the inhibitors' exceptional potency and drug-like properties. We highlight here our molecular design strategies to promote backbone hydrogen bonding interactions to combat drug-resistance and specific design of polycyclic ether templates to mimic peptide-like bonds in the HIV-1 protease active site. Our medicinal chemistry and drug development efforts led to the development of new generation inhibitors significantly improved over darunavir and displaying unprecedented antiviral activity against multidrug-resistant HIV-1 variants.
Topics: Darunavir; HIV-1; HIV Protease Inhibitors; Ether; Drug Design; HIV Protease; Drug Resistance; Peptides; Crystallography, X-Ray; Drug Resistance, Viral
PubMed: 36200462
DOI: 10.1039/d2cc04541a -
Journal of Clinical Pharmacology May 2021Although people living with human immunodeficiency virus and other comorbidities are expected to experience more grievous consequences with corona virus disease 2019... (Review)
Review
Although people living with human immunodeficiency virus and other comorbidities are expected to experience more grievous consequences with corona virus disease 2019 (COVID-19), recent cohort studies did not indicate this. Antiretrovirals (ARVs) might have a prophylactic role in these patients. The purpose of this study was to review the most recently published articles on the possible role of ARVs for pre- or postexposure prophylaxis against COVID-19. From June to October 2020, we searched scientific databases using specific key words to identify ongoing trials or articles published before October 2020 investigating any subgroups of ARVs for prophylaxis against COVID-19. Apart from molecular docking studies, in vitro, animal, and human studies are very limited for evaluating the prophylactic role of ARVs against severe acute respiratory syndrome-corona virus 2 (SARS-CoV-2) infection. According to our findings, there is no definite evidence to support use of protease inhibitors for this purpose, despite the promising results of molecular studies and limited clinical evidence for ritonavir-boosted lopinavir, darunavir, and nelfinavir when used early in the course of the disease. Nucleotide/nucleoside reverse-transcriptase inhibitors (NRTI) also have shown binding affinity to main enzymes of SARS-CoV-2 in molecular, in vitro, and animal studies. NRTIs like tenofovir and emtricitabine might exhibit a prophylactic role against SARS-CoV-2 infection. In conclusion, currently there is no evidence to justify the use of ARVs for prophylaxis against COVID-19.
Topics: Animals; Anti-Retroviral Agents; COVID-19; Cohort Studies; Humans; Molecular Docking Simulation; Post-Exposure Prophylaxis; Reverse Transcriptase Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33217030
DOI: 10.1002/jcph.1788 -
Acta Pharmaceutica (Zagreb, Croatia) Mar 2022The epidemic of the novel coronavirus disease (COVID-19) that started in 2019 has evoked an urgent demand for finding new potential therapeutic agents. In this study, we...
The epidemic of the novel coronavirus disease (COVID-19) that started in 2019 has evoked an urgent demand for finding new potential therapeutic agents. In this study, we performed a molecular docking of anti-HIV drugs to refine HIV protease inhibitors and nucleotide analogues to target COVID-19. The evaluation was based on docking scores calculated by AutoDock Vina and top binding poses were analyzed. Our results suggested that lopinavir, darunavir, atazanavir, remdesivir, and tipranavir have the best binding affinity for the 3-chymotrypsin-like protease of COVID-19. The comparison of the binding sites of three drugs, namely, darunavir, atazanavir and remdesivir, showed an overlap region of the protein pocket. Our study showed a strong affinity between lopinavir, darunavir, atazanavir, tipranavir and COVID-19 protease. However, their efficacy should be confirmed by studies since there are concerns related to interference with their active sites.
Topics: Humans; Lopinavir; Darunavir; Atazanavir Sulfate; Molecular Docking Simulation; Peptide Hydrolases; COVID-19; Protease Inhibitors; Antiviral Agents
PubMed: 36651526
DOI: 10.2478/acph-2022-0010 -
Journal of Biomolecular Structure &... May 2021Coronavirus disease strain (SARS-CoV-2) was discovered in 2019, and it is spreading very fast around the world causing the disease Covid-19. Currently, more than 1.6...
Coronavirus disease strain (SARS-CoV-2) was discovered in 2019, and it is spreading very fast around the world causing the disease Covid-19. Currently, more than 1.6 million individuals are infected, and several thousand are dead across the globe because of Covid-19. Here, we utilized the approaches to identify possible protease inhibitors against SARS-CoV-2. Potential compounds were screened from the CHEMBL database, ZINC database, FDA approved drugs and molecules under clinical trials. Our study is based on 6Y2F and 6W63 co-crystallized structures available in the protein data bank (PDB). Seven hundred compounds from ZINC/CHEMBL databases and fourteen hundred compounds from drug-bank were selected based on positive interactions with the reported binding site. All the selected compounds were subjected to standard-precision (SP) and extra-precision (XP) mode of docking. Generated docked poses were carefully visualized for known interactions within the binding site. Molecular mechanics-generalized born surface area (MM-GBSA) calculations were performed to screen the best compounds based on docking scores and binding energy values. Molecular dynamics (MD) simulations were carried out on four selected compounds from the CHEMBL database to validate the stability and interactions. MD simulations were also performed on the PDB structure 6YF2F to understand the differences between screened molecules and co-crystallized ligand. We screened 300 potential compounds from various databases, and 66 potential compounds from FDA approved drugs. Cobicistat, ritonavir, lopinavir, and darunavir are in the top screened molecules from FDA approved drugs. The screened drugs and molecules may be helpful in fighting with SARS-CoV-2 after further studies.Communicated by Ramaswamy H. Sarma.
Topics: Antiviral Agents; COVID-19; Humans; Molecular Docking Simulation; Peptides; SARS-CoV-2
PubMed: 32306822
DOI: 10.1080/07391102.2020.1757510 -
British Journal of Clinical Pharmacology Mar 2023Antiretroviral (ARV) therapy reduces inflammation and immune activation in people with HIV, but not down to the levels observed in people without HIV. Limited drug...
AIMS
Antiretroviral (ARV) therapy reduces inflammation and immune activation in people with HIV, but not down to the levels observed in people without HIV. Limited drug penetration within tissues has been argued as a potential mechanism of persistent inflammation. Data on the inflammation role on ARV plasma/intracellular (IC) pharmacokinetics (PK) through to expression of cytochrome P450 3A/membrane transporters are limited. The aim of this study was to investigate the correlation between inflammation markers (IM) and plasma/IC PK of ARV regimen in HIV-positive patients.
METHODS
We included ART-experienced patients switching to three different ARV regimens. Plasma and IC ARV drug concentration means at the end of dosing interval (T ), IM on samples concomitantly with ARV PK determination: sCD14, CRP, IL-6 and LPS were analysed.
RESULTS
Plasma and IC drug concentrations were measured in 60 samples. No significative differences between CRP, sCD14, IL-6 and LPS values in the three arms were observed. A significant inverse correlation between tenofovir plasma concentration and sCD14 (rho = -0.79, P < .001), and between DRV IC/plasma ratio and Log IL-6 concentrations (rho = -0.36, P = .040), and a borderline statistically significant positive trend between DRV plasma concentration and sCD14 (rho = 0.31, P = .070) were suggested. Furthermore, a borderline statistically significant inverse trend between DTG IC concentrations and sCD14 (rho = -0.34, P = .090) was observed in 24 patients on DTG-based triple therapy.
CONCLUSIONS
Our preliminary data support the hypothesis of lower DRV and DTG IC concentrations and lower TFV plasma exposure in patients with higher plasma IM suggesting an interplay between HIV drug penetration and persistent inflammation in cART-treated HIV-positive patients.
Topics: Humans; Tenofovir; Emtricitabine; Darunavir; Anti-HIV Agents; Lipopolysaccharide Receptors; Interleukin-6; Lipopolysaccharides; HIV Infections; Inflammation
PubMed: 36115063
DOI: 10.1111/bcp.15538 -
Drug Discoveries & Therapeutics May 2020The virus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is currently affecting more than 200 countries and territories worldwide. It has been declared as... (Review)
Review
The virus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is currently affecting more than 200 countries and territories worldwide. It has been declared as pandemic by World Health Organization (WHO) and the whole world is suffering from corona virus disease 2019 (COVID-19). Currently, no treatment for SARS-CoV-2 are approved because of lack of evidence, but a number of clinical trials are in process and we are expecting fruitful results very soon. This review focuses on various approaches of treatment and few of the most recent clinical trials carried out in this field.
Topics: Adenosine Monophosphate; Alanine; Amides; Antibodies, Monoclonal, Humanized; Antiviral Agents; Betacoronavirus; COVID-19; Chloroquine; Clinical Trials as Topic; Coronavirus Infections; Darunavir; Drug Combinations; Humans; Hydroxychloroquine; Immunization, Passive; Indoles; Interferon-alpha; Interferon-beta; Lopinavir; Pandemics; Pneumonia, Viral; Pyrazines; Ritonavir; SARS-CoV-2; COVID-19 Drug Treatment; COVID-19 Serotherapy
PubMed: 32336723
DOI: 10.5582/ddt.2020.03008