HIV Protease Inhibitors Research Articles

Machine learning-based prediction of bioactivity in HIV-1 protease: insights from electron density analysis.

Aim: To develop a model for predicting the biological activity of compounds targeting the HIV-1 protease and to establish factors influencing enzyme inhibition.Materials & methods: Machine learning models were built based on a combination of Richard Bader's theory of Atoms in Molecules and topological analysis of electron density using experimental x-ray 'protein-ligand' complexes and inhibition constants data.Results & conclusion: Among all the models tested, logistic regression achieved the highest accuracy of 0.76 on the test set. The model's ability to differentiate between less active and highly active classes was relatively good, as indicated by an AUC-ROC score of 0.77. The analysis identified several critical factors affecting the biological activity of HIV-1 protease inhibitors, including the electron density contribution of hydrogen atoms, bond-critical points and particular amino acid residues. These findings provide new insights into how these molecular factors influence HIV-1 protease inhibition, emphasizing the importance of hydrogen bonding, glycine's flexibility and hydrophobic interactions in ligand binding.

Synthesis of Pyridines/Dihydropyridines via Hantzsch Reaction, Structure-activity Relationship and Interactions with Targets: A Review

Pyridines/Dihydropyridines is a basic 6-membered organic aza-heterocyclic compound that has garnered the attention of many researchers in recent times. These molecules have been reported with a diverse range of pharmacological activities like anti-coagulant, antileishmanial and anti-trypanosomal, antitubercular agents, anti-microbial, antioxidant, HIV-1 protease inhibitors, anti-cancer, cardiovascular disease, etc. This review article focuses on different protocols for the Hantzsch reaction using acid catalysts, metal catalysts, and no catalysts for the synthesis of pyridine derivatives. The structure-activity relationship in relation to other biological activities of various pyridine-containing drugs and their interaction with different targets (receptors) has also been highlighted to provide a good understanding to researchers for future research on pyridines.

A new perspective on risk factors for progressive liver fibrosis in patients with HIV, HBV, HCV superinfection

Topicality. One of the risk factors for the progression of the fibrotic process in the liver in triple superinfection with HIV/HBV/HCV may be the order of entry of viral pathogens into the human body, as well as the time interval between the entry of different pathogens. The aim of the study was to assess the effect on the course of liver fibrosis in HIV/HBV/HCV superinfection of the sequence of pathogens entering the human body and the time between superinfection.Materials and methods. 97 people with a verified diagnosis of HIV/HBV/HCV superinfection were subjected to a retrospective analysis depending on the timing of pathogen intake, the severity of liver fibrosis and antiviral therapy. Among the examined, 80% were men. The age category of 18-44 years included 84% and the remaining patients were in the category of 45–49 years. All patients received antiviral therapy. Liver fibrosis was assessed using dynamic liver elastography.Outcomes. The most favorable from the point of view of the progression of liver fibrosis was the primary HIV infection with an interval of 1–5 years between infection with hepatitis B and C viruses. The predominance of the progressive course of the fibrotic process in the liver occurred in cases where the first pathogen was HBV, and the interval between superinfection with another virus (HIV, HCV) exceeded 10 years. In cases not included in this category of patients, a HCV viral load above 1,700,000 copies/ml may be a risk factor for triple superinfection.Findings. 1. In HIV/HBV/HCV superinfection, a high risk of progressive liver fibrosis is associated with situations when: the first superinfecting pathogen is HIV at an interval of 1–5 years before superinfection with hepatitis B and/or C viruses; the first superinfecting pathogen is HBV with an interval of more than 10 years prior to HIV and/or HCV superinfection. 2. In HIV/HBV/HCV superinfection, in the absence of a priority for superinfection, a HCV viral load of more than 1700000 copies/ml may be a risk factor for advanced liver fibrosis. A rational regimen for antiretroviral therapy in triple superinfection with HIV/HBV/HCV is a combination of nucleotide inhibitors of HIV and HBV reverse transcriptase and HIV protease inhibitors.

Susceptibility of HPV-18 Cancer Cells to HIV Protease Inhibitors.

Cervical cancer cases continue to rise despite all the advanced screening and preventative measures put in place, which include human papillomavirus (HPV) vaccination. These soaring numbers can be attributed to the lack of effective anticancer drugs against cervical cancer; thus, repurposing the human immunodeficiency virus protease inhibitors is an attractive innovation. Therefore, this work was aimed at evaluating the potential anticancer activities of HIV-PIs against cervical cancer cells. The MTT viability assay was used to evaluate the effect of HIV protease inhibitors on the viability of cervical cancer cells (HeLa) and non-cancerous cells (HEK-293). Further confirmation of the MTT assay was performed by confirming the IC50s of these HIV protease inhibitors on cervical cancer cells and non-cancerous cells using the Muse™ Count and Viability assay. To confirm the mode of death induced by HIV protease inhibitors in the HPV-associated cervical cancer cell line, apoptosis was performed using Annexin V assay. In addition, the Muse™ Cell Cycle assay was used to check whether the HIV protease inhibitors promote or halt cell cycle progression in cervical cancer cells. HIV protease inhibitors did not affect the viability of non-cancerous cells (HEK-293), but they decreased the viability of HeLa cervical cancer cells in a dose-dependent manner. HIV protease inhibitors induced apoptosis in HPV-related cervical cancer cells. Furthermore, they also induced cell cycle arrest, thus halting cell cycle progression. Therefore, the use of HIV drugs, particularly HIV-1 protease inhibitors, as potential cancer therapeutics represents a promising strategy. This is supported by our study demonstrating their anticancer properties, notably in HPV-associated cervical cancer cell line.

Quantum mechanical analysis of newly synthesized HIV-1 protease inhibitors: evaluation of wild-type and resistant strain binding interactions.

Inhibition of HIV-1 protease is a cornerstone of antiretroviral therapy. However, the notorious ability of HIV-1 to develop resistance to protease inhibitors (PIs), particularly darunavir (DRV), poses a major challenge. Using quantum chemistry and computer simulations, this study aims to investigate the interactions between two novel PIs, GRL-004 and GRL-063, as well as a wild-type (WT) HIV strain and a DRV-resistant mutant strain. To do this, we used molecular docking, molecular dynamics simulations, and quantum mechanical calculations to check how well GRL-004 and GRL-063 bound to both WT and DRV-resistant proteases. The results show that GRL-004 and GRL-063 bind very well to ASP29 in the WT strain. ASP29 is an important amino acid in the HIV protease dimer. Remarkably, amino acids such as ILE50 in the WT strains showed substantial binding energies to both drugs. Quantum energy calculations showed a slight reduction in the energy affinity of the interaction between the MUT strain and the ligand GRL-063, compared to the WT strain. GRL-004 showed similar interaction energy for both strains, suggesting that it has greater plasticity than GRL-063 despite its lower interaction affinity. Furthermore, GLY49B demonstrated strong binding energies regardless of mutations. Other relevant residues with strong binding energies include GLY49B, PHE82A, PRO81A, ASP29A, ASP25A and ALA28B. This study improves our understanding of receptor-ligand dynamics and the adaptability of new protease inhibitors (PIs), which has profound implications for the innovation of future antiretroviral drugs.

Improving Predictive Efficacy for Drug Resistance in Novel HIV-1 Protease Inhibitors through Transfer Learning Mechanisms.

The human immunodeficiency virus presents a significant global health challenge due to its rapid mutation and the development of resistance mechanisms against antiretroviral drugs. Recent studies demonstrate the impressive performance of machine learning (ML) and deep learning (DL) models in predicting the drug resistance profile of specific FDA-approved inhibitors. However, generalizing ML and DL models to learn not only from isolates but also from inhibitor representations remains challenging for HIV-1 infection. We propose a novel drug-isolate-fold change (DIF) model framework that aims to predict drug resistance score directly from the protein sequence and inhibitor representation. Various ML and DL models, inhibitor representations, and protein representations were analyzed through realistic validation mechanisms. To enhance the molecular learning capacity of DIF models, we employ a transfer learning approach by pretraining a graph neural network (GNN) model for activity prediction on a data set of 4855 HIV-1 protease inhibitors (PIs). By performing various realistic validation strategies on internal and external genotype-phenotype data sets, we statistically show that the learned representations of inhibitors improve the predictive ability of DIF-based ML and DL models. We achieved an accuracy of 0.802, AUROC of 0.874, and r of 0.727 for the unseen external PIs. By comparing the DIF-based models with a null model consisting of isolate-fold change (IF) architecture, it is observed that the DIF models significantly benefit from molecular representations. Combined results from various testing strategies and statistical tests confirm the effectiveness of DIF models in testing novel PIs for drug resistance in the presence of an isolate.

Identification of steroidal cardenolides from Calotropis procera as novel HIV-1 PR inhibitors: A molecular docking & molecular dynamics simulation study.

Background & objectives Despite advancements in antiretroviral therapy, drug-resistant strains of HIV (human immunodeficiency virus) remain a global health concern. Natural compounds from medicinal plants offer a promising avenue for developing new HIV-1 PR (protease) inhibitors. This study aimed to explore the potential of compounds derived from Calotropis procera, a medicinal plant, as inhibitors of HIV-1 PR. Methods This in silico study utilized natural compound information and the crystal structure of HIV-1 PR. Molecular docking of 17 steroidal cardenolides from Calotropis procera against HIV-1 PR was performed using AutoDock 4.2 to identify compounds with higher antiviral potential. A dynamic simulation study was performed to provide insights into the stability, binding dynamics, and potential efficacy of the top potential antiviral compound as an HIV-1 therapeutic. Results We found that all tested cardenolides had higher binding affinities than Amprenavir, indicating their potential as potent HIV-1 PR inhibitors. Voruscharin and uscharidin displayed the strongest interactions, forming hydrogen bonds and hydrophobic interactions with HIV-1 PR. Voruscharin showed improved stability with lower RMSD (Root Mean Square Deviation) values and reduced fluctuations in binding site residues but increased flexibility in certain regions. The radius of gyration analysis confirmed a stable binding pose between HIV-1 PR and Voruscharin. Interpretation & conclusions These findings suggest that Calotropis procera could potentially be a source of compounds for developing novel HIV-1 PR inhibitors, contributing to the efforts to combat HIV. Further studies and clinical trials are needed to evaluate the safety and efficacy of these compounds as potential drug candidates for the treatment of HIV-1 infection.

Bioavailability enhancement of atazanavir sulphate using mixed micelles: in vitro characterization and in vivo pharmacokinetic study.

This study aims to enhance the oral bioavailability of atazanavir sulphate, a human immunodeficiency virus-1 protease inhibitor known for its poor oral absorption, by formulating mixed micelles using Soluplus® and Kolliphor HS 15. Mixed micelles were prepared through the thin film hydration technique. The micelles were characterized for particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, drug loading, and confirmed for atazanavir sulphate encapsulation via FTIR studies. In vitro release studies were conducted, and the morphology of the micelles was examined using TEM. Atazanavir sulphate mixed micelles exhibited a particle size of 62.92nm, PDI of 0.221, zeta potential of - 17.8mV, high entrapment efficiency (99.76 ± 1.06), and drug loading (14 ± 0.82). In vitro release studies demonstrated sustained release up to 12h, with maximum solubility observed at 2h under pH 1.2 conditions. TEM analysis revealed spherical micelle morphology. Oral administration of atazanavir sulphate mixed micelles showed a 1.23-fold increase in relative bioavailability compared to pure drug suspension. The formulation of mixed micelles using Soluplus® and Kolliphor HS 15 offers a promising strategy to improve the oral bioavailability of atazanavir sulphate. These findings suggest the potential utility of mixed micelles as an effective delivery system for atazanavir sulphate, offering enhanced therapeutic outcomes for patients.

Symmetrical Phosphinic Acids: Synthesis and Esterification Optimization toward Potential HIV Prodrugs.

A highly efficient method to synthesize diverse symmetrical phosphinic acids with the potential to act as pivotal candidates in the design of HIV-1 protease inhibitors has been developed. Such compounds have been designed based on the enzyme-substrate specificity, and their elongated analogues are expected to demonstrate significant inhibition against the HIV-1 protease with IC50 values in the low nanomolar range. Moreover, a highly efficient esterification protocol with carbohydrates and flavonoids has been devised to address the inherent absorption challenges associated with phosphinic-based drugs. These esters not only exhibit low toxicity but also have the potential to generate flavonoid moieties in situ, which are associated with hepatoprotective effects, or naturally occurring carbohydrate metabolites. The methodology utilizes effective peptide coupling reagents, such as aminium-based TBTU and carbodiimide-based DIC, and affords the target products in excellent to quantitative yields. This research represents a promising avenue for the development of novel HIV-1 protease inhibitors with significant therapeutic benefits.

Pharmacokinetics of once-daily darunavir/ritonavir in second-line treatment in African children with HIV.

Darunavir is a potent HIV protease inhibitor with a high barrier to resistance. We conducted a nested pharmacokinetic sub-study within CHAPAS-4 to evaluate darunavir exposure in African children with HIV, taking once-daily darunavir/ritonavir for second-line treatment. We used data from the CHAPAS-4 pharmacokinetic sub-study treating children with once-daily darunavir/ritonavir (600/100 mg if 14-24.9 kg and 800/100 mg if ≥25 kg) with either tenofovir alafenamide fumarate (TAF)/emtricitabine (FTC), abacavir/lamivudine or zidovudine/lamivudine. Steady-state pharmacokinetic sampling was done at 0, 1, 2, 4, 6, 8, 12 and 24 hours after observed darunavir/ritonavir intake. Non-compartmental and population pharmacokinetic analyses were used to describe the data and identify significant covariates. Reference adult pharmacokinetic data were used for comparison. We simulated the World Health Organization (WHO) recommended 600/100 mg darunavir/ritonavir dose for the 25-34.9 kg weight band. Data from 59 children with median age and weight 10.9 (range 3.8-14.7) years and 26.0 (14.5-47.0) kg, respectively, were available. A two-compartment disposition model with transit absorption compartments and weight-based allometric scaling of clearance and volume best described darunavir data. Our population achieved geometric mean (%CV) darunavir AUC0-24h, 94.3(50) mg·h/L and Cmax, 9.1(35) mg/L, above adult reference values and Ctrough, 1.5(111) mg/L, like adult values. The nucleoside reverse-transcriptase inhibitor backbone was not found to affect darunavir concentrations. Simulated WHO-recommended darunavir/ritonavir doses showed exposures equivalent to adults. Higher alpha-1-acid glycoprotein increased binding to darunavir and decreased apparent clearance of darunavir. Darunavir exposures achieved in our trial are within safe range. Darunavir/ritonavir can safely be co-administered with TAF/FTC. Both WHO-recommended 600/100 mg and CHAPAS-4 800/100 mg darunavir/ritonavir doses for the 25-34.9 kg weight band offer favourable exposures. The choice between them can depend on tablet availability.

Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors.

Darunavir, a frontline treatment for HIV infection, faces limitations due to emerging multidrug resistant (MDR) HIV strains, necessitating the development of analogs with improved activity. In this study, a combinatorial in silico approach was used to initially design a series of HIV-1 PI analogs with modifications at key sites, P1' and P2', to enhance interactions with HIV-1 PR. Fifteen analogs with promising binding scores were selected for synthesis and evaluated for the HIV-1 PR inhibition activity. The variation of P2' substitution was found to be effective, as seen in 5aa (1.54 nM), 5ad (0.71 nM), 5ac (0.31 nM), 5ae (0.28 nM), and 5af (1.12 nM), featuring halogen, aliphatic, and alkoxy functionalities on the phenyl sulfoxide motif exhibited superior inhibition against HIV-1 PR compared to DRV, with minimal cytotoxicity observed in Vero and 293T cell lines. Moreover, computational studies demonstrated the potential of selected analogs to inhibit various HIV-1 PR mutations, including I54M and I84V. Further structural dynamics and energetic analyses confirmed the stability and binding affinity of promising analogs, particularly 5ae, which showed strong interactions with key residues in HIV-1 PR. Overall, this study underscores the importance of flexible moieties and interaction enhancement at the S2' subsite of HIV-1 PR in developing effective DRV analogs to combat HIV and other global health issues.

In Silico Evaluation of HIV Protease and RNA Polymerase Inhibitors as Potential COVID-19 Therapeutics.

The COVID-19 coronavirus, also known as the acute respiratory syndrome coronavirus, emerged as a significant global health concern. First identified in Wuhan, China, in December 2019, the virus rapidly spread to over 187 countries due to its high transmissibility. Until an effective treatment or vaccine is developed, preventive measures remain the only mandatory strategy to curb person-to-person transmission. The study aimed to explore potential therapeutic options for COVID-19 by repurposing existing drugs. Specifically, the objective was to evaluate a library of clinically approved or investigational antiviral compounds through docking studies to identify candidates with high binding affinity to COVID-19 proteins. The study employed molecular docking techniques using the Maestro interface (Schrodinger Suite, LLC, NY) to assess the interaction of selected compounds with various COVID-19 protein targets. A total of 15 compounds were analyzed for their binding potential to multiple forms of the virus's proteins. The docking studies revealed that several compounds, particularly HIV protease inhibitors and RNA-dependent RNA polymerase inhibitors, demonstrated strong binding affinities to key COVID-19 enzymes. These interactions suggest their potential as therapeutic candidates for COVID-19 treatment. The findings from this drug repurposing study highlight the potential of certain existing antiviral agents in the treatment of COVID-19. The identified compounds could serve as promising candidates for further investigation in the ongoing battle against the coronavirus pandemic.

The 3D-QSAR Study, Molecular Docking, and ADMET Analysis of Darunavir Derivatives of HIV-1 Protease Inhibitors

Background: Acquired Immunodeficiency Syndrome (AIDS) is one of most prevalent infectious diseases in the world , and HIV-1 protease (PR) is a vital target of drug design. Nowadays, three-dimensional quantitative structure-activity relationships (3D-QSAR) are applied to help design new protease inhibitions (PIs). Objective: The primary objective of this study is to apply the 3D-QSAR study to a series of 42 derivatives of Darunavir (DRV) and to design new molecules possessing high antivirus activity. Methods: Partial Least Squares (PLS) were used to cross-validate the dataset of compounds, and the optimal number of principal components (ONC), cross-validate coefficient (q²), standard error of estimate (SEE), non-cross-validated correlation coefficient (R²) and fisher test value (F) were calculated to assess model robustness. In this study, the CoMSIA-DAH model (q²=0.754, r²= 0.988, rpred2=0.57) possessed the highest predicted activity. Newly designed molecules were analyzed by docking studies with compound 25 taken as a template. Results: Within eight newly designed drugs, compound N02 possessed the highest antivirus activity (IC50=0.00461 nM) predicted by the CoMSIA-DAH model. The Surflex-Dock module of SYBYL-X 2.0 was used to affirm the predicted anti-PR activity of the newly designed compounds and the results of docking complex structure could be visualized. All newly designed molecules were in agreement with CSore above four and the docking study revealed that Asp29, Asp30, Ile50, Asp124, Asp128, Asp129 and Ile149 were critical residues in the process of inhibiting PR. Conclusion: One of the main aspects of this study is the successful design of a series of molecules with excellent investigatory values, which elucidates explicit quantitative structure-activity relationships of DRV derivatives and will provide significant suggestions for future pharmaceutical research.

Comparative study of two MIP-based electrochemical sensors for selective detection and quantification of the antiretroviral drug lopinavir in human serum

Thermal polymerization (TP) and electropolymerization (EP) are the two methods used in this study to explore the molecular imprinting process. To detect the antiviral medication lopinavir (LPV), an inhibitor of enzyme HIV-1 protease that is co-formulated with ritonavir (RTV) to extend its half-life in the body, with greater precision, these methods were merged with an electrochemical sensor. The sensors were created on glassy carbon electrodes (GCE) based on molecularly imprinted polymers (MIP) using TP with methacrylic acid (MAA) functional monomer and EP with p-aminobenzoic acid (PABA) functional monomer. Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and electrochemical methods were utilized to examine the technical features of the suggested sensors. For both approaches, the necessary optimization investigations were carried out. Different LPV concentrations, ranging from 1.0 pM to 17.5 pM in drug solution and commercial human serum samples, were used to validate the analytical efficiency of the two sensors and compare their electroanalytical behaviour. For TP-LPV@MIP/GCE and EP-LPV@MIP/GCE, the corresponding limit of detection (LOD) was 2.68 × 10−13 M (0.169 pg mL−1) and 1.79 × 10−13 M (0.113 pg mL−1) in standard solutions, and 2.87 × 10−13 M (0.180 pg mL−1) and 2.91 × 10−13 M (0.183 pg mL−1) in serum samples. For the measurement of LPV in tablet form and serum samples, the proposed TP-LPV@MIP/GCE and EP-LPV@MIP/GCE sensors provide good recovery, demonstrating 99.85–101.16 % and 100.36–100.97 % recovery, respectively. The imprinting factor was utilized to demonstrate the selectivity of the suggested sensors by utilizing several anti-viral drugs that are structurally comparable to LPV. Additionally, the constructed sensors were examined for the potential impacts of interferences and the stability during the storage.

Design of Novel HIV-1 Protease Inhibitors with Favorable Oral Properties using a Molecular Modelling Approach

Acquired immunodeficiency syndrome (AIDS) is a chronic and potentially fatal transmissible disease caused by the Human Immunodeficiency Virus (HIV). Since its discovery in 1981, an estimated 85 million cases and 40 million AIDS related deaths have occurred worldwide. Among the two types of HIV, HIV-1 accounts for over 90% of reported cases. Throughout the years, multiple drugs have been approved for the treatment of AIDS. However, these drugs face many drawbacks such as toxic side effects, non-optimal pharmacodynamic profile and drug resistance due to virus mutation. This study aims to design novel potent HIV-1 protease inhibitors that overcome these drawbacks through molecular modelling methods. Pubchem database was screened for potential lead compounds. Results were filtered through two phases of ADMET and docking studies. Finally, the chosen lead compound was optimized through fragment replacement to obtain the novel inhibitors.

Enthalpic Classification of Water Molecules in Target-Ligand Binding.

Water molecules play various roles in target-ligand binding. For example, they can be replaced by the ligand and leave the surface of the binding pocket or stay conserved in the interface and form bridges with the target. While experimental techniques supply target-ligand complex structures at an increasing rate, they often have limitations in the measurement of a detailed water structure. Moreover, measurements of binding thermodynamics cannot distinguish between the different roles of individual water molecules. However, such a distinction and classification of the role of individual water molecules would be key to their application in drug design at atomic resolution. In this study, we investigate a quantitative approach for the description of the role of water molecules during ligand binding. Starting from complete hydration structures of the free and ligand-bound target molecules, binding enthalpy scores are calculated for each water molecule using quantum mechanical calculations. A statistical evaluation showed that the scores can distinguish between conserved and displaced classes of water molecules. The classification system was calibrated and tested on more than 1000 individual water positions. The practical tests of the enthalpic classification included important cases of antiviral drug research on HIV-1 protease inhibitors and the Influenza A ion channel. The methodology of classification is based on open source program packages, Gromacs, Mopac, and MobyWat, freely available to the scientific community.

CARD8 inflammasome activation during HIV-1 cell-to-cell transmission.

Our previous work demonstrated that CARD8 detects HIV-1 infection by sensing the enzymatic activity of the HIV protease, resulting in CARD8-dependent inflammasome activation (Kulsuptrakul et al., 2023). CARD8 recognition of HIV-1 protease activity is conferred by a HIV protease substrate mimic within the CARD8 N-terminus, which when cleaved by HIV protease triggers CARD8 inflammasome activation. Here, we sought to understand CARD8 responses to HIV-1 when the virus is transmitted through cell-to-cell infection from infected cells to target cells via a viral synapse. We observed that cell-to-cell transmission of HIV-1 induces CARD8 inflammasome activation in immortalized cells and primary human monocyte-derived macrophages in a manner that is dependent on viral protease activity and largely independent of the NLRP3 inflammasome. Additionally, to further evaluate the viral determinants of CARD8 sensing, we tested a panel of HIV protease inhibitor resistant clones to establish how variation in HIV protease affects CARD8 activation. We identified mutant HIV-1 proteases that differentially cleave and activate CARD8 compared to wildtype HIV-1, thus indicating that natural variation in HIV protease affects not only the cleavage of the viral Gag-Pol polyprotein but also likely impacts innate sensing and inflammation.

Trabecular bone score assessed by dual-energy X ray absorption predicts vertebral fractures in HIV infected young adults

IntroductionBone mineral density (BMD) is reduced in patients with human immunodeficiency virus (HIV) infection. Trabecular bone score (TBS) is an additional feature calculated by dual-energy X ray absorption (DXA) that measures texture inhomogeneity at lumbar spine level, providing an index of bone microarchitecture. However, its clinical value still needs to be fully addressed. Aims of the study were to assess BMD and TBS in a cohort of patients with HIV compared to a population of healthy subjects and to investigate the prognostic value of TBS in HIV infected patients. MethodBone health was assessed by DXA in 165 patients with HIV infection (120 men, mean age 40 ± 7 years) and in 164 healthy subjects (53 male, mean age 37 ± 10 years). BMD was measured at level of lumbar spine (L1-L4), femoral neck and total hip. TBS was computed from the images of lumbar spine using machine proprietary software. ResultsBMD at femoral neck level was similar in HIV infected patients and healthy subjects (p = 0.57), whereas BMD measured in total femur was lower in HIV infected patients compared to healthy subjects (p < 0.05). Although mean BMD in lumbar spine was similar between HIV infected patients and healthy subjects (p = 0.90), mean lumbar TBS was lower in patients with HIV infection compared to healthy subjects (p < 0.05). Age, sex and HIV infection resulted independent predictors of reduced TBS. In HIV infected patients age, sex and protease inhibitor duration resulted independent predictors of reduced TBS. TBS was a significant predictor of vertebral fractures during follow-up (p < 0.05). ConclusionPatients with HIV infection have a significant reduction of TBS, a texture parameter related to bone microarchitecture that may provide skeletal information that is not captured from the standard BMD measurement.

Development of a triazole-linked bis-organosilane compound as dual-function agent: Sensing of Al3+ ion in aqueous environments and inhibition of HIV-1 protease

The increasing applications of aluminum metal have led to rising concerns regarding its adverse environmental impacts, particularly on marine life and human health, necessitating its efficient detection. Bis-organosilane compounds hold a pivotal position in organosilicon chemistry, contributing significantly to industrial processes and scientific research. In this study, a synthesized bis-1,2,3-triazole-linked bis-organosilane was employed as a sensor for the selective detection of Al³⁺ ions in a MeOH: H₂O (7:3, v/v) solvent system. This sensor demonstrated high selectivity and strong anti-interference capabilities, even in the presence of other metal ions. The detection limit for Al³⁺ was found to be significantly lower than the WHO-prescribed limits for drinking water. Using an actual water sample analysis experiment, its practical utility was also investigated. Additionally, bis-organosilane (6) capability as an antioxidant to stabilize free radicals was also tested. Given the biological significance of triazoles, compound (6) was evaluated for its inhibitory activity against HIV-1 protease using molecular docking tools. the current study emphasizes bis-organosilane (6) as an Al3+ sensor with dual activity as a possible HIV medication and a significant antioxidant.

Analysis of virus gene subtypes and drug resistance monitoring results of newly reported HIV/AIDS population in Anhui Province from 2020 to 2023

Objective: To investigate the genetic subtypes and drug resistance monitoring of newly reported human immunodeficiency virus (HIV) infection/AIDS virus in Anhui Province from 2020 to 2023. Methods: An observational design study was used to collect blood samples from patients diagnosed with HIV/AIDS in the AIDS Prevention and Control Department of Anhui Provincial Center for Disease Control and Prevention from January 2020 to December 2023.The HIV-1 pol gene was amplified by reverse transcription-nested PCR, and the genetic subtypes were identified by phylogenetic tree analysis using MEGA 7.0 software. The mutation sites of drug resistance were analyzed by the online software tool of Stanford University's HIV Drug resistance database. The influencing factors of drug resistance before treatment were analyzed by multivariate logistic analysis. Results: A total of 335 plasma samples were collected, and 332 HIV-1 pol gene sequences were obtained successfully. The main gene subtypes were CRF01-AE, accounting for 35.55% (118/332), followed by CRF07-BC, B and B+C types [29.22% (97/332), 11.74% (39/332), 9.93% (33/332)]. The total drug resistance rate before treatment was 30.12%(32/100), and the drug resistance rate of protease inhibitor (PIs) in HIV-1 was 6.33% (21/332). The drug resistance rate of nucleoside reverse transcriptase inhibitors (NRTI) before treatment was 6.33% (21/332). The drug resistance rate of non-nucleoside reverse transcriptase inhibitors (NNRTI) before treatment was 17.47% (58/332).The comparison of drug resistance rate of different drug types showed statistical significance (χ2=30.435, P<0.05).Among the 100 cases of drug resistance, the main mutation point of HIV-1 protease inhibitor was Q58E (21.00%), and the main mutation point of nucleoside reverse transcriptase inhibitor was M184V/I (6.00%). Non-nucleoside reverse transcriptase inhibitor resistance mutation points mainly K103N (22.00%).There were statistically significant differences in the starting time of antiviral therapy, the number of CD4+T cells at baseline and the drug resistance rate of gene subtypes (the chi-square values are respectively 24.152, 32.516, 11.652, P<0.05).Multivariate logistic analysis showed that the baseline CD4+T cell count was <200/μl, subtype B, subtype B+C, CRF01-AE subtype, CRF55-01B subtype and 01-BC subtype was the influential factor of drug resistance before treatment (the chi-square values are respectively 4.577, 8.202, 4.416, 5.206, 7.603 and 4.804, P<0.05). Conclusion: The newly reported HIV/AIDS population in Anhui Province from 2020 to 2023 has a variety of viral gene subtypes, and NNRTIs are the main types of drug resistance gene mutations before treatment. Attention should be paid to the number of baseline CD4+T cells, the duration of antiviral treatment, and the distribution of gene subtypes to reduce the drug resistance of HIV/AIDS patients before treatment.