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Viruses
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Antiviral Resistance Mutations
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Antiviral Resistance Mutations

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: 28 February 2025 | Viewed by 8059

Special Issue Editors

Dr. Ilaria Vicenti

E-Mail Website
Guest Editor
Department of Medical Biotechnologies, University of Siena, Siena, Italy
Interests: flaviviruses; HIV-1; SARS-COV-2; antivirals; cell-based viral assays; drug resistance; live virus neutralization
Special Issues, Collections and Topics in MDPI journals
Dr. Francesco Saladini

E-Mail Website
Guest Editor
Department of Medical Biotechnologies, University of Siena, Siena, Italy
Interests: HIV-1; flaviviruses; antivirals; cell-based viral assays; drug resistance; viral genetic evolution

Special Issue Information

Dear Colleagues,

In viral genomes, mutations occur spontaneously and rapidly, creating new viral strains with properties that differ from the parental or wild-type virus. The mutation rate varies across different families of viruses, with lower levels for DNA viruses and higher rates for RNA viruses and with genome size, viral polymerases and proofreading activity playing a key role. Many mutations have no effect or are harmful to the virus; however, some can alter the antigenicity or pathogenicity of the virus or lead to resistance to antiviral drugs. Depending on selective pressure, mutations can persist in chronically infected individuals and be transmitted to newly infected individuals. Antiviral drug resistance is a serious public health threat and may impact on our response to epidemics and pandemics. The emergence of SARS-CoV-2 variants, resulting in evasion from vaccine-induced immunity and from therapeutic monoclonal antibodies, and the extraordinary plasticity of HIV quasispecies conferring resistance to various classes of drugs are key examples of the global impact of antiviral resistance, underscoring the importance of ongoing research, surveillance, and adaptation of medical interventions. In this Special Issue, we provide original and review articles describing the phenomenon of viral resistance leading to escape from immune response (natural or artificial) and from antiviral therapies. The articles included in this Special Issue will focus on viral genome mutations leading to viral drug-resistant phenotypes in different contexts such as acute and persistent infections, natural and drug-driven virus evolution, and interactions among mutations and between mutations and fitness. Dealing with drug resistance is and will remain an obligatory step both in antiviral drug development and in clinical use of available antivirals. 

Dr. Ilaria Vicenti
Dr. Francesco Saladini
Guest Editors

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antiviral resistance
  • virus evolution
  • viral genome mutation
  • drug-resistant phenotypes
  • immune escape

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Published Papers (7 papers)

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Research

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11 pages, 250 KiB  
Article
Spectrum of Non-Nucleoside Reverse Transcriptase Inhibitor-Associated Drug Resistance Mutations in Persons Living with HIV-1 Receiving Rilpivirine
by Pavithra Nagarajan, Jinru Zhou, Giulia Di Teodoro, Francesca Incardona, Carole Seguin-Devaux, Rolf Kaiser, Ana B. Abecasis, Perpetua Gomes, Kaiming Tao, Maurizio Zazzi and Robert W. Shafer
Viruses 2024, 16(11), 1715; https://doi.org/10.3390/v16111715 - 31 Oct 2024
Viewed by 535
Abstract
Introduction: Few data are currently available on the nonnucleoside reverse transcriptase (RT) inhibitors (NNRTI) resistance mutations selected in persons living with HIV-1 (PLWH) who develop virological failure while receiving rilpivirine (RPV). Methods: We analyzed pooled HIV-1 RT genotypic data from 280 PLWH in [...] Read more.
Introduction: Few data are currently available on the nonnucleoside reverse transcriptase (RT) inhibitors (NNRTI) resistance mutations selected in persons living with HIV-1 (PLWH) who develop virological failure while receiving rilpivirine (RPV). Methods: We analyzed pooled HIV-1 RT genotypic data from 280 PLWH in the multicenter EuResist database and 115 PLWH in the Stanford HIV Drug Resistance Database (HIVDB) who received RPV as their only NNRTI. Results: Among the 395 PLWH receiving RPV, 180 (45.6%) had one or more NNRTI-associated DRMs. Overall, 44 NNRTI-associated DRMs were identified, including 26 that occurred in two or more PLWHs. Seven mutations had a prevalence ≥10% among the 180 PLWH with one or more NNRTI-associated DRM: E138K (32.2%), V90I (25.0%), K101E (17.8%), Y181C (17.2%), E138A (13.9%), H221Y (12.2%), and K103N (10.6%). Y181C was significantly more likely to co-occur with K101E, V179F, H221Y, and M230L. Ten novel non-polymorphic mutations at known NNRTI-associated mutation positions were also identified, usually in just one PLWH: L100F, V108A, T139I, P225S, M230V, Y232C, and T240A/I/M/S. Conclusions: Our analysis extends the spectrum of mutations emerging in PLWH receiving RPV. Additional phenotypic characterization of RPV-selected mutations is necessary to better understand their biological and possible clinical significance. Full article
(This article belongs to the Special Issue Antiviral Resistance Mutations)
16 pages, 265 KiB  
Article
A Comparison of Sanger Sequencing and Amplicon-Based Next Generation Sequencing Approaches for the Detection of HIV-1 Drug Resistance Mutations
by Camilla Biba, Lia Fiaschi, Ilenia Varasi, Chiara Paletti, Niccolò Bartolini, Maurizio Zazzi, Ilaria Vicenti and Francesco Saladini
Viruses 2024, 16(9), 1465; https://doi.org/10.3390/v16091465 - 14 Sep 2024
Viewed by 1209
Abstract
Background: Next-generation sequencing (NGS) kits are needed to finalise the transition from Sanger sequencing to NGS in HIV-1 genotypic drug resistance testing. Materials and Methods: We compared a homemade NGS amplicon-based protocol and the AD4SEQ HIV-1 Solution v2 (AD4SEQ) NGS kit from Arrow [...] Read more.
Background: Next-generation sequencing (NGS) kits are needed to finalise the transition from Sanger sequencing to NGS in HIV-1 genotypic drug resistance testing. Materials and Methods: We compared a homemade NGS amplicon-based protocol and the AD4SEQ HIV-1 Solution v2 (AD4SEQ) NGS kit from Arrow Diagnostics for identifying resistance-associated mutations (RAMs) above the 5% threshold in 28 plasma samples where Sanger sequencing previously detected at least one RAM. Results: The samples had a median 4.8 log [IQR 4.4–5.2] HIV-1 RNA copies/mL and were mostly subtype B (61%) and CRF02_AG (14%). Homemade NGS had a lower rate of samples with low-coverage regions (2/28) compared with AD4SEQ (13/28) (p < 0.001). Homemade NGS and AD4SEQ identified additional mutations with respect to Sanger sequencing in 13/28 and 9/28 samples, respectively. However, there were two and eight cases where mutations detected by Sanger sequencing were missed by homemade NGS and AD4SEQ-SmartVir, respectively. The discrepancies between NGS and Sanger sequencing resulted in a few minor differences in drug susceptibility interpretation, mostly for NNRTIs. Conclusions: Both the NGS systems identified additional mutations with respect to Sanger sequencing, and the agreement between them was fair. However, AD4SEQ should benefit from technical adjustments allowing higher sequence coverage. Full article
(This article belongs to the Special Issue Antiviral Resistance Mutations)
14 pages, 4458 KiB  
Article
Comparison of Different HIV-1 Resistance Interpretation Tools for Next-Generation Sequencing in Italy
by Daniele Armenia, Luca Carioti, Valeria Micheli, Isabella Bon, Tiziano Allice, Celestino Bonura, Bianca Bruzzone, Fiorenza Bracchitta, Francesco Cerutti, Giovanni Maurizio Giammanco, Federica Stefanelli, Maria Addolorata Bonifacio, Ada Bertoli, Marialinda Vatteroni, Gabriele Ibba, Federica Novazzi, Maria Rosaria Lipsi, Nunzia Cuomo, Ilaria Vicenti, Francesca Ceccherini-Silberstein, Barbara Rossetti, Antonia Bezenchek, Francesco Saladini, Maurizio Zazzi and Maria Mercedes Santoroadd Show full author list remove Hide full author list
Viruses 2024, 16(9), 1422; https://doi.org/10.3390/v16091422 - 6 Sep 2024
Cited by 1 | Viewed by 877
Abstract
Background: Next-generation sequencing (NGS) is gradually replacing Sanger sequencing for HIV genotypic drug resistance testing (GRT). This work evaluated the concordance among different NGS-GRT interpretation tools in a real-life setting. Methods: Routine NGS-GRT data were generated from viral RNA at 11 Italian laboratories [...] Read more.
Background: Next-generation sequencing (NGS) is gradually replacing Sanger sequencing for HIV genotypic drug resistance testing (GRT). This work evaluated the concordance among different NGS-GRT interpretation tools in a real-life setting. Methods: Routine NGS-GRT data were generated from viral RNA at 11 Italian laboratories with the AD4SEQ HIV-1 Solution v2 commercial kit. NGS results were interpreted by the SmartVir system provided by the kit and by two online tools (HyDRA Web and Stanford HIVdb). NGS-GRT was considered valid when the coverage was >100 reads (100×) at each PR/RT/IN resistance-associated position listed in the HIVdb 9.5.1 algorithm. Results: Among 629 NGS-GRT, 75.2%, 74.2%, and 70.9% were valid according to SmartVir, HyDRA Web, and HIVdb. Considering at least two interpretation tools, 463 (73.6%) NGS-GRT had a valid coverage for resistance analyses. The proportion of valid samples was affected by viremia <10,000–1000 copies/mL and non-B subtypes. Mutations at an NGS frequency >10% showed fair concordance among different interpretation tools. Conclusion: This Italian survey on NGS resistance testing suggests that viremia levels and HIV subtype affect NGS-GRT coverage. Within the current routine method for NGS-GRT, only mutations with frequency >10% seem reliably detected across different interpretation tools. Full article
(This article belongs to the Special Issue Antiviral Resistance Mutations)
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13 pages, 730 KiB  
Article
Development and Optimization of Oligonucleotide Ligation Assay (OLA) Probes for Detection of HIV-1 Resistance to Dolutegravir
by Ingrid A. Beck, Ceejay L. Boyce, Marley D. Bishop, Yen L. Vu, Amanda Fung, Sheila Styrchak, Nuttada Panpradist, Barry R. Lutz and Lisa M. Frenkel
Viruses 2024, 16(7), 1162; https://doi.org/10.3390/v16071162 - 19 Jul 2024
Viewed by 1075
Abstract
The WHO currently recommends dolutegravir (DTG)-based ART for persons living with HIV infection in resource-limited-settings (RLS). To expand access to testing for HIV drug resistance (DR) to DTG in RLS, we developed probes for use in the oligonucleotide ligation assay (OLA)-Simple, a near-point [...] Read more.
The WHO currently recommends dolutegravir (DTG)-based ART for persons living with HIV infection in resource-limited-settings (RLS). To expand access to testing for HIV drug resistance (DR) to DTG in RLS, we developed probes for use in the oligonucleotide ligation assay (OLA)-Simple, a near-point of care HIV DR kit. Genotypic data from clinical trials and case reports were used to determine the mutations in HIV-1 integrase critical to identifying individuals with DTG-resistance at virologic failure of DTG-based ART. Probes to detect G118R, Q148H/K/R, N155H and R263K in HIV-1 subtypes A, B, C, D and CRF01_AE were designed using sequence alignments from the Los Alamos database and validated using 61 clinical samples of HIV-1 subtypes A, B, C, D, CRF01_AE genotyped by PacBio (n = 15) or Sanger (n = 46). Initial OLA probes failed to ligate for 16/244 (6.5%) codons (9 at G118R and 7 at Q148H/K/R). Probes revised to accommodate polymorphisms interfering with ligation at codons G118R and Q148R reduced indeterminates to 3.7% (5 at G118R and 4 at Q148H/K/R) and detected DTG-mutations with a sensitivity of 96.5% and 100% specificity. These OLA DTG resistance probes appear highly sensitive and specific across HIV-1 subtypes common in RLS with high burden of HIV infection. Full article
(This article belongs to the Special Issue Antiviral Resistance Mutations)
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11 pages, 840 KiB  
Article
Increase of Synergistic Secondary Antiviral Mutations in the Evolution of A(H1N1)pdm09 Influenza Virus Neuraminidases
by Susanne C. Duwe, Jeanette Milde, Alla Heider, Marianne Wedde, Brunhilde Schweiger and Ralf Dürrwald
Viruses 2024, 16(7), 1109; https://doi.org/10.3390/v16071109 - 11 Jul 2024
Viewed by 1123
Abstract
The unexpected emergence of oseltamivir-resistant A(H1N1) viruses in 2008 was facilitated in part by the establishment of permissive secondary neuraminidase (NA) substitutions that compensated for the fitness loss due to the NA-H275Y resistance substitution. These viruses were replaced in 2009 by oseltamivir-susceptible A(H1N1)pdm09 [...] Read more.
The unexpected emergence of oseltamivir-resistant A(H1N1) viruses in 2008 was facilitated in part by the establishment of permissive secondary neuraminidase (NA) substitutions that compensated for the fitness loss due to the NA-H275Y resistance substitution. These viruses were replaced in 2009 by oseltamivir-susceptible A(H1N1)pdm09 influenza viruses. Genetic analysis and screening of A(H1N1)pdm09 viruses circulating in Germany between 2009 and 2024 were conducted to identify any potentially synergistic or resistance-associated NA substitutions. Selected viruses were then subjected to further characterization in vitro. In the NA gene of circulating A(H1N1)pdm09 viruses, two secondary substitutions, NA-V241I and NA-N369K, were identified. These substitutions demonstrated a stable lineage in phylogenetic analysis since the 2010–2011 influenza season. The data indicate a slight increase in viral NA bearing two additional potentially synergistic substitutions, NA-I223V and NA-S247N, in the 2023–2024 season, which both result in a slight reduction in susceptibility to NA inhibitors. The accumulation of secondary synergistic substitutions in the NA of A(H1N1)pdm09 viruses increases the probability of the emergence of antiviral-resistant viruses. Therefore, it is crucial to closely monitor the evolution of circulating influenza viruses and to develop additional antiviral drugs against different target proteins. Full article
(This article belongs to the Special Issue Antiviral Resistance Mutations)
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15 pages, 1832 KiB  
Article
Applying Next-Generation Sequencing to Track HIV-1 Drug Resistance Mutations Circulating in Portugal
by Victor Pimentel, Marta Pingarilho, Cruz S. Sebastião, Mafalda Miranda, Fátima Gonçalves, Joaquim Cabanas, Inês Costa, Isabel Diogo, Sandra Fernandes, Olga Costa, Rita Corte-Real, M. Rosário O. Martins, Sofia G. Seabra, Ana B. Abecasis and Perpétua Gomes
Viruses 2024, 16(4), 622; https://doi.org/10.3390/v16040622 - 17 Apr 2024
Cited by 1 | Viewed by 1463
Abstract
Background: The global scale-up of antiretroviral treatment (ART) offers significant health benefits by suppressing HIV-1 replication and increasing CD4 cell counts. However, incomplete viral suppression poses a potential threat for the emergence of drug resistance mutations (DRMs), limiting ART options, and increasing HIV [...] Read more.
Background: The global scale-up of antiretroviral treatment (ART) offers significant health benefits by suppressing HIV-1 replication and increasing CD4 cell counts. However, incomplete viral suppression poses a potential threat for the emergence of drug resistance mutations (DRMs), limiting ART options, and increasing HIV transmission. Objective: We investigated the patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) among HIV-1 patients in Portugal. Methods: Data were obtained from 1050 HIV-1 patient samples submitted for HIV drug resistance (HIVDR) testing from January 2022 to June 2023. Evaluation of DRM affecting viral susceptibility to nucleoside/tide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs) was performed using an NGS technology, the Vela Diagnostics Sentosa SQ HIV-1 Genotyping Assay. Results: About 71% of patients were ART naïve and 29% were experienced. Overall, 20% presented with any DRM. The prevalence of TDR and ADR was 12.6% and 41.1%, respectively. M184V, T215S, and M41L mutations for NRTI, K103N for NNRTI, and M46I/L for PIs were frequent in naïve and treated patients. E138K and R263K mutations against INSTIs were more frequent in naïve than treated patients. TDR and ADR to INSTIs were 0.3% and 7%, respectively. Patients aged 50 or over (OR: 1.81, p = 0.015), originating from Portuguese-speaking African countries (PALOPs) (OR: 1.55, p = 0.050), HIV-1 subtype G (OR: 1.78, p = 0.010), and with CD4 < 200 cells/mm3 (OR: 1.70, p = 0.043) were more likely to present with DRMs, while the males (OR: 0.63, p = 0.003) with a viral load between 4.1 to 5.0 Log10 (OR: 0.55, p = 0.003) or greater than 5.0 Log10 (OR: 0.52, p < 0.001), had lower chances of presenting with DRMs. Conclusions: We present the first evidence on TDR and ADR to INSTI regimens in followed up patients presenting for healthcare in Portugal. We observed low levels of TDR to INSTIs among ART-naïve and moderate levels in ART-exposed patients. Regimens containing PIs could be an alternative second line in patients with intermediate or high-level drug resistance, especially against second-generation INSTIs (dolutegravir, bictegravir, and cabotegravir). Full article
(This article belongs to the Special Issue Antiviral Resistance Mutations)
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Review

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18 pages, 1606 KiB  
Review
Archived HIV-1 Drug Resistance Mutations: Role of Proviral HIV-1 DNA Genotype for the Management of Virological Responder People Living with HIV
by Roberta Campagna, Chiara Nonne, Guido Antonelli and Ombretta Turriziani
Viruses 2024, 16(11), 1697; https://doi.org/10.3390/v16111697 - 30 Oct 2024
Viewed by 966
Abstract
Despite its effectiveness in controlling plasma viremia, antiretroviral therapy (ART) cannot target proviral DNA, which remains an obstacle to HIV-1 eradication. When treatment is interrupted, the reservoirs can act as a source of viral rebound, highlighting the value of proviral DNA as an [...] Read more.
Despite its effectiveness in controlling plasma viremia, antiretroviral therapy (ART) cannot target proviral DNA, which remains an obstacle to HIV-1 eradication. When treatment is interrupted, the reservoirs can act as a source of viral rebound, highlighting the value of proviral DNA as an additional source of information on an individual’s overall resistance burden. In cases where the viral load is too low for successful HIV-1 RNA genotyping, HIV-1 DNA can help identify resistance mutations in treated individuals. The absence of treatment history, the need to adjust ART despite undetectable viremia, or the presence of LLV further support the use of genotypic resistance tests (GRTs) on HIV-1 DNA. Conventionally, GRTs have been achieved through Sanger sequencing, but the advances in NGS are leading to an increase in its use, allowing the detection of minority variants present in less than 20% of the viral population. The clinical significance of these mutations remains under debate, with interpretations varying based on context. Additionally, proviral DNA is subject to APOBEC3-induced hypermutation, which can lead to defective, nonviable viral genomes, a factor that must be considered when performing GRTs on HIV-1 DNA. Full article
(This article belongs to the Special Issue Antiviral Resistance Mutations)
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