Search Results (41)

The global distribution of HIV-1 subtypes exhibits significant regional variations, with evolving epidemiological patterns over time. China currently experiences concurrent circulation of multiple HIV-1 subtypes, and the transmission landscape is becoming increasingly complex and diversified. We performed prospective molecular surveillance and drug-resistance profiling of HIV-1 in Wuhan City to delineate the local genotypic structure and to guide antiretroviral therapy. A total of 149 whole blood samples from HIV-1-infected individuals preserved in 2022 at a hospital in Wuhan were selected. Peripheral-blood mononuclear cells (PBMCs) were isolated, total RNA extracted, and the Gag, Pol, and Env regions were amplified by nested RT-PCR and sequenced. The sequencing and phylogenetic tree results revealed that subtype B constituted the predominant clade (73/149, 49.1%), followed by CRF07_BC (20, 13.4%), CRF01_AE (13, 8.7%), CRF55_01B (2, 1.3%), and subtype C (1, 0.7%). Drug resistance mutations were detected in 36 cases, involving 41 mutation sites across 21 distinct types. Resistance profiles included two protease inhibitor-associated mutation sites (2 types), seven nucleoside reverse transcriptase inhibitor (NRTI)-related mutation sites (6 types), and 32 non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutation sites (13 types). Full article

Background/Objectives: The emergence of drug-resistant HIV-1 strains challenges the long-term efficacy of current antiretroviral therapies. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are critical in HIV-1 treatment; however, the need for new candidates with improved resistance profiles and pharmacokinetics remains. This study aims to design and evaluate novel NNRTIs targeting both wild-type (WT) and mutant-type (MT) HIV-1 reverse transcriptase (RT) using integrated computational strategies. Methods: We conducted a 3D-QSAR study on 33 naphthyl-diarylpyrimidine derivatives using CoMFA and CoMSIA models. We designed thirty-five novel molecules based on contour map insights. We applied ADMET and drug-likeness filters to prioritize ten candidates. Molecular docking was performed on WT (PDB: 3HVT) and MT (PDB: 4PUO) RT structures. The top candidates underwent 100 ns molecular dynamics (MD) simulations. We analyzed structural stability via RMSD, RMSF, and Rg, while we used SASA and MolSA to assess solvent exposure and surface compactness. Results: The CoMFA and CoMSIA models demonstrated robust predictivity (R² = 0.979/0.920, Q² = 0.643/0.546, R²_test = 0.747/0.603). P14 and P43 showed higher binding affinities than nevirapine and favorable ADMET profiles. MD simulations confirmed stable binding in WT-RT and adaptive flexibility in MT-RT. SASA and MolSA analysis revealed favorable conformational compaction. Drug-likeness profiles indicated optimal log P, strong hydrogen bonding, and acceptable bioavailability. Conclusions: P14 and P43 demonstrate strong potential as NNRTI leads, combining binding affinity, structural stability, and favorable pharmacokinetics, supporting further experimental development. Full article

In Israel, irregular migrants (IMs) living with human immunodeficiency virus (HIV-1) that have no access to regular health insurance are provided with HIV-1-related health coverage under a public–private partnership (PPP) program initiated by the Ministry of Health in 2014. Here we characterized IMs referred to the PPP in 2019–2024 and used a linear mixed-effects model to follow up their CD4 and HIV-1 viral load (VL) counts for a median period of 16 months. Subtypes, resistance mutations and phylogenetic relationships were determined in all cases with viral failure and in selected cases with available blood remains. A total of 231 of 238 referred to the PPP initiated antiretroviral treatment (ART) with nucleoside reverse transcriptase inhibitors (NRTIs) and either non-nucleoside reverse transcriptase inhibitors (NNRTIs, 61.5%, 142/231) or protease inhibitors (PIs, 38.5%, 89/231). Irrespective of the treatment regimen, all these individuals increased their CD4 and decreased their VL trajectories over time (p < 0.001). However, mixed model analysis revealed two classes of CD4 trajectory patterns. Comparison between these two patterns revealed that Class-1 individuals started with lower initial CD4 counts compared to Class-2 individuals (median of 115 cells/mm³, IQR 70–171 compared to median of 312 cells/mm³, IQR 104–510, p < 0.001) and experienced slower recovery compared to Class-2. Most Class-1 individuals originated from Africa (78% vs. 52%, p = 0.016). Treatment failure was observed in 5.6% of all individuals receiving treatment under the program. Sequencing analysis, enabled in 23% of the treated cohort, revealed that the reverse transcriptases (RT) M184V (13%) and K103N (7.4%) were the most prevalent mutations. Conclusively, while treatment was not consistent with current recommendations for first-line therapy, the virological and immunological response of most patients was favorable and the prevalence of cases with resistance mutations was not higher than that identified in people living with HIV-1 who are covered by the national health insurance. Despite the limitations of the PPP, this program may provide a unique therapeutic opportunity for IMs with HIV-1. Full article

Background/Objectives: Fibroblast growth factor receptors (FGFRs) are frequently dysregulated in diverse cancers and represent important therapeutic targets. Here, we report the design and synthesis of a novel nucleoside-based scaffold which enables irreversible pan-FGFR inhibition as a potential anticancer strategy. Methods: A series of nucleoside analogues was synthesized and assessed through structure–activity relationship studies. Structural analyses, including X-ray co-crystallography and molecular dynamics simulations, were performed to define key determinants of potency and selectivity. Biochemical assays against FGFR1–4 proteins, cellular antiproliferative assays in HCT116 (FGFR1 amplification) and RT4 (FGFR3-TACC3) models, metabolic stability evaluations and covalent bonding confirmation were conducted to characterize representative compounds. Results: SAR studies revealed that fused aromatic substituents and 4′-thio ribose enhanced FGFR potency, whereas enantiomeric inversion of ribose reduced activity. X-ray co-crystallography further demonstrated that two hydroxyl groups form a key water-mediated hydrogen bond network, uniquely stabilizing the ligand and enhancing potency of inhibitors compared to reference compounds. The 7-methoxy-5-methylbenzo[b]thiophene scaffold and ribose moiety emerged as critical features. Compounds 13f, 19e, and 22f demonstrated potent inhibition of FGFR1-4 and dose-dependent suppression of FGFR1-mediated signaling, with strong antiproliferative activity in both FGFR-driven and wild-type cancer models. Compound 22f showed efficient irreversible covalent engagement of FGFRs, confirmed at the protein and cellular levels, and exhibited improved metabolic stability. Conclusions: Nucleoside analogues represent a privileged scaffold for covalent pan-FGFR inhibition. The findings highlight their potential as promising therapeutic candidates for targeting FGFR-driven malignancies. Future efforts will focus on further improving stability and optimizing physicochemical properties to advance these compounds toward translational development. Full article

I started my research career (in 1965) on interferon by identifying polyacrylic acid (PAA) as an interferon inducer. Poly(I).poly(C), discovered by Maurice Hilleman’s group, proved to be more potent as an interferon inducer, and through its mRNA, we were able to clone and express human β-interferon. The discovery of the reverse transcriptase (RT) by Temin and Baltimore (in 1970) brought me to the detection of suramin as a powerful RT inhibitor and enabled Sam Broder and his colleagues to identify suramin as the first inhibitor of HIV replication. In this capacity, it was subsequently superseded by AZT and other 2′,3′-dideoxynucleoside (ddN) analogs, including d4T. In collaboration with Antonín Holý, we discovered several acyclic nucleoside phosphonates as potent inhibitors of both HIV and HBV (hepatitis B virus) replication. In collaboration with Paul Janssen, we identified various non-nucleoside RT inhibitors (NNRTIs) of HIV-1 replication. Of the nucleotide RT inhibitors (NtRTTs), tenofovir emerged as the most promising congener. It was derivatized to its oral prodrugs TDF and TAF. To enhance their efficacy, they were combined with other anti-HIV drugs, and two of them were pursued (and found efficacious) in the Pre-Exposure Prophylaxis (PrEP) of HIV infections. Full article

Inspired by our previous work on the modification of diarylpyrimidine-typed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reported crystallographic studies, a series of novel amino acids (analogues)-substituted thiophene[3,2-d]pyrimidine derivatives were designed and synthesized by targeting the solvent-exposed region of the NNRTI-binding pocket. The biological evaluation results showed that compound 5k was the most active inhibitor, exhibiting moderate-to-excellent potency against HIV-1 wild-type (WT) and a panel of NNRTI-resistant strains, with EC₅₀ values ranging from 0.042 μM to 7.530 μM. Of special note, 5k exhibited the most potent activity against single-mutant strains (K103N and E138K), with EC₅₀ values of 0.031 μM and 0.094 μM, being about 4.3-fold superior to EFV (EC₅₀ = 0.132 μM) and 1.9-fold superior to NVP (EC₅₀ = 0.181 μM), respectively. In addition, 5k demonstrated lower cytotoxicity (CC₅₀ = 27.9 μM) and higher selectivity index values. The HIV-1 reverse transcriptase (RT) inhibition assay was further performed to confirm their binding target. Moreover, preliminary structure–activity relationships (SARs) and molecular docking studies were also discussed in order to provide valuable insights for further structural optimizations. In summary, 5k turned out to be a promising NNRTI lead compound for further investigations of treatments for HIV-1 infections. Full article

Background: Multidrug-resistant HIV strains challenge treatment efficacy and increase mortality rates. Next-generation sequencing (NGS) technology swiftly detects variants, facilitating personalized antiretroviral therapy. Aim: This study aimed to validate the Vela Diagnostics NGS platform for HIV drug resistance mutation analysis, rigorously assessed with clinical samples and CAP proficiency testing controls previously analyzed by Sanger sequencing. Method: The experimental approach involved the following: RNA extraction from clinical specimens, reverse transcription polymerase chain reaction (RT-PCR) utilizing the Sentosa SX 101 platform, library preparation with the Sentosa SQ HIV Genotyping Assay, template preparation, sequencing using the Sentosa SQ301 instrument, and subsequent data analysis employing the Sentosa SQ Suite and SQ Reporter software. Drug resistance profiles were interpreted using the Stanford HIV Drug Resistance Database (HIVdb) with the HXB2 reference sequence. Results: The Vela NGS system successfully identified a comprehensive array of drug resistance mutations across the tested samples: 28 nucleoside reverse transcriptase inhibitors (NRTI), 25 non-nucleoside reverse transcriptase inhibitors (NNRTI), 25 protease inhibitors (PI), and 10 integrase gene-specific variants. Dilution experiments further validated the system’s sensitivity, detecting drug resistance mutations even at viral loads lower than the recommended threshold (1000 copies/mL) set by Vela Diagnostics. Scope: This study underscores the validation and clinical applicability of the Vela NGS system, and its implementation may offer clinicians enhanced precision in therapeutic decision-making for individuals living with HIV. Full article

HIV drug resistance compromises the ability of anti-retroviral therapy (ART) to suppress viral replication, resulting in treatment failure. This study investigates the prevalence of pre-treatment drug resistance (PDR) in newly diagnosed individuals in a prosperous city (Wenzhou) in Southeastern China. A cross-sectional investigation was carried out among 473 newly diagnosed ART-naive HIV-1-infected individuals between January and December 2022. The protease–reverse transcriptase (PR-RT) region and integrase (IN) region of HIV-1 were amplified by two separately nested PCRs, followed by sequencing. Drug resistance mutations (DRMs) and drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and integrase strand transfer inhibitors (INSTIs) were analyzed. The PDR prevalence was 6.5% [95% CI: 4.4–9.1] for any anti-retroviral drug, 0.9% [95% CI: 0.3–2.3] for NRTIs, 4.1% [95% CI: 2.5–6.5] for NNRTIs, 1.8% [95% CI: 0.8–3.6] for PIs and 0.5% [95% CI: 0.1–1.8] for INSTIs. According to the subtyping results of the PR-RT region, 11 different subtypes and 31 unique recombinant forms (URFs) were found. CRF07_BC was the dominant subtype (53.7%, 233/434), followed by CRF01_AE (25.3%, 110/434). V179D (1.6%) and K103N (1.4%) were the most predominant types of NNRTI DRMs. Q58E (1.2%) and M184V (0.7%) were the most frequent PI DRMs and NRTI DRMs, respectively. The INSTI-related DRMs Y143S (causes high-level resistance to RAL) and G163K (causes low-level resistance to EVG and RAL) were found in one patient each. Given the relatively high PDR prevalence of NNRTI (4.1%), non-NNRTI-based ART may be preferred in the future. It is recommended to include genotypic resistance testing before starting ART in regions where feasible. Full article

Brain somatic gene recombination (SGR) and the endogenous reverse transcriptases (RTs) that produce it have been implicated in the etiology of Alzheimer’s disease (AD), suggesting RT inhibitors as novel prophylactics or therapeutics. This retrospective, proof-of-concept study evaluated the incidence of AD in people with human immunodeficiency virus (HIV) with or without exposure to nucleoside RT inhibitors (NRTIs) using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy. The cumulative incidence of new AD cases over the ensuing 2.75-year observation period was lowest in patients with NRTI exposure and highest in controls. Age- and sex-adjusted hazard ratios showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88, p < 0.05) and 3 (HR 0.84, p < 0.05). Sub-grouping identified a decreased AD risk in patients with NRTI exposure but without protease inhibitor (PI) exposure. Prospective clinical trials and the development of next-generation agents targeting brain RTs are warranted. Full article

At the end of the last century, it was revealed that quinones with one, two, and three aromatic rings could inhibit HIV-1 protease, an enzyme crucial for HIV (Human Immunodeficiency Virus) replication. Since HIV-1 protease acts as key target for AIDS (Acquired Immunodeficiency Syndrome) medications, the development of efficient inhibitor of this protein would lead to an increase in medical treatment and a decrease in the drug resistance. Later research revealed that hydroxyquinones can block HIV-1 protease at the micromolar level, which enabled a direction for the creation of HIV medications. Anthrarufin (1,5-dihydroxy-9,10-anthraquinone) is an anthraquinone that possesses a moderate antioxidative capacity and antimalaric activity. In this study, molecular docking simulations were used to examine the molecular interactions between anthrarufin, its monoanion and dianion as ligands, and HIV-1 reverse transcriptase (HIV-1 RT) as a target protein. Using AGFR software, the binding site of the HIV-1 RT was identified. The three-dimensional crystal structure of HIV-1 RT was downloaded from the Protein Data Bank (PDB ID: 2ZD1). Dolutegravir, nevirapine, anthrarufin, anthrarufin-anion and anthrarufin-dianion are used as ligands in the molecular docking simulations together with rilpivirine (TMC278), a non-nucleoside inhibitor of estimated protein. The AutoDock 4.0 program is used for molecular docking simulations. Anthrarufin, its monoanion and dianion can be considered as a potential HIV-1 RT inhibitors because they have similar inhibitory potency to other ligands under consideration, according to the results of the free energy of binding (∆G_bind) and inhibition constant (K_i) values. Full article

In this paper, the Y188C mutant HIV-1 reverse transcriptase (Y188CM-RT) target protein was constructed by homology modeling, and new ligands based on nevirapine (NVP) skeleton were designed by means of fragment growth. The binding activity of new ligands to Y188CM-RT was evaluated by structural analysis, ADMET prediction, molecular docking, energy calculation and molecular dynamics. Results show that 10 new ligands had good absorbability, and their binding energies to Y188CM-RT were significantly higher than those of wild-type HIV-1 reverse transcriptase(wt). The binding mode explained that fragment growth contributed to larger ligands, leading to improved suitability at the docking pocket. In the way of fragment growth, the larger side chain with extensive contact at terminal is obviously better than substituted benzene ring. The enhancement of docking activity is mainly due to the new fragments such as alkyl chains and rings with amino groups at NVP terminal, resulting in a large increase in hydrophobic bonding and the new addition of hydrogen bonding or salt bonding. This study is expected to provide reference for the research on non-nucleoside reverse transcriptase inhibitors resistance and AIDS treatment. Full article

The enzyme reverse transcriptase (RT) plays a central role in the life cycle of human immunodeficiency virus (HIV), and RT has been an important drug target. Elucidations of the RT structures trapping and detailing the enzyme at various functional and conformational states by X-ray crystallography have been instrumental for understanding RT activities, inhibition, and drug resistance. The structures have contributed to anti-HIV drug development. Currently, two classes of RT inhibitors are in clinical use. These are nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, the error-prone viral replication generates variants that frequently develop resistance to the available drugs, thus warranting a continued effort to seek more effective treatment options. RT also provides multiple additional potential druggable sites. Recently, the use of single-particle cryogenic electron microscopy (cryo-EM) enabled obtaining structures of NNRTI-inhibited HIV-1 RT/dsRNA initiation and RT/dsDNA elongation complexes that were unsuccessful by X-ray crystallography. The cryo-EM platform for the structural study of RT has been established to aid drug design. In this article, we review the roles of structural biology in understanding and targeting HIV RT in the past three decades and the recent structural insights of RT, using cryo-EM. Full article

LINE1 retrotransposons, which are thought to be the remnants of ancient integrations of retrovirus-like elements, are aberrantly (re)activated in many cancer cells. Due to LINE1-induced alterations in target gene expression and/or chromosomal rearrangements, they may be important drivers of tumorigenesis. Moreover, LINE1 encoded proteins, Open Reading Frame (ORF)1 and ORF2, may have pro-oncogenic potential through inductors of oncogenic transcription factors or inhibitors of cell cycle suppressors. The current study therefore aimed to investigate in vitro and in vivo anti-tumorigenic effects of two well-known antiretroviral drugs, zidovudine, a nucleoside analogue inhibitor of RT (NRTI), and efavirenz, a non-nucleoside RT inhibitor (NNRTI). Our data demonstrate that both drugs in clinically relevant doses significantly reduced the proliferation of murine and human cancer cell lines, as well as growth of tumors in a murine subcutaneous model. Intriguingly, we found that the combination of both zidovudine and efavirenz almost entirely blocked tumorigenesis in vivo. Because both drugs are FDA-approved agents and the combination was very well tolerated in mice, the combination therapy as presented in our paper might be an opportunity to treat colorectal tumors and metastasis to the liver in an inexpensive way. Full article

Drug-resistant cases of human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitors (NRTI) are constantly accumulating due to the frequent mutations of the reverse transcriptase (RT). Predicting the potential drug resistance of HIV-1 NRTIs could provide instructions for the proper clinical use of available drugs. In this study, a novel proteochemometric (PCM) model was constructed to predict the drug resistance between six NRTIs against different variants of RT. Forty-seven dominant mutation sites were screened using the whole protein of HIV-1 RT. Thereafter, the physicochemical properties of the dominant mutation sites can be derived to generate the protein descriptors of RT. Furthermore, by combining the molecular descriptors of NRTIs, PCM modeling can be constructed to predict the inhibition ability between RT variants and NRTIs. The results indicated that our PCM model could achieve a mean AUC value of 0.946 and a mean accuracy of 0.873 on the external validation set. Finally, based on PCM modeling, the importance of features was calculated to reveal the dominant amino acid distribution and mutation patterns on RT, to reflect the characteristics of drug-resistant sequences. Full article

The human immunodeficiency virus type 1 (HIV-1), one of the leading causes of infectious death globally, generates severe damages to people’s immune systems and makes them susceptible to serious diseases. To date, there are no drugs that completely remove HIV from the body. This paper focuses on screening 224,205 natural compounds of ZINC15 NPs subset to identify those with bioactivity similar to non-nucleoside reverse transcriptase inhibitors (NNRTIs) as promising candidates to treat HIV-1. To reach the goal, an in silico approach involving 3D-similarity search, ADMETox, HIV protein-inhibitor prediction, docking, and MM-GBSA free-binding energies was trained. The FDA-approved HIV drugs, efavirenz, etravirine, rilpivirine, and doravirine, were used as queries. The prioritized compounds were subjected to ADMETox, docking, and MM-GBSA studies against HIV-1 reverse transcriptase (RT). Lys101, Tyr181, Tyr188, Trp229, and Tyr318 residues and free-binding energies have proved that ligands can stably bind to HIV-1 RT. Three natural products (ZINC37538901, ZINC38321654, and ZINC67912677) containing oxan and oxolan rings with hydroxyl substituents and one (ZINC2103242) having 3,6,7,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-1,4-dione core exhibited comparable profiles to etravirine and doravirine, with ZINC2103242 being the most promising anti-HIV candidate in terms of drug metabolism and safety profile. These findings may open new avenues to guide the rational design of novel HIV-1 NNRTIs. Full article