Drug-resistant Virus Research Articles

Identification of new triazolo annulated dipyridodiazepine derivatives as HIV-1 reverse transcriptase inhibitors: Design, synthesis, DFT, molecular modelling and in silico studies

With the tremendous increase in viral infection spread and drug resistance, it is imperative to explore new efficient antiviral agents. Two series of novel compounds, triazole-annulated dipyridodiazepines 9(a–e) and methyl-substituted triazole-annulated dipyridodiazepines 10(a–e), were successfully synthesised and characterised by IR, NMR spectroscopy and mass spectrometry. The in vitro reverse transcriptase inhibitory ability of synthesized derivatives was determined using an HIV-1 reverse transcriptase assay kit. Results revealed that 9a and 10a were most potent with an IC50 of 66 and 71 nM compared with reference drug nevirapine 88nM. A density functional theory (DFT) study of the synthesized compound showed that both triazole series possess noticeably distorted butterfly-like structures, triazole and pyridine rings tilted relative to the diazepine ring and the phenyl ring is perpendicular to the diazepine ring. Significant HOMO/LUMO gap values for both series, 3.71–4.59 eV for the compounds 9(a–e) and 3.69–4.68 eV for compounds 10(a–e), suggest their quite noticeable stability. Further, these analogues were in silico analysed for molecular docking, drug-likeness, physicochemical and ADMET studies. The good binding scores (high interaction energies) obtained in the molecular docking studies are in good agreement with the molecular electrostatic potential (MEP) analysis results showing accumulations of negative and positive electrostatic potential on different parts of the molecules of the compounds studied. In conclusion, all these results suggest that synthesized analogues could be a potential candidate to inhibit HIV-1 reverse transcriptase and may be considered as lead molecules in the development of new anti-reverse transcriptase agents.

Full-Length Genome Sequencing and Analysis of Hepatitis B Viruses Isolated from Iraqi Patients.

Hepatitis B virus (HBV) causes liver diseases (chronic hepatitis, cirrhosis, and hepatocellular carcinoma) and is a leading health problem worldwide. Sequencing of the whole HBV genome provides insight into the virus genotype, subgenotype, serotype, genetic variation, and viral drug resistance. To date, no study has been conducted on the whole genome sequence of HBV obtained from Iraqi patients. Therefore, this is the first study to sequence clinical samples from these patients. Viral genomic DNA was isolated and amplified using five primer sets to amplify five overlapping regions covering the entire HBV genome. The amplicons were sequenced, aligned to a reference sequence, annotated, and submitted to the National Center for Biotechnology Information GenBank database. Sequence analysis showed that the genome size of the tested viral samples was 3,182 bp and belonged to genotype D, subgenotype D1, and serotype ayw2. Missense mutations were found in the four regions (X, PreS1-S, PreC-C, and P) of the tested samples, leading to amino acid substitutions, which were 8.4%, 5.1%, 4.7%, and 4.6%, respectively. These mutations may cause severe liver diseases.

Computer aided design, synthesis and characterisation of thiazolidinedione acetic acid derivatives as brest- cancer inhibitors

The development of new anti-cancer drugs is a dynamic process that is continuously fueled, at the basic level, by the identification of new molecular targets for chemotherapeutic intervention, and, at the clinical level, by the problems (i.e. adherence, tolerability, toxicity, and virus-drug resistance) encountered with existing drugs. Thiazolidin-2,4-dione acetic acids are a class of heterocyclic compounds which possess the aforementioned pharmacophoric features. Thus several benzylidene-thiazolidin-2,4-dione compounds were designed. A total number of 12 compounds were synthesized successfully with good purity. The structures of these compounds have been confirmed by IR & Mass spectrometry. In-vitro studies of the synthesized compounds are yet to be performed & it is expected that these studies will reflect the effectiveness of these molecules as barest cancer inhibitors and will open a new dimension for the synthesis of novel anti-cancer agents. The labile structure of the synthesized compounds allows the possibility of elaborating the present work by increasing the number of derivatives & by altering the positions of substitutions on the root nucleus followed by SAR & QSAR studies. Moreover, compounds of similar nature can be designed which will lead to the synthesis of many more structural analogues.

Antimicrobial and Antiviral Nanofibers Halt Co-Infection Spread via Nuclease-Mimicry and Photocatalysis.

The escalating spread of drug-resistant bacteria and viruses is a grave concern for global health. Nucleic acids dominate the drug-resistance and transmission of pathogenic microbes. Here, imidazolium-type poly(ionic liquid)/porphyrin (PIL-P) based electrospun nanofibrous membrane and its cerium (IV) ion complex (PIL-P-Ce) are developed. The obtained PIL-P-Ce membrane exhibits high and stable efficiency in eradicating various microorganisms (bacteria, fungi, and viruses) and decomposing microbial antibiotic resistance genes and viral nucleic acids under light. The nuclease-mimetic and photocatalytic mechanisms of the PIL-P-Ce are elucidated. Co-infection wound models in mice with methicillin-resistant S. aureus and hepatitis B virus demonstrate that PIL-P-Ce integrate the triple effects of cationic polymer, photocatalysis, and nuclease-mimetic activities. As revealed by proteomic analysis, PIL-P-Ce shows minimal phototoxicity to normal tissues. Hence, PIL-P-Ce has potential as a "green" wound dressing to curb the spread of drug-resistant bacteria and viruses in clinical settings.

High Prevalence of Hepatitis B Virus Drug Resistance Mutations to Lamivudine among People with HIV/HBV Coinfection in Rural and Peri-Urban Communities in Botswana.

(1) Background: We aimed to determine the prevalence of hepatitis B virus (HBV) resistance-associated mutations (RAMs) in people with HBV and human immunodeficiency virus (HBV/HIV) in Botswana. (2) Methods: We sequenced HBV deoxyribonucleic acid (DNA) from participants with HBV/HIV from the Botswana Combination Prevention Project study (2013-2018) using the Oxford Nanopore GridION platform. Consensus sequences were analyzed for genotypic and mutational profiles. (3) Results: Overall, 98 HBV sequences had evaluable reverse transcriptase region coverage. The median participant age was 43 years (IQR: 37, 49) and 66/98 (67.4%) were female. Most participants, i.e., 86/98 (87.8%) had suppressed HIV viral load (VL). HBV RAMs were identified in 61/98 (62.2%) participants. Most RAMs were in positions 204 (60.3%), 180 (50.5%), and 173 (33.3%), mostly associated with lamivudine resistance. The triple mutations rtM204V/L180M/V173L were the most predominant (17/61 [27.9%]). Most participants (96.7%) with RAMs were on antiretroviral therapy for a median duration of 7.5 years (IQR: 4.8, 10.5). Approximately 27.9% (17/61) of participants with RAMs had undetectable HBV VL, 50.8% (31/61) had VL < 2000 IU/mL, and 13/61 (21.3%) had VL ≥ 2000 IU/mL. (4) Conclusions: The high prevalence of lamivudine RAMs discourages the use of ART regimens with 3TC as the only HBV-active drug in people with HIV/HBV.

Adults with Perinatally Acquired HIV; Emerging Clinical Outcomes and Data Gaps.

In resourced settings, adults living with perinatally acquired HIV are approaching the 5th decade of life. Their clinical and psychological outcomes highlight potential future issues for the much larger number of adolescents growing up with HIV in sub-Saharan Africa, and will inform the development of appropriate healthcare services. Lifelong exposure to HIV, and increasingly to antiretroviral therapy throughout growth and development, contrasts with adults acquiring HIV in later life. This review describes the clinical outcomes for adults living with perinatally acquired HIV including post transition mortality, morbidity and retention in care. Rates of viral suppression, drug resistance and immunological function are explored. Co-morbidities focus on metabolic, cardiovascular, respiratory and bone health with quality-of-life data including neurocognitive functioning and mental health. Sexual and reproductive health including vaccine-preventable disease and the prevention of onward transmission to partners and infants are considered. The data gaps and future research questions to optimise outcomes for this emerging adult cohort are highlighted.

Platycodin D facilitates antiviral immunity through inhibiting cytokine storm via targeting K63-linked TRAF6 ubiquitination.

Influenza virus infection is a worldwide challenge that causes heavy burdens on public health. The mortality rate of severe influenza patients is often associated with hyperactive immunological abnormalities characterized by hypercytokinemia. Due to the continuous mutations and the occurrence of drug-resistant influenza virus strains, the development of host-directed immunoregulatory drugs is urgently required. Platycodon grandiflorum is among the top 10 herbs of traditional Chinese medicine used to treat pulmonary diseases. As one of the major terpenoid saponins extracted from Platycodon grandiflorum, Platycodin D (PD) has been reported to play several roles, including anti-inflammation, analgesia, anti-cancer, hepatoprotection, and immunoregulation. However, the therapeutic roles of PD to treat influenza virus infection remains unknown. Here, we show that PD can protect the body weight loss in severely infected influenza mice, alleviate lung damage, and thus improve the survival rate. More specifically, PD protects flu mice via decreasing the immune cell infiltration into lungs and downregulating the overactivated inflammatory response. Western blot and immunofluorescence assays exhibited that PD could inhibit the activation of TAK1/IKK/NF-κB and MAPK pathways. Besides that, CETSA, SPR and immunoprecipitation assays indicated that PD binds with TRAF6 to decrease its K63 ubiquitination after R837 stimulation. Additionally, siRNA interference experiments exhibited that PD could inhibit the secretion of IL-1β and TNF-α in TRAF6-dependent manner. Altogether, our results suggested that PD is a promising drug candidate for treating influenza. Our study also offered a scientific explanation for the commonly used Platycodon grandiflorum in many anti-epidemic classic formulas. Due to its host-directed regulatory role, PD may serve as an adjuvant therapeutic drug in conjunction with other antiviral drugs to treat the flu.

Global viralepidemias! - truce is the future of global public health?

Background: In premodern times, human diseases like Tuberculosis, Polio, Smallpox, and Diphtheria circulated widely, and caused substantial morbidity and mortality. The advent of antibiotics and vaccines in the past two decades, aided by medical advances, improved access to health care and improved sanitation have reduced the overall mortality and morbidity linked to infectious diseases, particularly of bacterial origins like lower respiratory tract infections and diarrhoeal diseases. Since 2020 entire world has been concerned with viral infections, with at least three out of- SARS-Cov-2, Dengue, Influenza, RSV, Hepatitis B, and Japanese encephalitis bothering every country. While in High-income countries three infectious diseases COVID-19, Influenza, and Dengue of viral origin are challenging public health in low and lower-middle-income countries in addition to three, Tuberculosis, enteric fevers, and other neglected tropical diseases add to public health challenges. Materials and methods: Available data on the internet from various sources from key countries, clinical manifestations, and complications, the management practices and epidemiology, and learnings of many preventive strategies and control efforts. The data sources used are WHO disease-wise releases from headquarters and Regional Offices, COVID 19 Wordometer, CDC Atlanta reports for US outbreaks, Europe the ECDC Communicable Disease Threats Reports (CDTR bulletin), NHM India, NCDC India, The National Health Commission of the People’s Republic of China notification to WHO, for search keywords used were burden, outbreaks total cases, deaths, Incidence, Prevalence, etc. by each disease Results: The war against microbes started with the discovery of the antibiotic Penicillin in 1928, but their overuse has made many of them resistant to antibiotics. Since the beginning of the 20th century, Vaccines and antivirals have drastically reduced the number of cases of viral diseases such as polio, measles, chickenpox, the flu, hepatitis A, hepatitis B, Human Papillomavirus (HPV), and others. The treatment of viral infections has proved more challenging than that of bacterial infections, primarily because viruses are relatively tiny, reproduce inside cells, and do not succumb to antibiotics. However, antiviral medications have become available for herpes simplex virus, HIV/AIDS, and influenza, their indiscriminate may lead to the development of drug-resistant viruses. Conclusion: The swift development of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine speaks to the efficacy of modern science in rapidly countering threats from emerging pathogens. In such situations, People must learn and use as many preventive strategies as possible. This article is a review of Viral diseases currently bothering all countries and reflecting the challenges of the decade to come.

Amino acid pattern reveals multi-functionality of ORF3 protein from HEV.

The smallest open reading frame (ORF) encoded protein ORF3 of hepatitis E virus (HEV), recently, has been demonstrated to perform multiple functions besides accessory roles. ORF3 could act as a target for vaccine against HEV infections. The IDR (intrinsically disordered region); IDP (ID protein)/IDPR (ID protein region), plays critical role in various regulatory functions of viruses. The dark proteome of HEV-ORF3 protein including its structure and function was systematically examined by computer predictors to explicate its role in viral pathogenesis and drug resistance beyond its functions as accessory viral protein. Amino acid distribution showed ORF3 enrichment with disorder-promoting residues (Ala, Pro, Ser, Gly) while deficiency in order-promoting residues (Asn, Ile, Phe, Tyr and Trp). Initial investigation revealed ORF3 as IDP (entirely disordered protein) or IDPR (proteins consisting of IDRs with structured globular domains). Structural examination revealed preponderance of disordered regions interpreting ORF3 as moderately/highly disordered protein. Further disorder predictors categorized ORF3 as highly disordered protein/IDP. Identified sites and associated-crucial molecular functions revealed ORF3 involvement in diverse biological processes, substantiating them as targets of regulation. As ORF3 functions are yet to completely explored, thus, data on its disorderness could help in elucidating its disorder related functions.

The combination of pleconaril, rupintrivir, and remdesivir efficiently inhibits enterovirus infections in vitro, delaying the development of drug-resistant virus variants

Enteroviruses are a significant global health concern, causing a spectrum of diseases from the common cold to more severe conditions like hand-foot-and-mouth disease, meningitis, myocarditis, pancreatitis, and poliomyelitis. Current treatment options for these infections are limited, underscoring the urgent need for effective therapeutic strategies. To find better treatment option we analyzed toxicity and efficacy of 12 known broad-spectrum anti-enterovirals both individually and in combinations against different enteroviruses in vitro. We identified several novel, synergistic two-drug and three-drug combinations that demonstrated significant inhibition of enterovirus infections in vitro. Specifically, the triple-drug combination of pleconaril, rupintrivir, and remdesivir exhibited remarkable efficacy against echovirus (EV) 1, EV6, EV11, and coxsackievirus (CV) B5, in human lung epithelial A549 cells. This combination surpassed the effectiveness of single-agent or dual-drug treatments, as evidenced by its ability to protect A549 cells from EV1-induced cytotoxicity across seven passages. Additionally, this triple-drug cocktail showed potent antiviral activity against EV-A71 in human intestinal organoids. Thus, our findings highlight the therapeutic potential of the pleconaril-rupintrivir-remdesivir combination as a broad-spectrum treatment option against a range of enterovirus infections. The study also paves the way towards development of strategic antiviral drug combinations with virus family coverage and high-resistance barriers.

Molecular Determinants of Drug Resistance and Mutation Patterns in Influenza Viruses Circulating in Poland Across Multiple Epidemic Seasons: Implications for Vaccination Strategies.

BACKGROUND According to the WHO, up to 650 000 people die each year from seasonal flu-related respiratory illnesses. The most effective method of fighting the virus is seasonal vaccination. However, if an infection does occur, antiviral medications should be used as soon as possible. No studies of drug resistance in influenza viruses circulating in Poland have been systematically conducted. Therefore, the aim of the present study was to investigate the drug resistance and genetic diversity of influenza virus strains circulating in Poland by determining the presence of mutations in the neuraminidase gene. MATERIAL AND METHODS A total of 258 clinical specimens were collected during the 2016-2017, 2017-2018, and 2018-2019 epidemic seasons. The samples containing influenza A and B were analyzed by RT-PCR and Sanger sequencing. RESULTS Differences were found between the influenza virus strains detected in different epidemic seasons, demonstrating the occurrence of mutations. Influenza A virus was found to be more genetically variable than influenza B virus (P<0.001, Kruskal-Wallis test). However, there was no significant difference in the resistance prevalence between the influenza A subtypes A/H1N1/pdm09 (4.8%) and A/H3N2/ (6.1%). In contrast, more mutations of drug-resistance genes were found in the influenza B virus (P<0.001, chi-square test). In addition, resistance mutations appeared en masse in vaccine strains circulating in unvaccinated populations. CONCLUSIONS It seems important to determine whether the influenza virus strains tested for drug resistance as part of global influenza surveillance are equally representative of viruses circulating in populations with high and low vaccination rates, for all countries. Our results suggest that countries with low levels of influenza immunization may constitute reservoirs of drug-resistant influenza viruses.

Antiviral drug on hepatitis B virus genotypes and drug resistance genes

Antiviral drug on hepatitis B virus genotypes and drug resistance genes

An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity.

The repertoire of currently available antiviral drugs spans therapeutic applications against a number of important human pathogens distributed worldwide. These include cases of the pandemic severe acute respiratory coronavirus type 2 (SARS-CoV-2 or COVID-19), human immunodeficiency virus type 1 (HIV-1 or AIDS), and the pregnancy- and posttransplant-relevant human cytomegalovirus (HCMV). In almost all cases, approved therapies are based on direct-acting antivirals (DAAs), but their benefit, particularly in long-term applications, is often limited by the induction of viral drug resistance or side effects. These issues might be addressed by the additional use of host-directed antivirals (HDAs). As a strong input from long-term experiences with cancer therapies, host protein kinases may serve as HDA targets of mechanistically new antiviral drugs. The study demonstrates such a novel antiviral strategy by targeting the major virus-supportive host kinase CDK7. Importantly, this strategy focuses on highly selective, 3D structure-derived CDK7 inhibitors carrying a warhead moiety that mediates covalent target binding. In summary, the main experimental findings of this study are as follows: (1) the in vitro verification of CDK7 inhibition and selectivity that confirms the warhead covalent-binding principle (by CDK-specific kinase assays), (2) the highly pronounced antiviral efficacies of the hit compounds (in cultured cell-based infection models) with half-maximal effective concentrations that reach down to picomolar levels, (3) a particularly strong potency of compounds against strains and reporter-expressing recombinants of HCMV (using infection assays in primary human fibroblasts), (4) additional activity against further herpesviruses such as animal CMVs and VZV, (5) unique mechanistic properties that include an immediate block of HCMV replication directed early (determined by Western blot detection of viral marker proteins), (6) a substantial drug synergism in combination with MBV (measured by a Loewe additivity fixed-dose assay), and (7) a strong sensitivity of clinically relevant HCMV mutants carrying MBV or ganciclovir resistance markers. Combined, the data highlight the huge developmental potential of this host-directed antiviral targeting concept utilizing covalently binding CDK7 inhibitors.

Anti-rheumatic colchicine phytochemical exhibits potent antiviral activities against avian and seasonal Influenza A viruses (IAVs) via targeting different stages of IAV replication cycle

BackgroundThe continuous evolution of drug-resistant influenza viruses highlights the necessity for repurposing naturally-derived and safe phytochemicals with anti-influenza activity as novel broad-spectrum anti-influenza medications.MethodsIn this study, nitrogenous alkaloids were tested for their viral inhibitory activity against influenza A/H1N1 and A/H5N1 viruses. The cytotoxicity of tested alkaloids on MDCK showed a high safety range (CC50 > 200 µg/ml), permitting the screening for their anti-influenza potential. ResultsHerein, atropine sulphate, pilocarpine hydrochloride and colchicine displayed anti-H5N1 activities with IC50 values of 2.300, 0.210 and 0.111 µg/ml, respectively. Validation of the IC50 values was further depicted by testing the three highly effective alkaloids, based on their potent IC50 values against seasonal influenza A/H1N1 virus, showing comparable IC50 values of 0.204, 0.637 and 0.326 µg/ml, respectively. Further investigation suggests that colchicine could suppress viral infection by primarily interfering with IAV replication and inhibiting viral adsorption, while atropine sulphate and pilocarpine hydrochloride could directly affect the virus in a cell-free virucidal effect. Interestingly, the in silico molecular docking studies suggest the abilities of atropine, pilocarpine, and colchicine to bind correctly inside the active sites of the neuraminidases of both influenza A/H1N1 and A/H5N1 viruses. The three alkaloids exhibited good binding energies as well as excellent binding modes that were similar to the co-crystallized ligands. On the other hand, consistent with in vitro results, only colchicine could bind correctly against the M2-proton channel of influenza A viruses (IAVs). This might explicate the in vitro antiviral activity of colchicine at the replication stage of the virus replication cycle.ConclusionThis study highlighted the anti-influenza efficacy of biologically active alkaloids including colchicine. Therefore, these alkaloids should be further characterized in vivo (preclinical and clinical studies) to be developed as anti-IAV agents.

Distribution of hepatitis С virus drug resistance mutations among patients with recurrence of the disease during therapy with direct antiviral drugs

The aim of the study was to identify the prevalence of drug resistance mutations in the hepatitis C virus among patients with relapse of the disease on therapy with direct antiviral drugs.Materials and methods. The study material included 31 blood plasma samples from patients with chronic hepatitis C with relapse of the disease on therapy with direct antiviral drugs. Samples were screened for the presence of HCV RNA. In case of detection of HCV RNA, amplification was carried out using a set of primers jointly flanking the NS3, NS5A, NS5B genes. After sequencing the nucleotide sequences of these genes, the subtype of the virus was determined and drug resistance mutations were identified.Results and discussion. The age of the patients ranged from 33 to 62 and averaged 45.8±8.38 years. The number of men in the group prevailed compared to women — 21 (67%) and 10 (33%), respectively. Viral load determination results ranged from 3.1×103 to 4.2×107 IU/ml. The distribution of genotypes was as follows: 1a — 26% (n=8), 1b — 29% (n=9), 3a — 45% (n=14). The nucleotide sequence of the NS3, NS5A, NS5B regions was determined in all samples. Mutations associated with drug resistance were detected in 87% (n=27). In all identified cases, the mutations resulted in viral resistance to at least one drug included in the patient’s current treatment regimen. In one patient, amino acid substitutions were found in three regions at once, which led to the emergence of resistance to two drugs in the regimen.Conclusion. Conducting a preliminary examination of patients to identify mutations of drug resistance to direct antiviral drugs can affect the effectiveness of the planned treatment and the choice of the optimal regimen.

Virologic Nonsuppression and HIV Drug Resistance Among People Who Inject Drugs and Their Sexual and Injecting Partners in Kenya.

We evaluated the prevalence and correlates of HIV viral nonsuppression and HIV drug resistance (HIV-DR) in a cohort of people who inject drugs living with HIV (PWID-LH) and their sexual and injecting partners living with HIV in Kenya. HIV-DR testing was performed on participants with viral nonsuppression. Of 859 PWID-LH and their partners, 623 (72.5%) were on antiretroviral therapy (ART) ≥4 months and 148/623 (23.8%) were not virally suppressed. Viral nonsuppression was more common among younger participants and those on ART for a shorter duration. Among 122/148 (82.4%) successfully sequenced samples, 55 (45.1%) had detectable major HIV-DR mutations, mainly to non-nucleoside and nucleotide reverse transcriptase inhibitors (NNRTI and NRTI). High levels of HIV-DR among those with viral nonsuppression suggests need for viral load monitoring, adherence counseling, and timely switching to alternate ART regimens in this key population.

LSTM-driven drug design using SELFIES for target-focused de novo generation of HIV-1 protease inhibitor candidates for AIDS treatment.

The battle against viral drug resistance highlights the need for innovative approaches to replace time-consuming and costly traditional methods. Deep generative models offer automation potential, especially in the fight against Human immunodeficiency virus (HIV), as they can synthesize diverse molecules effectively. In this paper, an application of an LSTM-based deep generative model named "LSTM-ProGen" is proposed to be tailored explicitly for the de novo design of drug candidate molecules that interact with a specific target protein (HIV-1 protease). LSTM-ProGen distinguishes itself by employing a long-short-term memory (LSTM) architecture, to generate novel molecules target specificity against the HIV-1 protease. Following a thorough training process involves fine-tuning LSTM-ProGen on a diverse range of compounds sourced from the ChEMBL database. The model was optimized to meet specific requirements, with multiple iterations to enhance its predictive capabilities and ensure it generates molecules that exhibit favorable target interactions. The training process encompasses an array of performance evaluation metrics, such as drug-likeness properties. Our evaluation includes extensive silico analysis using molecular docking and PCA-based visualization to explore the chemical space that the new molecules cover compared to those in the training set. These evaluations reveal that a subset of 12 de novo molecules generated by LSTM-ProGen exhibit a striking ability to interact with the target protein, rivaling or even surpassing the efficacy of native ligands. Extended versions with further refinement of LSTM-ProGen hold promise as versatile tools for designing efficacious and customized drug candidates tailored to specific targets, thus accelerating drug development and facilitating the discovery of new therapies for various diseases.

Current Perspectives on Letermovir and Maribavir for the Management of Cytomegalovirus Infection in Solid Organ Transplant Recipients.

Cytomegalovirus (CMV) infection is arguably the most important infectious complication that negatively affects the outcome of solid organ transplantation. For decades, CMV management after transplantation has relied on antiviral drugs that inhibit viral DNA polymerase (ganciclovir, foscarnet, and cidofovir). However, their use has been complicated by myelosuppression, nephrotoxicity, and selection of drug-resistant viruses. During the past few years, the therapeutic armamentarium for the management of CMV in solid organ transplant recipients has expanded with the approval of letermovir for CMV prophylaxis in high-risk CMV D+/R- kidney recipients, and maribavir for the treatment of refractory and resistant CMV infection. Both drugs offer significant improvement when compared to standard anti-CMV therapies; letermovir was as efficacious for CMV prevention, whereas maribavir was more effective in treating refractory and resistant CMV infections. Both letermovir and maribavir have favorable safety profiles compared to CMV DNA polymerase inhibitors, without the risk of neutropenia and leukopenia associated with ganciclovir and renal toxicities associated with foscarnet and cidofovir. Moreover, letermovir and maribavir are orally bioavailable, which allows convenient outpatient treatment. However, letermovir and maribavir have a significant drug interaction potential in solid organ transplant recipients, resulting in higher levels of calcineurin inhibitors (cyclosporine and tacrolimus) and mTOR inhibitors (sirolimus and everolimus). Both letermovir and maribavir are CMV-specific and do not have clinical efficacy against other herpes viruses. Thus, there is a need for additional antiviral drugs to prevent herpes simplex and other herpes viruses when clinically indicated. This article provides a comprehensive review of the clinical data supporting the use of letermovir and maribavir in clinical practice. The author provides perspectives on the role of these newly approved drugs in the current management landscape of CMV infection in solid organ transplantation.

Validation of nuclear receptor RORγ isoform 1 as a novel host-directed antiviral target based on the modulation of cholesterol levels

Currently, the clinically approved repertoire of antiviral drugs predominantly comprises direct-acting antivirals (DAAs). However, the use of DAAs is frequently limited by adverse effects, restriction to individual virus species, or the induction of viral drug resistance. These issues will likely be resolved by the introduction of host-directed antivirals (HDAs) targeting cellular proteins crucial for viral replication. However, experiences with the development of antiviral HDAs and clinical applications are still in their infancy. With the present study, we explored the human nuclear receptor and transcription factor RORγ isoform 1 (RORγ1), a member of the retinoic acid receptor-related orphan receptor (ROR) family, as a putative target of antiviral HDAs. To this end, cell culture models were used to investigate major viral human pathogens, i.e. the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human cytomegalovirus (HCMV), varicella zoster virus (VZV) and human immunodeficiency virus 1 (HIV-1). Our results demonstrated (i) an antiviral activity of the clinically relevant RORγ modulators cedirogant and others, (ii) that isoform RORγ1 acts as the responsible determinant and drug target in the analyzed cell culture-based models, (iii) a selectivity of the antiviral effect for RORγ1 over related receptors RORα and RORβ, (iv) a late-phase inhibition exerted by cedirogant in HCMV replication and (v) a mechanistic link to the cellular cholesterol biosynthesis. Combined, the data highlight this novel RORγ-specific antiviral targeting concept and the developmental potential of RORγ-directed small molecules.

1601. Transmitted Drug Resistance in Treatment-Naïve People Living with HIV in Costa Rica

Abstract Background Transmitted drug resistance (TDR) occurs in people living with HIV infection (PLWH) who are not exposed to antiretroviral drugs but who are infected with a virus with mutations associated with resistance. In Costa Rica, HIV genotyping is performed in PLWH failing their first-line ART regimen, but it is not routinely done for all treatment-naïve PLWH before ART initiation, therefore, little is known about TDR prevalence. Methods The aim of this study was to determine the prevalence of TDR and the HIV mutation patterns. During 2020, 162 cases of newly diagnosed treatment-naïve PLWH from all of the country’s HIV clinics were included for a genotyping study. Viral ARN was extracted from plasma samples obtained from the HIV National Reference Laboratory and protease (PR), reverse transcriptase (RT), and integrase (IN) regions were amplified and sequenced. The HIV database Program (Stanford University) and the World Health Organization (WHO) 2009 TDR surveillance mutation list were used for interpretation of resistance-associated mutations. Results The overall prevalence of TDR was 36% (N=59/162). According to ART class, TDR was 22% in the nucleoside reverse transcriptase inhibitors (NRTI), followed by 13% in the non-nucleoside reverse transcriptase inhibitors (NNRTI); for the protease inhibitors (PI) and the integrase inhibitors (INI), TDR was 8% and 3%, respectively. (Figures 1-3). Most common mutations were: in NRTI, M41L (9.9%), and M184I (6.8%); in NNRTI, K103N (7.4%); in PI, M46I (4.3%); in INI, T97A (1.9%). (Table 1). The median age was 32 years-old (range: 16-71), and 91% were male. Median CD4 count was 420 cells/uL (range: 11-1670) and median viral load was 588337 copies/mL (range: 1220-10000000). According to CDC classification, 20% were stage C-3. Source: local database Source: local database Source: local database Conclusion This study population has a moderate level of HIV drug resistance (HIVDR) in ART-naïve PLWH and strongly implies the need to introduce HIVDR surveillance in Costa Rica. These findings confirm the TDR and highlight the need for systematic viral load monitoring and drug resistance testing at diagnosis. Continuous surveillance of newly infected individuals is required to help strategize the best ART regimen for these patients, and should prompt a change in current local recommendations for starting ART. Source: local database Disclosures All Authors: No reported disclosures