DOCSLIB.ORG

Emergence of HIV-1 Drug Resistance Mutations in Mothers on Treatment

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Emergence of HIV-1 Drug Resistance Mutations in Mothers on Treatment Martin-Odoom et al. Virology Journal (2018) 15:143 https://doi.org/10.1186/s12985-018-1051-2 RESEARCH Open Access Emergence of HIV-1 drug resistance mutations in mothers on treatment with a history of prophylaxis in Ghana Alexander Martin-Odoom1* , Charles Addoquaye Brown1, John Kofi Odoom2, Evelyn Yayra Bonney2, Nana Afia Asante Ntim2, Elena Delgado3, Margaret Lartey4, Kwamena William Sagoe1, Theophilus Adiku1 and William Kwabena Ampofo2 Abstract Background: Antiretrovirals have been available in Ghana since 2003 for HIV-1 positive pregnant women for prevention of mother-to-child transmission (PMTCT). Suboptimal responses to treatment observed post-PMTCT interventions necessitated the need to investigate the profile of viral mutations generated. This study investigated HIV-1 drug resistance profiles in mothers in selected centres in Ghana on treatment with a history of prophylaxis. Methods: Genotypic Drug Resistance Testing for HIV-1 was carried out. Subtyping was done by phylogenetic analysis and Stanford HIV Database programme was used for drug resistance analysis and interpretation. To compare the significance between the different groups and the emergence of drug resistance mutations, p values were used. Results: Participants who had prophylaxis before treatment, those who had treatment without prophylaxis and those yet to initiate PMTCT showed 32% (8), 5% (3) and 15% (4) HIV-1 drug resistance associated mutations respectively. The differences were significant with p value < 0.05. Resistance Associated Mutations (RAMs) were seen in 14 participants (35%) to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). The most common NRTI mutation found was M184 V; K103 N and A98G were the most common NNRTI mutations seen. Thymidine Analogue Mutations (TAMs) such as M41 L, K70R and T215Y were found in all the groups; the most common of the TAMs found were M41 L and T215Y. Majority of the subtypes were CRF02_AG (82%). Conclusion: In Ghana initiation of uninterrupted treatment upon diagnosis, coupled with drug resistance testing, would produce a better treatment outcome for HIV-1 positive pregnant women. Keywords: Antiretroviral therapy, Phylogenetic analysis, Drug resistance profiles, Treatment outcome Background emergence of HIV-1 drug resistance viral strains is a major Antiretroviral therapy (ART) was started in Ghana in 2003 obstacle in the effective management of HIV infection and and has gone through a number of revisions to provide AIDS. Drug resistant strains may develop due to exposure appropriate health care and support for HIV positive to drugs but drug naïve persons could also be infected with persons across the whole of Ghana [1]. The National AIDS/ drug-resistant strains [3]. The Ghana HIV Drug Resistance STI Control Programme (NACP) of the Ghana Health (HIVDR) Threshold Survey was initiated in 2007 [4]togen- Service implemented various research-backed interventions erate information on the presence of HIV drug-resistant to monitor drug resistance known to arise in HIV patients strains in the locality where Ghana’sARTforHIVwasfirst through the use of the Antiretrovirals (ARVs) [2]. The introduced. It was also to seek information on active trans- mission of HIV drug-resistant strains in drug-naïve persons in the country so as to signal action to address transmitted * Correspondence: [email protected]; [email protected] 1Department of Medical Laboratory Sciences, School of Biomedical & Allied HIV drug resistance (HIVDR) in Ghana. A Survey of Emer- Health Sciences, College of Health Sciences, University of Ghana, P.O. Box KB gence of HIV Drug Resistance was also initiated by the 143, Korle Bu, Accra, Ghana NACP to monitor the emergence of HIV drug resistance in Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Martin-Odoom et al. Virology Journal (2018) 15:143 Page 2 of 9 Ghana amongst patients initiating antiretroviral therapy until labour onset when a single dose Nevirapine (sd NVP), (ART). These two surveys were designed to monitor the im- an NNRTI, was added. In post-PMTCT periods when these pact of HIV-1 drug resistance on the ART programme [4]. mothers needed ARVs for their own health, they were given However, a group of patients fall in a grey area not cov- the same drugs as during the prophylaxis phase- 3TC, AZT ered directly by the two surveys. This group comprised and NVP or Efavirenz (EFV-another NNRTI) but this time HIV positive women given antiretrovirals as prophylaxis as a triple therapy. Didanosine (DDI) or Abacavir (ABC)– to prevent the transmission of HIV to their babies during both NRTIs, or Tenofovir (TDF), a Nucleotide Reverse pregnancy and subsequently given treatment for their own Transcriptase Inhibitor (NtRTI) substituted AZT for some health post-partum. Bearing in mind the emergence of of the participants. HIV-positive pregnant women who drug resistance in the face of antiretroviral pressure, these reported at the Care and Support Centres and had CD4 women were given the same ARVs in the treatment phase levels below 350cells/μL were given the triple therapy with- as they were given during the prophylaxis or the phase of out a prophylactic phase [2]. preventing the transmission of the infection from the mother to the infant [2]. The effectiveness of the ARVs Sample Collection & Processing with such a background was becoming questionable in the A structured questionnaire was used to obtain basic absence of data on the resistance profiles of these women. socio-demographic and clinical data from cases and con- This study was thus designed to determine HIV-1 drug trols. Upon explaining the study and obtaining written resistance mutations present in Ghanaian women, to informed consent from the patients at the study sites, characterize any resistance mutations found according whole blood sample was taken from the antecubital vein to the class of antiretrovirals (ARVs) used during treat- of each participant into Ethylenediamine tetra-acetic ment and to provide data on the profile of HIV-1 drug acid (EDTA) treated tubes. The samples were placed in resistance present in Ghanaian women on treatment. an ice chest with frozen ice packs and transported to the Virology Department of Noguchi Memorial Institute for Methods Medical Research (NMIMR) at Legon, Accra, Ghana, Study design and sites where the plasma was separated from the whole blood This was a cross-sectional study carried out between 1st through centrifugation at 2000 g for 10 min and stored November, 2010 and 30th November, 2011 and used the at minus (−) 70 °C until analyzed. convenient sampling technique to enroll 116 HIV-1 positive Ghanaian women who accessed care and sup- HIV-1 drug-resistance genotyping port at seven National AIDS/STI Control Programme Viral RNA was extracted from 140 μL of plasma samples (NACP) centres in three regions of Ghana. using QIAamp viral RNA mini kit (Qiagen, USA). QIAGEN One-Step RT-PCR Kit was used for the amplification, Study participants according to the manufacturer’sprotocol[5]. Primers used The study involved two groups of HIV-infected mothers for the RT gene and the PR gene in the Round 1 amplifica- and a group of HIV positive pregnant women at gesta- tion were DRRT1L/DRRT4L and DRPRO5/DRPRO2L re- tional periods less than 28 weeks. One group of mothers spectively, as has previously been described [6]. The thermal (Group 1) was made up of HIV-positive mothers who cycling conditions applied were described previously [7]. had been on antiretroviral prophylaxis for prevention of Further amplification of the round 1 products was done transmission of the virus to the foetus when they were by nested PCR using AmpliTaq Gold Master Mix Kit (ABI, pregnant and had subsequently been put on full ART for USA) with primers DRRT7L/DRRT6L and DRPRO1M/ their own health needs post-partum (Prophylaxis plus DRPRO6 for RT and PR genes respectively, and the thermal ART Group). The second group (Group 2) comprised cycling conditions used were as previously described [6, 7]. HIV-positive pregnant women who had not had any The products of the RT and PR gene from the nested prior exposure to ARVs at the time of the study PCR assay were verified through the use of agarose gel (Drug-Naïve) and were pregnant at less than 28 weeks. electrophoresis and the bands in the gel were visualized A third group (Group 3) was made up of mothers who using a Gel Documentation system (GEL-LOGIC 100 had initiated ART when they were pregnant without Imaging System from Kodak) with a High Performance prophylaxis (Drug-experienced without prophylaxis) be- Ultraviolet-Transilluminator (UVP, UK). The amplicons cause their CD4 count levels were below 350 cells /μLat were purified using QIAquick PCR Purification Kit the time of ARVs initiation. (QIAGEN, USA) to obtain the DNA products needed During the study period, the PMTCT programme in for sequencing, following the manufacturer’s instruc- Ghana administered a combination of Zidovudine (AZT) tions. Cycle sequencing was performed on the purified and Lamivudine (3TC), both NRTIs, (known as Combivir) PCR products using the Big Dye Terminator Cycle Se- to the patients from 28 weeks of pregnancy as prophylaxis quencing Kit vs 3.1 from Applied Biosystems Inc. (ABI), Martin-Odoom et al. Virology Journal (2018) 15:143 Page 3 of 9 USA.
Load more

Recommended publications
  • Characterization of Resistance to a Potent D-Peptide HIV Entry Inhibitor
    Smith et al. Retrovirology (2019) 16:28 https://doi.org/10.1186/s12977-019-0489-7 Retrovirology RESEARCH Open Access Characterization of resistance to a potent D-peptide HIV entry inhibitor Amanda R. Smith1†, Matthew T. Weinstock1†, Amanda E. Siglin2, Frank G. Whitby1, J. Nicholas Francis1, Christopher P. Hill1, Debra M. Eckert1, Michael J. Root2 and Michael S. Kay1* Abstract Background: PIE12-trimer is a highly potent D-peptide HIV-1 entry inhibitor that broadly targets group M isolates. It specifcally binds the three identical conserved hydrophobic pockets at the base of the gp41 N-trimer with sub- femtomolar afnity. This extremely high afnity for the transiently exposed gp41 trimer provides a reserve of binding energy (resistance capacitor) to prevent the viral resistance pathway of stepwise accumulation of modest afnity- disrupting mutations. Such modest mutations would not afect PIE12-trimer potency and therefore not confer a selective advantage. Viral passaging in the presence of escalating PIE12-trimer concentrations ultimately selected for PIE12-trimer resistant populations, but required an extremely extended timeframe (> 1 year) in comparison to other entry inhibitors. Eventually, HIV developed resistance to PIE12-trimer by mutating Q577 in the gp41 pocket. Results: Using deep sequence analysis, we identifed three mutations at Q577 (R, N and K) in our two PIE12-trimer resistant pools. Each point mutant is capable of conferring the majority of PIE12-trimer resistance seen in the poly- clonal pools. Surface plasmon resonance studies demonstrated substantial afnity loss between PIE12-trimer and the Q577R-mutated gp41 pocket. A high-resolution X-ray crystal structure of PIE12 bound to the Q577R pocket revealed the loss of two hydrogen bonds, the repositioning of neighboring residues, and a small decrease in buried surface area.
    [Show full text]
  • HIV Genotyping and Phenotyping AHS – M2093
    Corporate Medical Policy HIV Genotyping and Phenotyping AHS – M2093 File Name: HIV_genotyping_and_phenotyping Origination: 1/2019 Last CAP Review: 2/2021 Next CAP Review: 2/2022 Last Review: 2/2021 Description of Procedure or Service Description Human immunodeficiency virus (HIV) is an RNA retrovirus that infects human immune cells (specifically CD4 cells) causing progressive deterioration of the immune system ultimately leading to acquired immune deficiency syndrome (AIDS) characterized by susceptibility to opportunistic infections and HIV-related cancers (CDC, 2014). Related Policies Plasma HIV-1 and HIV-2 RNA Quantification for HIV Infection Scientific Background Human immunodeficiency virus (HIV) targets the immune system, eventually hindering the body’s ability to fight infections and diseases. If not treated, an HIV infection may lead to acquired immunodeficiency syndrome (AIDS) which is a condition caused by the virus. There are two main types of HIV: HIV-1 and HIV-2; both are genetically different. HIV-1 is more common and widespread than HIV-2. HIV replicates rapidly; a replication cycle rate of approximately one to two days ensures that after a single year, the virus in an infected individual may be 200 to 300 generations removed from the initial infection-causing virus (Coffin & Swanstrom, 2013). This leads to great genetic diversity of each HIV infection in a single individual. As an RNA retrovirus, HIV requires the use of a reverse transcriptase for replication purposes. A reverse transcriptase is an enzyme which generates complimentary DNA from an RNA template. This enzyme is error-prone with the overall single-step point mutation rate reaching ∼3.4 × 10−5 mutations per base per replication cycle (Mansky & Temin, 1995), leading to approximately one genome in three containing a mutation after each round of replication (some of which confer drug resistance).
    [Show full text]
  • Summary of Neuraminidase Amino Acid Substitutions Associated with Reduced Inhibition by Neuraminidase Inhibitors
    Summary of neuraminidase amino acid substitutions associated with reduced inhibition by neuraminidase inhibitors. Susceptibility assessed by NA inhibition assays Source of Type/subtype Amino acid N2 b (IC50 fold change vs wild type [NAI susceptible virus]) viruses/ References Comments substitutiona numberinga Oseltamivir Zanamivir Peramivir Laninamivir selection withc A(H1N1)pdm09 I117R 117 NI (1) RI (10) ? ?d Sur (1) E119A 119 NI/RI (8-17) RI (58-90) NI/RI (7-12) RI (82) RG (2, 3) E119D 119 RI (25-23) HRI (583-827) HRI (104-286) HRI (702) Clin/Zan; RG (3, 4) E119G 119 NI (1-7) HRI (113-1306) RI/HRI (51-167) HRI (327) RG; Clin/Zan (3, 5, 6) E119V 119 RI (60) HRI (571) RI (25) ? RG (5) Q136K/Q 136 NI (1) RI (20) ? ? Sur (1) Q136K 136 NI (1) HRI (86-749) HRI (143) RI (42-45) Sur; RG; in vitro (2, 7, 8) Q136R was host Q136R 136 NI (1) HRI (200) HRI (234) RI (33) Sur (9) cell selected D151D/E 151 NI (3) RI (19) RI (14) NI (5) Sur (9) D151N/D 151 RI (22) RI (21) NI (3) NI (3) Sur (1) R152K 152 RI(18) NI(4) NI(4) ? RG (3, 6) D199E 198 RI (16) NI (7) ? ? Sur (10) D199G 198 RI (17) NI (6) NI (2) NI (2) Sur; in vitro; RG (2, 5) I223K 222 RI (12–39) NI (5–6) NI (1–4) NI (4) Sur; RG (10-12) Clin/No; I223R 222 RI (13–45) NI/RI (8–12) NI (5) NI (2) (10, 12-15) Clin/Ose/Zan; RG I223V 222 NI (6) NI (2) NI (2) NI (1) RG (2, 5) I223T 222 NI/RI(9-15) NI(3) NI(2) NI(2) Clin/Sur (2) S247N 246 NI (4–8) NI (2–5) NI (1) ? Sur (16) S247G 246 RI (15) NI (1) NI (1) NI (1) Clin/Sur (10) S247R 246 RI (36-37) RI (51-54) RI/HRI (94-115) RI/HRI (90-122) Clin/No (1)
    [Show full text]
  • HIV-1 Protease: Structural Perspectives on Drug Resistance
    Viruses 2009, 1, 1110-1136; doi:10.3390/v1031110 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review HIV-1 Protease: Structural Perspectives on Drug Resistance Irene T. Weber * and Johnson Agniswamy Department of Biology, Molecular Basis of Disease Program, Georgia State University, Atlanta, GA 30303, USA; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-404-413-5411; Fax: +1-404-413-5301. Received: 1 October 2009; in revised form: 30 November 2009 / Accepted: 1 December 2009 / Published: 3 December 2009 Abstract: Antiviral inhibitors of HIV-1 protease are a notable success of structure-based drug design and have dramatically improved AIDS therapy. Analysis of the structures and activities of drug resistant protease variants has revealed novel molecular mechanisms of drug resistance and guided the design of tight-binding inhibitors for resistant variants. The plethora of structures reveals distinct molecular mechanisms associated with resistance: mutations that alter the protease interactions with inhibitors or substrates; mutations that alter dimer stability; and distal mutations that transmit changes to the active site. These insights will inform the continuing design of novel antiviral inhibitors targeting resistant strains of HIV. Keywords: protease inhibitors; drug resistance; aspartic protease; molecular mechanism; darunavir 1. Introduction The structures and activities of HIV protease and its drug-resistant variants and their interactions with inhibitors have been studied for nearly 20 years in order to combat the challenges of AIDS antiviral therapy and the evolution of HIV drug resistance [1]. About 25 different antiretroviral drugs (ARV) are currently used in the combat against human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS).
    [Show full text]
  • Drug Resistance Mutations in HIV-1 Volume 11 Issue 6 November/December 2003
    Special Contribution - Drug Resistance Mutations in HIV-1 Volume 11 Issue 6 November/December 2003 Drug Resistance Mutations in HIV-1 Victoria A. Johnson, MD, Françoise Brun-Vézinet, MD, PhD, Bonaventura Clotet, MD, PhD, Brian Conway, MD, Richard T. D'Aquila, MD, Lisa M. Demeter, MD, Daniel R. Kuritzkes, MD, Deenan Pillay, MD, PhD, Jonathan M. Schapiro, MD, Amalio Telenti, MD, PhD, and Douglas D. Richman, MD The International AIDS Society–USA pressure), resistant strains may be pre- V32I and the I84A/C have been added to (IAS–USA) Drug Resistance Mutations sent at levels below the limit of detec- the list of accumulated mutations con- Group is a volunteer panel of experts tion of the test; analyzing stored sam- ferring multi-PI resistance (see User that meets regularly to review and inter- ples (collected under selection pressure) Note 9).13-18 In addition, mutations have pret new data on HIV-1 resistance. The could be useful in this setting; and (3) been added for tipranavir/ritonavir, focus of the group is to identify muta- recognizing that virologic failure of the which is currently available through an tions associated with clinical resistance first regimen typically involves HIV-1 expanded access protocol and is not to HIV-1. These mutations have been isolates with resistance to only 1 or 2 of approved for use by the US FDA. A num- identified by 1 or more of the following the drugs in the regimen; in this setting, ber of major (L33I/F/V, V82L/T, I84V, and criteria: (1) in vitro passage experiments resistance most commonly develops
    [Show full text]
  • Improving Viral Protease Inhibitors to Counter Drug Resistance
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Trends Microbiol Manuscript Author . Author Manuscript Author manuscript; available in PMC 2017 July 01. Published in final edited form as: Trends Microbiol. 2016 July ; 24(7): 547–557. doi:10.1016/j.tim.2016.03.010. Improving Viral Protease Inhibitors to Counter Drug Resistance Nese Kurt Yilmaz1, Ronald Swanstrom2, and Celia A. Schiffer1,* 1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA 2Department of Biochemistry and Biophysics, and the UNC Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA Abstract Drug resistance is a major problem in health care, undermining therapy outcomes and necessitating novel approaches to drug design. Extensive studies on resistance to viral protease inhibitors, particularly those of HIV-1 and hepatitis C virus (HCV) protease, revealed a plethora of information on the structural and molecular mechanisms underlying resistance. These insights led to several strategies to improve viral protease inhibitors to counter resistance, such as exploiting the essential biological function and leveraging evolutionary constraints. Incorporation of these strategies into structure-based drug design can minimize vulnerability to resistance, not only for viral proteases but for other quickly evolving drug targets as well, toward designing inhibitors one step ahead of evolution to counter resistance with more intelligent and rational design. Keywords drug resistance; protease inhibitors; HIV-1 protease; substrate envelope; structure based drug design; resistance mutations Drug Resistance and Viral Proteases as Drug Targets Drug resistance is a major health burden in a wide range of diseases from cancer to bacterial and viral infections, causing treatment failure as well as severe economic impact on the healthcare system.
    [Show full text]
  • Hiv Drug Resistance: Problems and Perspectives
    Title: HIV DRUG RESISTANCE: PROBLEMS AND PERSPECTIVES Author: Pleuni S Pennings Affiliation: Stanford University Running title: HIV DRUG RESISTANCE REVIEW Submitted to: Infectious Disease Reports http://www.pagepress.org/journals/index.php/idr/index Acknowledgements: I would like to thank Daniel Rosenbloom, Alison Hill, Stefany Moreno, Jonathan Li and Nandita Garud for useful comments on an earlier version of this manuscript. Version: Jan 20th 2013 Corresponding author: Pleuni Pennings, email: [email protected] OR [email protected] address: Department of Biology 371 Serra St. Stanford University Stanford, CA 94305-5020 Keywords: HIV, drug resistance, resistance, antiviral therapy, ART Authors' contributions: PSP wrote the paper Conflicts of interest: there are no conflicts of interest HIV DRUG RESISTANCE: PROBLEMS AND PERSPECTIVES Abstract Access to combination antiretroviral treatment (ART) has improved greatly over recent years. At the end of 2011, more than eight million HIV infected people were receiving antiretroviral therapy in low-income and middle-income countries. ART generally works well in keeping the virus suppressed and the patient healthy. However, treatment only works as long as the virus is not resistant against the drugs used. In the last decades, HIV treatments have become better and better at slowing down the evolution of drug resistance, so that some patients are treated for many years without having any resistance problems. However, for some patients, especially in low-income countries, drug resistance is still a serious threat to their health. This essay will review what is known about transmitted and acquired drug resistance, multi-class drug resistance, resistance to newer drugs, resistance due to treatment for the prevention of mother-to-child transmission, the role of minority variants (low-frequency drug-resistance mutations), and resistance due to pre-exposure prophylaxis.
    [Show full text]
  • Hepatitis B Virus Resistance to Tenofovir
    Wellcome Open Research 2020, 5:151 Last updated: 04 JUN 2021 SYSTEMATIC REVIEW Hepatitis B virus resistance to tenofovir: fact or fiction? A systematic literature review and structural analysis of drug resistance mechanisms [version 1; peer review: 3 approved] Jolynne Mokaya 1, Anna L. McNaughton 1, Phillip A Bester2, Dominique Goedhals2, Eleanor J. Barnes1,3,4, Brian D Marsden 5,6, Philippa C. Matthews 1,4,7 1Nuffield Department of Medicine, University of Oxford, Medawar Building, South Parks Road, Oxford, OX1 3SY, UK 2Division of Virology, National Health Laboratory Service/University of the Free State, Bloemfontein, South Africa 3Department of Hepatology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK 4National Institutes of Health Research Health Informatics Collaborative, NIHR Oxford Biomedical Research Centre, Garsington Road, Oxford, OX4 2PG, UK 5Structural Genomics Consortium, University of Oxford, Oxford, UK 6Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, UK 7Department of Microbiology and Infectious Diseases, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK v1 First published: 29 Jun 2020, 5:151 Open Peer Review https://doi.org/10.12688/wellcomeopenres.15992.1 Latest published: 29 Jun 2020, 5:151 https://doi.org/10.12688/wellcomeopenres.15992.1 Reviewer Status Invited Reviewers Abstract Background: Tenofovir (TFV) is a widely used treatment for chronic 1 2 3 hepatitis B virus (HBV) infection. There is a high genetic barrier to the selection of TFV resistance-associated mutations (RAMs), but the version 1 distribution and clinical significance of TFV RAMs are not well 29 Jun 2020 report report report understood.
    [Show full text]
  • NNRTI) Resistance Mutations
    Nonnucleoside RT inhibitor (NNRTI) resistance mutations The NNRTIs bind to a hydrophobic pocket in the RT located between the β6-β10-β9 and β 2-β13-β14 sheets of the p66 subunit (Hsiou et al., 2001) (Figure 7). A small portion of the pocket is also formed by residues from the p51 subunit. The NNRTI-binding pocket is close to but not contiguous with, the active site. The NNRTIs inhibit HIV-1 replication allosterically by displacing the catalytic aspartate residues relative to the polymerase-binding site (Kohlstaedt et al., 1992; Esnouf et al., 1995; Spence et al., 1995). The hydrophobic NNRTI-binding pocket is less well conserved than the dNTP-binding site. Indeed, HIV-1 Group O and HIV-2 (Shih et al., 1991; Hizi et al., 1993; Yang et al., 1996; Descamps et al., 1997) are intrinsically resistant to most NNRTIs. A single mutation in the NNRTI-binding pocket may result in high-level resistance to one or more of the NNRTIs. Resistance usually emerges rapidly when NNRTIs are administered as monotherapy or in the presence of incomplete virus suppression, suggesting that resistance is caused by the selection of a pre-existing population of mutant viruses within an individual (Wei et al., 1995; Havlir et al., 1996; Jackson et al., 2000; Conway et al., 2001). Several studies have shown that a single dose of nevirapine used to prevent mother-to-child HIV transmission can select for NNRTI-resistant mutants that are detectable for at least two months (Jackson et al., 2000; Cunningham et al., 2002; Kantor et al., 2003).
    [Show full text]
  • An Overview of Antiviral Drug Resistance Data Presented
    An Overview of Antiviral Drug Resistance Data presented at Options for the Control of Influenza VII Hong Kong, September 2010 // An Overview of Antiviral Drug Resistance Data presented at Options for the Control of Influenza VII Contents Introduction 03 Pandemic H1N1 Viruses 04 Seasonal Influenza Viruses 05 Clinical Trials 06 Ferret Models 07 In Vitro Methods for Resistance Testing 08 In Vitro Studies of Resistance 08 Conclusions 09 References 10 Recommended Citation 14 Acknowledgments 14 Table 1. Reports of Resistance to Neuraminidase Inhibitors in Pandemic H1N1 Virus 15 // An Overview of Antiviral Drug Resistance Data presented at Options for the Control of Influenza VII Introduction At the time when the neuraminidase inhibitors (NAIs) zanamivir and oseltamivir became available for general clinical use the Neuraminidase Inhibitor Susceptibility Network (NISN) was one of a very few independent groups conducting antiviral resistance surveillance and testing as well as related studies in the influenza field [1,2,3]. However, prompted by more recent events, including: human infection associated with the epizootic of highly pathogenic avian H5N1 influenza, the unexpected circulation of a seasonal H1N1 virus carrying the H275Y neuraminidase (NA) mutation conferring resistance to oseltamivir and then the emergence of another H1N1 virus (from swine) which resulted in the 2009 influenza pandemic, many laboratories worldwide, particularly those in the World Health Organization (WHO) Global Influenza Surveillance Network (GISN), have now carried out surveillance of drug resistance of influenza viruses and studied the properties of those resistant viruses. As a consequence, much new data on drug resistance of influenza viruses and related topics were presented at the “Options VII” conference in September 2010; here NISN summarizes and comments on the new findings.
    [Show full text]
  • HIV-1 Drug Resistance Mutations in the Second Decade of HAART
    AIDSRobert Rev. W. 2008;10:67-84Shafer, Jonathan M. Schapiro: HIV-1 Drug Resistance Mutations in the Second Decade of HAART HIV-1 Drug Resistance Mutations: an Updated Framework for the Second Decade of HAART Robert W. Shafer1 and Jonathan M. Schapiro2 1Division of Infectious Diseases, Department of Medicine, Stanford University, USA; 2National Hemophilia Center, Tel Hashomer, Israel Abstract More than 200 mutations are associated with antiretroviral resistance to drugs belonging to six licensed antiretroviral classes. More than 50 reverse transcriptase mutations are associated with nucleoside reverse transcriptase inhibitor resistance including M184V, thymidine analog mutations, mutations associated with non-thymidine analog containing regimens, multi-nucleoside resistance mutations, and several recently identified accessory mutations. More than 40 reverse transcriptase mutations are associated with nonnucleoside reverse transcriptase inhibitor resistance including major primary and secondary mutations, non-polymorphic minor mutations, and polymorphic accessory mutations. More than 60 mutations are associated with protease inhibitor resistance including major protease, accessory protease, and protease cleavage site mutations. More than 30 integrase mutations are associated with the licensed integrase inhibitor raltegravir and the investigational inhibitor elvitegravir. More than 15 gp41 mutations are associated with the fusion inhibitor enfuvirtide. CCR5 inhibitor resistance results from mutations that promote gp120 binding to an inhibitor-bound
    [Show full text]
  • Drug Resistance Evolution in Patients with Human Immunodeficiency Virus
    Li et al. Virology Journal (2019) 16:5 https://doi.org/10.1186/s12985-018-1112-6 RESEARCH Open Access Drug resistance evolution in patients with human immunodeficiency virus-1 under long-term antiretroviral treatment-failure in Yunnan Province, China Jianjian Li, Yawen Xu, Jiafa Liu, Bihui Yang, Cuixian Yang, Mi Zhang* and Xingqi Dong* Abstract Background: Understanding the prevalence and evolution of HIV-1 drug resistance (DR) and associated mutation patterns is critical to implementing free antiretroviral therapy in Yunnan, the first antiretroviral treatment location in China. Here We provide a basis for understanding the occurrence and development of HIV-1 resistance in Yunnan and a theoretical foundational for strategy to delay HIV-1 drug resistance and achieve successful individualized treatment. Methods: Plasma samples from different cities/prefectures were collected at Yunnan Provincial Hospital of Infectious Disease from January 2010 to September 2016, and those from drug-resistant individuals were genotyped using in-house assays, 88 patients were selected for the study who had been on treatment for ≥6 months (and for whom drug resistance was then measured), and each patient had at least 3 genotype resistance tests and who were enrolled to analyze mutation and evolution of HIV resistance. Results: 264 Pol sequences of 88 patients were obtained. Drug resistance levels to eight drugs increased to varying degrees with prolonged treatment. Resistance to efavirenz (EFV) and etravirine (ETR) showed the highest change, comparisons of resistant changes to second and first and to third and second agents showed altered level of drug resistance were 25 and 20 cases, 28 and 18 cases, respectively.
    [Show full text]