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Special Issue "HIV Drug Resistance"

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (30 June 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Karen S. Anderson

Professor of Pharmacology and Molecular Biophysics & Biochemistry, Co-Director Developmental Therapeutics, Yale Comprehensive Cancer Center, Yale University School of Medicine, 333 Cedar Street, SHM B-350B, P.O. Box 208066, New Haven, CT 06520-8066, USA
Website | E-Mail
Fax: +203 785 7670
Interests: enzyme function; anti-viral agents

Special Issue Information

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1500 CHF (Swiss Francs).

Published Papers (11 papers)

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Editorial

Jump to: Research, Review, Other

Open AccessEditorial Remembering Professor Walter A. Scott
Viruses 2014, 6(10), 3873-3874; doi:10.3390/v6103873
Received: 9 October 2014 / Accepted: 14 October 2014 / Published: 20 October 2014
PDF Full-text (236 KB) | HTML Full-text | XML Full-text
Abstract
Walter Scott was a Biochemistry professor at the University of Miami, Miller School of Medicine and a leading figure in the field of HIV drug resistance. His untimely passing in January 2013 marked a loss for his family, as well as for students
[...] Read more.
Walter Scott was a Biochemistry professor at the University of Miami, Miller School of Medicine and a leading figure in the field of HIV drug resistance. His untimely passing in January 2013 marked a loss for his family, as well as for students and colleagues who knew him as a dedicated and unassuming scholar, and a lively scientist with a great sense of humor. Full article
(This article belongs to the Special Issue HIV Drug Resistance)

Research

Jump to: Editorial, Review, Other

Open AccessArticle Low-Frequency NNRTI-Resistant HIV-1 Variants and Relationship to Mutational Load in Antiretroviral-Naïve Subjects
Viruses 2014, 6(9), 3428-3437; doi:10.3390/v6093428
Received: 27 June 2014 / Revised: 22 August 2014 / Accepted: 3 September 2014 / Published: 16 September 2014
Cited by 5 | PDF Full-text (431 KB) | HTML Full-text | XML Full-text
Abstract
Low-frequency HIV variants possessing resistance mutations against non‑nucleoside reverse transcriptase inhibitors (NNRTI), especially at HIV reverse transcriptase (RT) amino acid (aa) positions K103 and Y181, have been shown to adversely affect treatment response. Therapeutic failure correlates with both the mutant viral variant frequency
[...] Read more.
Low-frequency HIV variants possessing resistance mutations against non‑nucleoside reverse transcriptase inhibitors (NNRTI), especially at HIV reverse transcriptase (RT) amino acid (aa) positions K103 and Y181, have been shown to adversely affect treatment response. Therapeutic failure correlates with both the mutant viral variant frequency and the mutational load. We determined the prevalence of NNRTI resistance mutations at several RT aa positions in viruses from 204 antiretroviral (ARV)-naïve HIV-infected individuals using deep sequencing, and examined the relationship between mutant variant frequency and mutational load for those variants. Deep sequencing to ≥0.4% levels found variants with major NNRTI-resistance mutations having a Stanford-HIVdb algorithm value ≥30 for efavirenz and/or nevirapine in 52/204 (25.5%) ARV-naïve HIV-infected persons. Eighteen different major NNRTI mutations were identified at 11 different positions, with the majority of variants being at frequency >1%. The frequency of these variants correlated strongly with the mutational load, but this correlation weakened at low frequencies. Deep sequencing detected additional major NNRTI-resistant viral variants in treatment-naïve HIV-infected individuals. Our study suggests the significance of screening for mutations at all RT aa positions (in addition to K103 and Y181) to estimate the true burden of pre-treatment NNRTI-resistance. An important finding was that variants at low frequency had a wide range of mutational loads (>100-fold) suggesting that frequency alone may underestimate the impact of specific NNRTI-resistant variants. We recommend further evaluation of all low-frequency NNRTI-drug resistant variants with special attention given to the impact of mutational loads of these variants on treatment outcomes. Full article
(This article belongs to the Special Issue HIV Drug Resistance)

Review

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Open AccessReview Resistance Patterns Associated with HCV NS5A Inhibitors Provide Limited Insight into Drug Binding
Viruses 2014, 6(11), 4227-4241; doi:10.3390/v6114227
Received: 27 August 2014 / Revised: 22 October 2014 / Accepted: 22 October 2014 / Published: 6 November 2014
Cited by 14 | PDF Full-text (1123 KB) | HTML Full-text | XML Full-text
Abstract
Direct-acting antivirals (DAAs) have significantly improved the treatment of infection with the hepatitis C virus. A promising class of novel antiviral agents targets the HCV NS5A protein. The high potency and broad genotypic coverage are favorable properties. NS5A inhibitors are currently assessed in
[...] Read more.
Direct-acting antivirals (DAAs) have significantly improved the treatment of infection with the hepatitis C virus. A promising class of novel antiviral agents targets the HCV NS5A protein. The high potency and broad genotypic coverage are favorable properties. NS5A inhibitors are currently assessed in advanced clinical trials in combination with viral polymerase inhibitors and/or viral protease inhibitors. However, the clinical use of NS5A inhibitors is also associated with new challenges. HCV variants with decreased susceptibility to these drugs can emerge and compromise therapy. In this review, we discuss resistance patterns in NS5A with focus prevalence and implications for inhibitor binding. Full article
(This article belongs to the Special Issue HIV Drug Resistance)
Open AccessReview Current Perspectives on HIV-1 Antiretroviral Drug Resistance
Viruses 2014, 6(10), 4095-4139; doi:10.3390/v6104095
Received: 28 July 2014 / Revised: 8 October 2014 / Accepted: 20 October 2014 / Published: 24 October 2014
Cited by 20 | PDF Full-text (913 KB) | HTML Full-text | XML Full-text
Abstract
Current advancements in antiretroviral therapy (ART) have turned HIV-1 infection into a chronic and manageable disease. However, treatment is only effective until HIV-1 develops resistance against the administered drugs. The most recent antiretroviral drugs have become superior at delaying the evolution of acquired
[...] Read more.
Current advancements in antiretroviral therapy (ART) have turned HIV-1 infection into a chronic and manageable disease. However, treatment is only effective until HIV-1 develops resistance against the administered drugs. The most recent antiretroviral drugs have become superior at delaying the evolution of acquired drug resistance. In this review, the viral fitness and its correlation to HIV-1 mutation rates and drug resistance are discussed while emphasizing the concept of lethal mutagenesis as an alternative therapy. The development of resistance to the different classes of approved drugs and the importance of monitoring antiretroviral drug resistance are also summarized briefly. Full article
(This article belongs to the Special Issue HIV Drug Resistance)
Figures

Open AccessReview The Lysine 65 Residue in HIV-1 Reverse Transcriptase Function and in Nucleoside Analog Drug Resistance
Viruses 2014, 6(10), 4080-4094; doi:10.3390/v6104080
Received: 13 August 2014 / Revised: 19 October 2014 / Accepted: 20 October 2014 / Published: 23 October 2014
Cited by 2 | PDF Full-text (520 KB) | HTML Full-text | XML Full-text
Abstract
Mutations in HIV-1 reverse transcriptase (RT) that confer nucleoside analog RT inhibitor resistance have highlighted the functional importance of several active site residues (M184, Q151 and K65) in RT catalytic function. Of these, K65 residue is notable due to its pivotal position in
[...] Read more.
Mutations in HIV-1 reverse transcriptase (RT) that confer nucleoside analog RT inhibitor resistance have highlighted the functional importance of several active site residues (M184, Q151 and K65) in RT catalytic function. Of these, K65 residue is notable due to its pivotal position in the dNTP-binding pocket, its involvement in nucleoside analog resistance and polymerase fidelity. This review focuses on K65 residue and summarizes a substantial body of biochemical and structural studies of its role in RT function and the functional consequences of the K65R mutation. Full article
(This article belongs to the Special Issue HIV Drug Resistance)
Open AccessReview Impact of Human Immunodeficiency Virus Type-1 Sequence Diversity on Antiretroviral Therapy Outcomes
Viruses 2014, 6(10), 3855-3872; doi:10.3390/v6103855
Received: 17 July 2014 / Revised: 9 October 2014 / Accepted: 13 October 2014 / Published: 20 October 2014
Cited by 4 | PDF Full-text (453 KB) | HTML Full-text | XML Full-text
Abstract
Worldwide circulating HIV-1 genomes show extensive variation represented by different subtypes, polymorphisms and drug-resistant strains. Reports on the impact of sequence variation on antiretroviral therapy (ART) outcomes are mixed. In this review, we summarize relevant published data from both resource-rich and resource-limited countries
[...] Read more.
Worldwide circulating HIV-1 genomes show extensive variation represented by different subtypes, polymorphisms and drug-resistant strains. Reports on the impact of sequence variation on antiretroviral therapy (ART) outcomes are mixed. In this review, we summarize relevant published data from both resource-rich and resource-limited countries in the last 10 years on the impact of HIV-1 sequence diversity on treatment outcomes. The prevalence of transmission of drug resistant mutations (DRMs) varies considerably, ranging from 0% to 27% worldwide. Factors such as geographic location, access and availability to ART, duration since inception of treatment programs, quality of care, risk-taking behaviors, mode of transmission, and viral subtype all dictate the prevalence in a particular geographical region. Although HIV-1 subtype may not be a good predictor of treatment outcome, review of emerging evidence supports the fact that HIV-1 genome sequence-resulting from natural polymorphisms or drug-associated mutations-matters when it comes to treatment outcomes. Therefore, continued surveillance of drug resistant variants in both treatment-naïve and treatment-experienced populations is needed to reduce the transmission of DRMs and to optimize the efficacy of the current ART armamentarium. Full article
(This article belongs to the Special Issue HIV Drug Resistance)
Open AccessReview Drug Resistance in Non-B Subtype HIV-1: Impact of HIV-1 Reverse Transcriptase Inhibitors
Viruses 2014, 6(9), 3535-3562; doi:10.3390/v6093535
Received: 16 July 2014 / Revised: 9 September 2014 / Accepted: 9 September 2014 / Published: 24 September 2014
Cited by 7 | PDF Full-text (2243 KB) | HTML Full-text | XML Full-text
Abstract
Human immunodeficiency virus (HIV) causes approximately 2.5 million new infections every year, and nearly 1.6 million patients succumb to HIV each year. Several factors, including cross-species transmission and error-prone replication have resulted in extraordinary genetic diversity of HIV groups. One of these groups,
[...] Read more.
Human immunodeficiency virus (HIV) causes approximately 2.5 million new infections every year, and nearly 1.6 million patients succumb to HIV each year. Several factors, including cross-species transmission and error-prone replication have resulted in extraordinary genetic diversity of HIV groups. One of these groups, known as group M (main) contains nine subtypes (A-D, F-H and J-K) and causes ~95% of all HIV infections. Most reported data on susceptibility and resistance to anti-HIV therapies are from subtype B HIV infections, which are prevalent in developed countries but account for only ~12% of all global HIV infections, whereas non-B subtype HIV infections that account for ~88% of all HIV infections are prevalent primarily in low and middle-income countries. Although the treatments for subtype B infections are generally effective against non-B subtype infections, there are differences in response to therapies. Here, we review how polymorphisms, transmission efficiency of drug-resistant strains, and differences in genetic barrier for drug resistance can differentially alter the response to reverse transcriptase-targeting therapies in various subtypes. Full article
(This article belongs to the Special Issue HIV Drug Resistance)
Open AccessReview Is Resistance to Dolutegravir Possible When This Drug Is Used in First-Line Therapy?
Viruses 2014, 6(9), 3377-3385; doi:10.3390/v6093377
Received: 18 June 2014 / Revised: 8 August 2014 / Accepted: 21 August 2014 / Published: 27 August 2014
Cited by 16 | PDF Full-text (734 KB) | HTML Full-text | XML Full-text
Abstract
Dolutegravir (DTG) is an HIV integrase inhibitor that was recently approved for therapy by the Food and Drug Administration in the United States. When used as part of first-line therapy, DTG is the only HIV drug that has not selected for resistance mutations
[...] Read more.
Dolutegravir (DTG) is an HIV integrase inhibitor that was recently approved for therapy by the Food and Drug Administration in the United States. When used as part of first-line therapy, DTG is the only HIV drug that has not selected for resistance mutations in the clinic. We believe that this is due to the long binding time of DTG to the integrase enzyme as well as greatly diminished replication capacity on the part of viruses that might become resistant to DTG. We further speculate that DTG might be able to be used in strategies aimed at HIV eradication. Full article
(This article belongs to the Special Issue HIV Drug Resistance)
Open AccessReview The Emerging Profile of Cross-Resistance among the Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors
Viruses 2014, 6(8), 2960-2973; doi:10.3390/v6082960
Received: 2 June 2014 / Revised: 17 July 2014 / Accepted: 22 July 2014 / Published: 31 July 2014
Cited by 17 | PDF Full-text (623 KB) | HTML Full-text | XML Full-text
Abstract
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are widely used to treat HIV-1-infected individuals; indeed most first-line antiretroviral therapies typically include one NNRTI in combination with two nucleoside analogs. In 2008, the next-generation NNRTI etravirine was approved for the treatment of HIV-infected antiretroviral therapy-experienced individuals,
[...] Read more.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are widely used to treat HIV-1-infected individuals; indeed most first-line antiretroviral therapies typically include one NNRTI in combination with two nucleoside analogs. In 2008, the next-generation NNRTI etravirine was approved for the treatment of HIV-infected antiretroviral therapy-experienced individuals, including those with prior NNRTI exposure. NNRTIs are also increasingly being included in strategies to prevent HIV-1 infection. For example: (1) nevirapine is used to prevent mother-to-child transmission; (2) the ASPIRE (MTN 020) study will test whether a vaginal ring containing dapivirine can prevent HIV-1 infection in women; (3) a microbicide gel formulation containing the urea-PETT derivative MIV-150 is in a phase I study to evaluate safety, pharmacokinetics, pharmacodynamics and acceptability; and (4) a long acting rilpivirine formulation is under-development for pre-exposure prophylaxis. Given their widespread use, particularly in resource-limited settings, as well as their low genetic barriers to resistance, there are concerns about overlapping resistance between the different NNRTIs. Consequently, a better understanding of the resistance and cross-resistance profiles among the NNRTI class is important for predicting response to treatment, and surveillance of transmitted drug-resistance. Full article
(This article belongs to the Special Issue HIV Drug Resistance)
Open AccessReview Resistance Analyses of Integrase Strand Transfer Inhibitors within Phase 3 Clinical Trials of Treatment-Naive Patients
Viruses 2014, 6(7), 2858-2879; doi:10.3390/v6072858
Received: 23 May 2014 / Revised: 10 July 2014 / Accepted: 10 July 2014 / Published: 22 July 2014
Cited by 9 | PDF Full-text (729 KB) | HTML Full-text | XML Full-text
Abstract
The integrase (IN) strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG), comprise the newest drug class approved for the treatment of HIV-1 infection, which joins the existing classes of reverse transcriptase, protease and binding/entry inhibitors. The efficacy of first-line regimens
[...] Read more.
The integrase (IN) strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG), comprise the newest drug class approved for the treatment of HIV-1 infection, which joins the existing classes of reverse transcriptase, protease and binding/entry inhibitors. The efficacy of first-line regimens has attained remarkably high levels, reaching undetectable viral loads in 90% of patients by Week 48; however, there remain patients who require a change in regimen due to adverse events, virologic failure with emergent resistance or other issues of patient management. Large, randomized clinical trials conducted in antiretroviral treatment-naive individuals are required for drug approval in this population in the US, EU and other countries, with the primary endpoint for virologic success at Week 48. However, there are differences in the definition of virologic failure and the evaluation of drug resistance among the trials. This review focuses on the methodology and tabulation of resistance to INSTIs in phase 3 clinical trials of first-line regimens and discusses case studies of resistance. Full article
(This article belongs to the Special Issue HIV Drug Resistance)

Other

Jump to: Editorial, Research, Review

Open AccessBrief Report Genetic Diversity in HIV-1 Subtype C LTR from Brazil and Mozambique Generates New Transcription Factor-Binding Sites
Viruses 2014, 6(6), 2495-2504; doi:10.3390/v6062495
Received: 13 November 2013 / Revised: 12 January 2014 / Accepted: 24 January 2014 / Published: 23 June 2014
Cited by 1 | PDF Full-text (907 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The HIV-1 subtype C has been substituting the subtype B population in southern Brazil. This phenomenon has been previously described in other countries, suggesting that subtype C may possess greater fitness than other subtypes. The HIV-1 long-terminal repeat (LTR) is an important regulatory
[...] Read more.
The HIV-1 subtype C has been substituting the subtype B population in southern Brazil. This phenomenon has been previously described in other countries, suggesting that subtype C may possess greater fitness than other subtypes. The HIV-1 long-terminal repeat (LTR) is an important regulatory region critical for the viral life cycle. Sequence insertions immediately upstream of the viral enhancer are known as the most frequent naturally occurring length polimorphisms (MFNLP). Previous reports demonstrated that the MFNLP could lead to the duplication of transcription factor binding sites (TFBS) enhancing the activity of the HIV-1 subtype C LTR. Here, we amplified and sequenced the LTR obtained from proviral DNA samples collected from patients infected with subtype C from the Southern Region of Brazil (naïve or treatment failure) and Mozambique (only naïve). We confirm the presence of different types of insertions in the LTR sequences of both the countries leading to the creation of additional TFBS. In the Brazilian clinical samples, the frequency of the sequence insertion was significantly higher in subjects experiencing treatment failure than in antiretroviral naïve patients. Full article
(This article belongs to the Special Issue HIV Drug Resistance)

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