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Special Issue "HIV Drug Resistance 2010"

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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 (15 August 2010)

Special Issue Editor

Guest Editor
Dr. Vinay Pathak (Website)

HIV Drug Resistance Program, National Cancer Institute NCI-Frederick, P.O. Box B, Building 535, Frederick, MD 21702-1201, USA
Phone: 301-846-1710
Fax: +1 301 846 6013
Interests: viral and host factors that generate mutations in HIV-1 and MLV; antiviral drug resistance, in vivo reverse transcription

Published Papers (10 papers)

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Review

Open AccessReview Clinical Management of HIV Drug Resistance
Viruses 2011, 3(4), 347-378; doi:10.3390/v3040347
Received: 9 March 2011 / Accepted: 30 March 2011 / Published: 14 April 2011
Cited by 27 | PDF Full-text (687 KB)
Abstract
Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. [...] Read more.
Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
Open AccessReview Comparison of the Mechanisms of Drug Resistance among HIV, Hepatitis B, and Hepatitis C
Viruses 2010, 2(12), 2696-2739; doi:10.3390/v2122696
Received: 24 October 2010 / Revised: 15 November 2010 / Accepted: 7 December 2010 / Published: 14 December 2010
Cited by 19 | PDF Full-text (586 KB)
Abstract
Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are the most prevalent deadly chronic viral diseases. HIV is treated by small molecule inhibitors. HBV is treated by immunomodulation and small molecule inhibitors. HCV is currently treated primarily [...] Read more.
Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are the most prevalent deadly chronic viral diseases. HIV is treated by small molecule inhibitors. HBV is treated by immunomodulation and small molecule inhibitors. HCV is currently treated primarily by immunomodulation but many small molecules are in clinical development. Although HIV is a retrovirus, HBV is a double-stranded DNA virus, and HCV is a single-stranded RNA virus, antiviral drug resistance complicates the development of drugs and the successful treatment of each of these viruses. Although their replication cycles, therapeutic targets, and evolutionary mechanisms are different, the fundamental approaches to identifying and characterizing HIV, HBV, and HCV drug resistance are similar. This review describes the evolution of HIV, HBV, and HCV within individuals and populations and the genetic mechanisms associated with drug resistance to each of the antiviral drug classes used for their treatment. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
Open AccessReview Molecular Basis for Drug Resistance in HIV-1 Protease
Viruses 2010, 2(11), 2509-2535; doi:10.3390/v2112509
Received: 8 October 2010 / Revised: 22 October 2010 / Accepted: 28 October 2010 / Published: 12 November 2010
Cited by 46 | PDF Full-text (946 KB)
Abstract
HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-based drug design, thus the atomic details of how the inhibitors bind [...] Read more.
HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-based drug design, thus the atomic details of how the inhibitors bind are well characterized. From this structural understanding the molecular basis for drug resistance in HIV-1 protease can be elucidated. Selected mutations in response to therapy and diversity between clades in HIV-1 protease have altered the shape of the active site, potentially altered the dynamics and even altered the sequence of the cleavage sites in the Gag polyprotein. All of these interdependent changes act in synergy to confer drug resistance while simultaneously maintaining the fitness of the virus. New strategies, such as incorporation of the substrate envelope constraint to design robust inhibitors that incorporate details of HIV-1 protease’s function and decrease the probability of drug resistance, are necessary to continue to effectively target this key protein in HIV-1 life cycle. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
Open AccessReview The “Connection” Between HIV Drug Resistance and RNase H
Viruses 2010, 2(7), 1476-1503; doi:10.3390/v2071476
Received: 21 June 2010 / Revised: 20 July 2010 / Accepted: 20 July 2010 / Published: 21 July 2010
Cited by 22 | PDF Full-text (481 KB) | HTML Full-text | XML Full-text
Abstract
Currently, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are two classes of antiretroviral agents that are approved for treatment of HIV-1 infection. Since both NRTIs and NNRTIs target the polymerase (pol) domain of reverse transcriptase (RT), most genotypic [...] Read more.
Currently, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are two classes of antiretroviral agents that are approved for treatment of HIV-1 infection. Since both NRTIs and NNRTIs target the polymerase (pol) domain of reverse transcriptase (RT), most genotypic analysis for drug resistance is limited to the first ~300 amino acids of RT. However, recent studies have demonstrated that mutations in the C-terminal domain of RT, specifically the connection subdomain and RNase H domain, can also increase resistance to both NRTIs and NNRTIs. In this review we will present the potential mechanisms by which mutations in the C-terminal domain of RT influence NRTI and NNRTI susceptibility, summarize the prevalence of the mutations in these regions of RT identified to date, and discuss their importance to clinical drug resistance. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
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Open AccessReview Role of Gag in HIV Resistance to Protease Inhibitors
Viruses 2010, 2(7), 1411-1426; doi:10.3390/v2071411
Received: 7 April 2010 / Revised: 21 June 2010 / Accepted: 25 June 2010 / Published: 5 July 2010
Cited by 9 | PDF Full-text (671 KB) | HTML Full-text | XML Full-text
Abstract
Cleavage of Gag and Gag-Pol precursors by the viral protease is an essential step in the replication cycle of HIV. Protease inhibitors, which compete with natural cleavage sites, strongly impair viral infectivity and have proven to be highly valuable in the treatment [...] Read more.
Cleavage of Gag and Gag-Pol precursors by the viral protease is an essential step in the replication cycle of HIV. Protease inhibitors, which compete with natural cleavage sites, strongly impair viral infectivity and have proven to be highly valuable in the treatment of HIV-infected subjects. However, as with all other antiretroviral drugs, the clinical benefit of protease inhibitors can be compromised by resistance. One key feature of HIV resistance to protease inhibitors is that the mutations that promote resistance are not only located in the protease itself, but also in some of its natural substrates. The best documented resistance-associated substrate mutations are located in, or near, the cleavage sites in the NC/SP2/p6 region of Gag. These mutations improve interactions between the substrate and the mutated enzyme and correspondingly increase cleavage. Initially described as compensatory mutations able to partially correct the loss of viral fitness that results from protease mutations, changes in Gag are now recognized as being directly involved in resistance. Besides NC/SP2/p6 mutations, polymorphisms in other regions of Gag have been found to exert various effects on viral fitness and or resistance, but their importance deserves further evaluation. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
Open AccessReview Resistance to Integrase Inhibitors
Viruses 2010, 2(7), 1347-1366; doi:10.3390/v2071347
Received: 27 April 2010 / Revised: 17 June 2010 / Accepted: 19 June 2010 / Published: 25 June 2010
Cited by 63 | PDF Full-text (1107 KB) | HTML Full-text | XML Full-text
Abstract
Integrase (IN) is a clinically validated target for the treatment of human immunodeficiency virus infections and raltegravir exhibits remarkable clinical activity. The next most advanced IN inhibitor is elvitegravir. However, mutant viruses lead to treatment failure and mutations within the IN coding [...] Read more.
Integrase (IN) is a clinically validated target for the treatment of human immunodeficiency virus infections and raltegravir exhibits remarkable clinical activity. The next most advanced IN inhibitor is elvitegravir. However, mutant viruses lead to treatment failure and mutations within the IN coding sequence appear to confer cross-resistance. The characterization of those mutations is critical for the development of second generation IN inhibitors to overcome resistance. This review focuses on IN resistance based on structural and biochemical data, and on the role of the IN flexible loop i.e., between residues G140-G149 in drug action and resistance. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
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Open AccessReview HIV-1 Entry, Inhibitors, and Resistance
Viruses 2010, 2(5), 1069-1105; doi:10.3390/v2051069
Received: 23 February 2010 / Revised: 16 April 2010 / Accepted: 18 April 2010 / Published: 29 April 2010
Cited by 29 | PDF Full-text (901 KB) | HTML Full-text | XML Full-text
Abstract
Entry inhibitors represent a new class of antiretroviral agents for the treatment of infection with HIV-1. While resistance to other HIV drug classes has been well described, resistance to this new class is still ill defined despite considerable clinical use. Several potential [...] Read more.
Entry inhibitors represent a new class of antiretroviral agents for the treatment of infection with HIV-1. While resistance to other HIV drug classes has been well described, resistance to this new class is still ill defined despite considerable clinical use. Several potential mechanisms have been proposed: tropism switching (utilization of CXCR4 instead of CCR5 for entry), increased affinity for the coreceptor, increased rate of virus entry into host cells, and utilization of inhibitor-bound receptor for entry. In this review we will address the development of attachment, fusion, and coreceptor entry inhibitors and explore recent studies describing potential mechanisms of resistance. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
Open AccessReview HIV-1 RT Inhibitors with a Novel Mechanism of Action: NNRTIs that Compete with the Nucleotide Substrate
Viruses 2010, 2(4), 880-899; doi:10.3390/v2040880
Received: 22 January 2010 / Revised: 20 February 2010 / Accepted: 5 March 2010 / Published: 30 March 2010
Cited by 19 | PDF Full-text (888 KB) | HTML Full-text | XML Full-text
Abstract
HIV-1 reverse transcriptase (RT) inhibitors currently used in antiretroviral therapy can be divided into two classes: (i) nucleoside analog RT inhibitors (NRTIs), which compete with natural nucleoside substrates and act as terminators of proviral DNA synthesis, and (ii) non-nucleoside RT inhibitors (NNRTIs), [...] Read more.
HIV-1 reverse transcriptase (RT) inhibitors currently used in antiretroviral therapy can be divided into two classes: (i) nucleoside analog RT inhibitors (NRTIs), which compete with natural nucleoside substrates and act as terminators of proviral DNA synthesis, and (ii) non-nucleoside RT inhibitors (NNRTIs), which bind to a hydrophobic pocket close to the RT active site. In spite of the efficiency of NRTIs and NNRTIs, the rapid emergence of multidrug-resistant mutations requires the development of new RT inhibitors with an alternative mechanism of action. Recently, several studies reported the discovery of novel non-nucleoside inhibitors with a distinct mechanism of action. Unlike classical NNRTIs, they compete with the nucleotide substrate, thus forming a new class of RT inhibitors: nucleotide-competing RT inhibitors (NcRTIs). In this review, we discuss current progress in the understanding of the peculiar behavior of these compounds. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
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Open AccessReview HIV Genetic Diversity and Drug Resistance
Viruses 2010, 2(2), 503-531; doi:10.3390/v2020503
Received: 18 November 2009 / Revised: 11 December 2009 / Accepted: 1 February 2010 / Published: 2 February 2010
Cited by 22 | PDF Full-text (244 KB) | HTML Full-text | XML Full-text
Abstract
Most of the current knowledge on antiretroviral (ARV) drug development and resistance is based on the study of subtype B of HIV-1, which only accounts for 10% of the worldwide HIV infections. Cumulative evidence has emerged that different HIV types, groups and [...] Read more.
Most of the current knowledge on antiretroviral (ARV) drug development and resistance is based on the study of subtype B of HIV-1, which only accounts for 10% of the worldwide HIV infections. Cumulative evidence has emerged that different HIV types, groups and subtypes harbor distinct biological properties, including the response and susceptibility to ARV. Recent laboratory and clinical data highlighting such disparities are summarized in this review. Variations in drug susceptibility, in the emergence and selection of specific drug resistance mutations, in viral replicative capacity and in the dynamics of resistance acquisition under ARV selective pressure are discussed. Clinical responses to ARV therapy and associated confounding factors are also analyzed in the context of infections by distinct HIV genetic variants. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
Open AccessReview The Role of Nucleotide Excision by Reverse Transcriptase in HIV Drug Resistance
Viruses 2010, 2(2), 372-394; doi:10.3390/v2020372
Received: 10 December 2009 / Revised: 15 January 2010 / Accepted: 25 January 2010 / Published: 28 January 2010
Cited by 13 | PDF Full-text (416 KB) | HTML Full-text | XML Full-text
Abstract
Nucleoside reverse transcriptase (RT) inhibitors of HIV block viral replication through the ability of HIV RT to incorporate chain-terminating nucleotide analogs during viral DNA synthesis. Once incorporated, the chain-terminating residue must be removed before DNA synthesis can continue. Removal can be accomplished [...] Read more.
Nucleoside reverse transcriptase (RT) inhibitors of HIV block viral replication through the ability of HIV RT to incorporate chain-terminating nucleotide analogs during viral DNA synthesis. Once incorporated, the chain-terminating residue must be removed before DNA synthesis can continue. Removal can be accomplished by the excision activity of HIV RT, which catalyzes the transfer of the 3'-terminal residue on the blocked DNA chain to an acceptor substrate, probably ATP in most infected cells. Mutations of RT that enhance excision activity are the most common cause of resistance to 3'-azido-3'-deoxythymidine (AZT) and exhibit low-level cross-resistance to most other nucleoside RT inhibitors. The resistance to AZT is suppressed by a number of additional mutations in RT, most of which were identified because they conferred resistance to other RT inhibitors. Here we review current understanding of the biochemical mechanisms responsible for increased or decreased excision activity due to these mutations. Full article
(This article belongs to the Special Issue HIV Drug Resistance 2010)
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