subject:(Integrase Inhibitors)

Wayne State University

1. Ross, Kyla Nicole. Hiv Integrase Mechanisms Of Resistance To Raltegravir, Elvitegravir, And Dolutegravir.

Degree: MS, Biochemistry and Molecular Biology, 2015, Wayne State University

URL: https://digitalcommons.wayne.edu/oa_theses/458

► ABSTRACT HIV INTEGRASE MECHANISMS OF RESISTANCE TO RALTEGRAVIR, ELVITEGRAVIR, AND DOLUTEGRAVIR by KYLA ROSS December 2015 Advisor: Dr. Ladislau Kovari Major: Biochemistry and Molecular… (more)

▼ ABSTRACT HIV INTEGRASE MECHANISMS OF RESISTANCE TO RALTEGRAVIR, ELVITEGRAVIR, AND DOLUTEGRAVIR by KYLA ROSS December 2015 Advisor: Dr. Ladislau Kovari Major: Biochemistry and Molecular Biology Degree: Master of Science HIV-1 integrase (HIV-1 IN or IN) is a multimeric enzyme that integrates the HIV-1 genome into the chromosomes of infected CD4+ T-cells. Currently there are three FDA approved HIV-1 IN strand transfer inhibitors (INSTIs) used in clinical practice: raltegravir (RAL), elvitegravir (ELV), and dolutegravir (DTG). The [Q148H], [Q148H, G140S], [Q148R], [Q148R, G140A] and [N155H, E92Q] mutations decrease IN susceptibility to RAL and ELV and may result in therapeutic failure. As an indicator of protein flexibility, the root mean square deviation (RMSD) of each HIV-1 IN residue in the last 5 ns of a 40 ns molecular dynamics simulation was calculated for HIV-1 IN catalytic core domain as an apoprotein and in complex with RAL, ELV, and DTG to study how the mutations affect HIV-1 IN flexibility. In addition, we studied the relationship between HIV-1 IN flexibility and resistance. We found that the mutants reduced overall HIV-1 IN flexibility relative to the WT IN apoprotein. We also observed that the catalytic 140s loop in the HIV-1 IN-INSTI complexes were more flexible in mutants that displayed higher reported EC50 FC (fold change) values. To further investigate the mutations effect on the more complexed full length HIV-1 IN structure, we used molecular dynamics simulations to study the impact of the mutants on binary (IN-viral DNA complex) and ternary (IN-viral DNA- INSTI) IN flexibility. RMSD analyses revealed that that the mutants have a rigid structure relative to the WT IN. Furthermore, mutant IN showed transient changes in the secondary structure of the 140s loop compared to the WT. In addition to these reduced flexibility and structural changes, resistance mutations alter the binding mode of RAL, ELV, and DTG to IN and viral DNA. This study is the first to identify a structural basis of IN mechanism of resistance to INSTIs that develops under treatment pressure in HIV-1 IN. Advisors/Committee Members: Dr. Ladislau Kovari.

Subjects/Keywords: HIV-1; HIV-1 Integrase Resistance Mutations; Integrase Resistance; Integrase Strand Transfer Inhibitors; Protein Flexibility; Biochemistry; Bioinformatics; Virology

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APA (6^th Edition):

Ross, K. N. (2015). Hiv Integrase Mechanisms Of Resistance To Raltegravir, Elvitegravir, And Dolutegravir. (Masters Thesis). Wayne State University. Retrieved from https://digitalcommons.wayne.edu/oa_theses/458

Chicago Manual of Style (16^th Edition):

Ross, Kyla Nicole. “Hiv Integrase Mechanisms Of Resistance To Raltegravir, Elvitegravir, And Dolutegravir.” 2015. Masters Thesis, Wayne State University. Accessed March 07, 2021. https://digitalcommons.wayne.edu/oa_theses/458.

MLA Handbook (7^th Edition):

Ross, Kyla Nicole. “Hiv Integrase Mechanisms Of Resistance To Raltegravir, Elvitegravir, And Dolutegravir.” 2015. Web. 07 Mar 2021.

Vancouver:

Ross KN. Hiv Integrase Mechanisms Of Resistance To Raltegravir, Elvitegravir, And Dolutegravir. [Internet] [Masters thesis]. Wayne State University; 2015. [cited 2021 Mar 07]. Available from: https://digitalcommons.wayne.edu/oa_theses/458.

Council of Science Editors:

Ross KN. Hiv Integrase Mechanisms Of Resistance To Raltegravir, Elvitegravir, And Dolutegravir. [Masters Thesis]. Wayne State University; 2015. Available from: https://digitalcommons.wayne.edu/oa_theses/458

The Ohio State University

2. Patel, Pratiq A. Functionalization of Nitrogen-Containing Heterocycles in the Synthesis of Biologically Active Molecules.

Degree: PhD, Chemistry, 2013, The Ohio State University

URL: http://rave.ohiolink.edu/etdc/view?acc_num=osu1382064973

► Nitrogen-containing heterocycles are commonly seen both in the pharmacophores of drug molecules and also in the cores of natural products. This dissertation explores the… (more)

▼ Nitrogen-containing heterocycles are commonly seen both in the pharmacophores of drug molecules and also in the cores of natural products. This dissertation explores the functionalization of nitrogen-containing heteroaromatic rings to access the highly substituted scaffolds of bioactive molecules within two distinct projects. Part I features medicinal chemistry efforts in the synthesis and derivatization of functionalized quinolines, indoles, pyridines, and pyrroles as novel HIV allosteric integrase inhibitors. Alternatively, part II involves synthetic efforts towards the indole subunit of the bioactive natural product, sespendole. HIV integrase (IN) plays a crucial role in the replication of the HIV virus as it catalyzes the transfer of the viral genetic code into the host genome. Raltegravir (Merck & Co) is the first FDA drug targeting this strand transfer catalytic activity; however, rapid viral mutation has since led to drug-resistance and a renewed interest in developing new integrase inhibitors. In this regard, the host enzyme lens-epithelium derived growth factor (LEDGF)-integrase interaction served as new targets for generating novel integrase inhibitors. Recently, independent studies by other groups resulted in the identification of 2-(quinolin-3-yl)acetic acid derivatives as allosteric integrase inhibitors (ALLINIs). Development of synthetic routes to these inhibitors and a series of structural analogues have facilitated elucidation of the novel multifunctional mechanism of action for this class of compounds. Additionally, the design of novel scaffolds as ALLINIs was investigated through a scaffold hopping technique, the derivatization of leads from an in silico screen, and a fragment-based drug design approach. These drug discovery methods have resulted in the syntheses of a structurally diverse class of compounds that have provided an insight on the structural and functional requirements of the binding pocket. Sespendole, an indolosesquiterpene alkaloid isolated from the fungus Pseudobotrytis terrestris FKA-25, was reported as a potent inhibitor of lipid droplet synthesis. The proposed biosynthesis of sespendole, which involves a carbocation induced cyclization/rearrangement cascade, initially intrigued our group and spurred our interest in the synthesis of this complex molecule. This dissertation focuses on the synthesis of the highly substituted indole subunit of sespendole. Direct functionalization of the indole nucleus at the C4 and C5 positions via application of Bartoli's Grignard addition and halogen-metal exchange chemistry resulted in the successful synthesis of the fully substituted indole subunit of sespendole. Advisors/Committee Members: Fuchs, James (Advisor), Forsyth, Craig (Committee Co-Chair).

Subjects/Keywords: Organic Chemistry; Chemistry; nitrogen-containing heterocycles; indole functionalization; HIV integrase; allosteric integrase inhibitors; integrase multimerization; sespendole; Bartoli Grignard addition

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APA (6^th Edition):

Patel, P. A. (2013). Functionalization of Nitrogen-Containing Heterocycles in the Synthesis of Biologically Active Molecules. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1382064973

Chicago Manual of Style (16^th Edition):

Patel, Pratiq A. “Functionalization of Nitrogen-Containing Heterocycles in the Synthesis of Biologically Active Molecules.” 2013. Doctoral Dissertation, The Ohio State University. Accessed March 07, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1382064973.

MLA Handbook (7^th Edition):

Patel, Pratiq A. “Functionalization of Nitrogen-Containing Heterocycles in the Synthesis of Biologically Active Molecules.” 2013. Web. 07 Mar 2021.

Vancouver:

Patel PA. Functionalization of Nitrogen-Containing Heterocycles in the Synthesis of Biologically Active Molecules. [Internet] [Doctoral dissertation]. The Ohio State University; 2013. [cited 2021 Mar 07]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1382064973.

Council of Science Editors:

Patel PA. Functionalization of Nitrogen-Containing Heterocycles in the Synthesis of Biologically Active Molecules. [Doctoral Dissertation]. The Ohio State University; 2013. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1382064973

3. Kashani Moghaddam, Matinehalsadat. Improving HIV-1 Integrase Inhibitors Prediction Using Hybrid Differential Evolution-Binary Particle Swarm Algorithm .

Degree: 2015, California State University – San Marcos

URL: http://hdl.handle.net/10211.3/139174

► Due to the mutation of HIV enzymes and their resistance against current drugs, drug companies are exploring ways to develop stronger mutant resistant drugs. Dimeric… (more)

Subjects/Keywords: DE-BPSO; Linear Models; HIV-1 Integrase Inhibitors

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APA (6^th Edition):

Kashani Moghaddam, M. (2015). Improving HIV-1 Integrase Inhibitors Prediction Using Hybrid Differential Evolution-Binary Particle Swarm Algorithm . (Thesis). California State University – San Marcos. Retrieved from http://hdl.handle.net/10211.3/139174

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kashani Moghaddam, Matinehalsadat. “Improving HIV-1 Integrase Inhibitors Prediction Using Hybrid Differential Evolution-Binary Particle Swarm Algorithm .” 2015. Thesis, California State University – San Marcos. Accessed March 07, 2021. http://hdl.handle.net/10211.3/139174.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kashani Moghaddam, Matinehalsadat. “Improving HIV-1 Integrase Inhibitors Prediction Using Hybrid Differential Evolution-Binary Particle Swarm Algorithm .” 2015. Web. 07 Mar 2021.

Vancouver:

Kashani Moghaddam M. Improving HIV-1 Integrase Inhibitors Prediction Using Hybrid Differential Evolution-Binary Particle Swarm Algorithm . [Internet] [Thesis]. California State University – San Marcos; 2015. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10211.3/139174.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kashani Moghaddam M. Improving HIV-1 Integrase Inhibitors Prediction Using Hybrid Differential Evolution-Binary Particle Swarm Algorithm . [Thesis]. California State University – San Marcos; 2015. Available from: http://hdl.handle.net/10211.3/139174

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

4. Slaughter, Alison Paige. Mechanism of action of allosteric HIV-1 integrase inhibitors.

Degree: PhD, Pharmacy, 2015, The Ohio State University

URL: http://rave.ohiolink.edu/etdc/view?acc_num=osu1428684473

► An essential step in the HIV-1 replication cycle is the integration of the viral DNA into the host chromatin, which is catalyzed by the viral… (more)

▼ An essential step in the HIV-1 replication cycle is the integration of the viral DNA into the host chromatin, which is catalyzed by the viral enzyme integrase (IN). The cellular cofactor lens epithelial growth factor (LEDGF)/p75 plays a significant role in integration by acting as a bimodal tether between IN and chromatin. These interactions are crucial for HIV-1 replication and present attractive targets for antiviral therapy. Herein, I will present research aimed at dissecting the mechanism of action of novel allosteric HIV-1 IN inhibitors. Chapter 1 introduces HIV-1 IN biology, function and its inhibition. This chapter will focus on the structural biology and function of HIV-1 IN. The role of LEDGF/p75 in replication and integration site selection will be discussed. Finally, the chapter will discuss three mechanisms of IN inhibition: (I) FDA approved active site inhibitors; (2) IN multimerization as a therapeutic target; and (3) IN-LEDGF/p75 binding as a drug target.Chapter 2 presents the findings that novel allosteric HIV-1 IN inhibitors (ALLINIs) have a multimodal mechanism of action. We demonstrate that this class of compounds impairs both IN-LEDGF/p75 binding and LEDGF/p75-independent IN catalytic activities with similar IC50 values, defining them as bona fide allosteric inhibitors of IN function. Our findings argue strongly that improved ALLINI derivatives could exhibit desirable clinical properties.Chapters 3 and 4 dissect the structural and mechanistic basis for resistance to ALLINIs. The A128T IN and H171T IN substitution emerges under ALLINI-1 and BI-D selective pressure, respectively. Chapter 3 demonstrates that the A128T substitution does not affect inhibitor binding but alters the positioning of the inhibitor at the IN dimer interface. As a result, ALLINIs are no longer able to promote aberrant higher order IN oligomers. We conclude that ALLINIs primarily target IN multimerization rather than IN-LEDGF/p75 binding. Chapter 4 shows that the H171T substitution significantly reduces the affinity for BI-D binding to recombinant H171T IN CCD. X-ray crystal structures coupled with binding free energy calculations reveal the importance of the Nd- protonated imidazole group of His171 for high affinity BI-D binding. These findings reveal a distinct mechanism of resistance for the H171T IN mutation to ALLINI BI-D. Chapter 5 presents the design of small molecules that allowed us to probe the role of HIV-1 IN multimerization independently from IN-LEDGF/p75 interactions in infected cells. The most potent multimerization selective inhibitor potently blocks HIV-1 replication by inducing aberrant IN multimerization in virus particles. These findings delineate the significance of correctly ordered IN structure for HIV-1 particle morphogenesis and present a novel class of multimerization selective IN inhibitors as investigational probes for HIV-1 molecular biology.Finally, chapter 6 summarizes the findings and significance of this dissertation research as well as provides future perspectives. In summary, this… Advisors/Committee Members: Kvaratskhelia, Mamuka (Advisor).

Subjects/Keywords: Pharmacy Sciences; Virology; HIV Integrase; LEDGF; Allosteric inhibitors; Drug Resistance

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Slaughter, A. P. (2015). Mechanism of action of allosteric HIV-1 integrase inhibitors. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1428684473

Chicago Manual of Style (16^th Edition):

Slaughter, Alison Paige. “Mechanism of action of allosteric HIV-1 integrase inhibitors.” 2015. Doctoral Dissertation, The Ohio State University. Accessed March 07, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1428684473.

MLA Handbook (7^th Edition):

Slaughter, Alison Paige. “Mechanism of action of allosteric HIV-1 integrase inhibitors.” 2015. Web. 07 Mar 2021.

Vancouver:

Slaughter AP. Mechanism of action of allosteric HIV-1 integrase inhibitors. [Internet] [Doctoral dissertation]. The Ohio State University; 2015. [cited 2021 Mar 07]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1428684473.

Council of Science Editors:

Slaughter AP. Mechanism of action of allosteric HIV-1 integrase inhibitors. [Doctoral Dissertation]. The Ohio State University; 2015. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1428684473

5. Scarry, Sarah Chajkowski. Design and synthesis of HIV-1 integrase inhibitors.

Degree: PhD, Biomolecular Sciences, 2012, University of Mississippi

URL: https://egrove.olemiss.edu/etd/1447

► In recent years, HIV-1 integrase (IN) has emerged as an attractive target for the treatment of human immunodeficiency virus type 1 (HIV-1), the causative pathogen… (more)

Subjects/Keywords: AIDS; HIV-1 Integrase; inhibitors; medicinal chemistry; oxalamate; synthesis; Pharmacy and Pharmaceutical Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Scarry, S. C. (2012). Design and synthesis of HIV-1 integrase inhibitors. (Doctoral Dissertation). University of Mississippi. Retrieved from https://egrove.olemiss.edu/etd/1447

Chicago Manual of Style (16^th Edition):

Scarry, Sarah Chajkowski. “Design and synthesis of HIV-1 integrase inhibitors.” 2012. Doctoral Dissertation, University of Mississippi. Accessed March 07, 2021. https://egrove.olemiss.edu/etd/1447.

MLA Handbook (7^th Edition):

Scarry, Sarah Chajkowski. “Design and synthesis of HIV-1 integrase inhibitors.” 2012. Web. 07 Mar 2021.

Vancouver:

Scarry SC. Design and synthesis of HIV-1 integrase inhibitors. [Internet] [Doctoral dissertation]. University of Mississippi; 2012. [cited 2021 Mar 07]. Available from: https://egrove.olemiss.edu/etd/1447.

Council of Science Editors:

Scarry SC. Design and synthesis of HIV-1 integrase inhibitors. [Doctoral Dissertation]. University of Mississippi; 2012. Available from: https://egrove.olemiss.edu/etd/1447

University of Georgia

6. Blue, Shawn Kendale. Pharmacokinetics of anti-HIV agents in rodents.

Degree: 2014, University of Georgia

URL: http://hdl.handle.net/10724/26575

► The treatment of HIV/AIDS is one of, if not, the most challenging medical enigmas of the 20th and 21st centuries. At the time of its… (more)

▼ The treatment of HIV/AIDS is one of, if not, the most challenging medical enigmas of the 20th and 21st centuries. At the time of its discovery, HIV patients were predominantly homosexual White males in America. The demographics have changed drastically over the past two decades. Now women make up nearly 50% of global HIV/AIDS patients. The current feminization of HIV demographics has led to another obstacle, mother to child transmission (MTCT). These statistics, coupled with the fact that vertical transmission is the largest factor in the number of newly diagnosed juvenile HIV/AIDS patients, create a need to optimize treatment of HIV positive pregnant women, to reduce vertical transmission of HIV. It has been shown that administration of anti-HIV medications during pregnancy, delivery and to the infant after birth greatly reduces the risk of vertical transmission. Understanding the pharmacokinetics of HIV/AIDS medications alone and in combination during pregnancy is necessary in the development of more effective methods of vertical transmission prophylaxis. Using a pregnant rat model, we have developed analytical methods and investigated the pharmacokinetics and placental transport of anti-HIV drugs alone and in combination. These studies allowed us to determine and understand any possible interactions between drugs in combination. Studies were performed on timed-pregnant Sprague-Dawley rats and pharmacokinetic analysis was performed using WinNonlin. While current methods of treating HIV/AIDS patients have been highly successful, the chance of viral mutations and resistance to Anti-Retroviral Therapy often occurs. In order to combat the resistance of reverse transcriptase inhibitors (NRTI and NNRTI) and protease inhibitors, scientists have continually searched for additional targets on HIV. For instance, integrase inhibitors, block the action of integrase, a viral enzyme, which integrates HIV DNA into the target cells. We have determined the pharmacokinetic profile of an investigational integrase inhibitor. In vivo animal studies were being performed on male Sprague-Dawley rats and female PXR-KO and hPXR transgenic mice and pharmacokinetic analysis was performed using WinNonlin.

Subjects/Keywords: HIV; Pharmacokinetics; Stavudine; Lamivudine; D4T; DDC; Placental Transport; NRTI; Nucleoside Reverse Transcriptase Inhibitors; HPLC; Antiviral Drugs; Integrase Inhibitors

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Blue, S. K. (2014). Pharmacokinetics of anti-HIV agents in rodents. (Thesis). University of Georgia. Retrieved from http://hdl.handle.net/10724/26575

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Blue, Shawn Kendale. “Pharmacokinetics of anti-HIV agents in rodents.” 2014. Thesis, University of Georgia. Accessed March 07, 2021. http://hdl.handle.net/10724/26575.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Blue, Shawn Kendale. “Pharmacokinetics of anti-HIV agents in rodents.” 2014. Web. 07 Mar 2021.

Vancouver:

Blue SK. Pharmacokinetics of anti-HIV agents in rodents. [Internet] [Thesis]. University of Georgia; 2014. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10724/26575.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Blue SK. Pharmacokinetics of anti-HIV agents in rodents. [Thesis]. University of Georgia; 2014. Available from: http://hdl.handle.net/10724/26575

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

7. Sharma, Horrick. Synthesis and Computational Studies on Hiv-1 Integrase Inhibitors.

Degree: PhD, Pharmaceutical Sciences, 2011, University of Tennessee Health Science Center

URL: https://dc.uthsc.edu/dissertations/239

► HIV-1 integrase (IN) is essential for viral replication and offers a promising target for the development of anti-retroviral drugs. Two decades of extensive research has… (more)

▼ HIV-1 integrase (IN) is essential for viral replication and offers a promising target for the development of anti-retroviral drugs. Two decades of extensive research has lead to the recent approval of raltegravir as the first IN inhibitor. Advancement of drug candidate elvitegravir, which is currently in Phase III clinical trial, has furthermore accelerated efforts against this potential target for combating HIV. However, the emergence of resistance against raltegravir and elvitegravir demands exploration of novel chemical scaffolds that could circumvent resistance against currently used HIV-1 IN inhibitors. With the goal of discovering new agents targeting HIV, a novel structural class of HIV-IN inhibitors have been designed and synthesized. Substantial computational studies were also performed that could aid the design and development of potent HIV IN inhibitors. A part of this dissertation research, covered in Chapter 3, details the design, synthesis, and biological evaluation of 3-keto salicylic acid chalcones as novel HIV-1 IN inhibitors. In the chalcone series, the most active compound, 5-bromo-2-hydroxy-3-[3-(2,3,6-trichloro-phenyl)- acryloyl]-2-hydroxybenzoic acid (96) was selectively active against IN strand transfer (ST) with IC50 of 3.7 µM. While most of the compounds exhibit ST selectivity, a few were nonselective, such as 5-bromo-3-[3-(4-bromo-phenyl)-acryloyl]-2-hydroxybenzoic acid (86), which was active against both 3!-processing (3!-P) and ST with IC50 values of 11 ± 4 and 5 ± 2 "M, respectively. The compounds also inhibited HIV-1 replication with potencies comparable to their integrase inhibitory activities. Thus, compounds 96 and 86 inhibited HIV-1 replication with EC50 values of 7.3 and 8.7 "M, respectively. Chapter 4 describes the synthesis of structurally related amide derivatives which were designed by modification of the chalcone moiety. In the amide series, the most active compound, 5-bromo-3-[(3-chloro-2,4-difluoro benzyl)- carbamoyl]-2-hydroxybenzoic acid (151), inhibited ST with an IC50 of 4 µM. Chapter 5 discloses the synthesis, and biological studies of halogenated phenanthrene-diketo acids as novel HIV-1 IN inhibitors. The two most active compounds of the series, 4-(8-chlorophenanthren-3-yl)-2,4-dioxobutanoic acid (179) and 4-(6-chlorophenanthren-2-yl)-2,4-dioxobutanoic acid (177) had ST IC50 values of 1.2 and 1.3 "M, respectively, and corresponding 3!-P values of 11.0 and 5.0 "M. In the last section of the dissertation detailed in Chapter 6, computational studies were conducted with the aim of exploring the possible binding modes of potent IN inhibitors and evaluating the structural requirements for IN inhibition. To determine the physicochemical parameters important for ligand binding, in the first part of this chapter, a PHASE pharmacophore hypothesis was developed and used for molecular alignments in the initial comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) 3D-quantitative structure activity relationship (3D-QSAR) modeling of the… Advisors/Committee Members: John K. Buolamwini, Ph.D..

Subjects/Keywords: Inhibitors; AIDS; Biological Evaluation; Computational Studies; HIV-1; Integrase Inhibitors; Synthesis; Medicine and Health Sciences; Pharmacy and Pharmaceutical Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Sharma, H. (2011). Synthesis and Computational Studies on Hiv-1 Integrase Inhibitors. (Doctoral Dissertation). University of Tennessee Health Science Center. Retrieved from https://dc.uthsc.edu/dissertations/239

Chicago Manual of Style (16^th Edition):

Sharma, Horrick. “Synthesis and Computational Studies on Hiv-1 Integrase Inhibitors.” 2011. Doctoral Dissertation, University of Tennessee Health Science Center. Accessed March 07, 2021. https://dc.uthsc.edu/dissertations/239.

MLA Handbook (7^th Edition):

Sharma, Horrick. “Synthesis and Computational Studies on Hiv-1 Integrase Inhibitors.” 2011. Web. 07 Mar 2021.

Vancouver:

Sharma H. Synthesis and Computational Studies on Hiv-1 Integrase Inhibitors. [Internet] [Doctoral dissertation]. University of Tennessee Health Science Center; 2011. [cited 2021 Mar 07]. Available from: https://dc.uthsc.edu/dissertations/239.

Council of Science Editors:

Sharma H. Synthesis and Computational Studies on Hiv-1 Integrase Inhibitors. [Doctoral Dissertation]. University of Tennessee Health Science Center; 2011. Available from: https://dc.uthsc.edu/dissertations/239

Université Montpellier II

8. Moustapha Abba Moussa, Daouda. Développement d'inhibiteurs de la dimérisation du complexe de la Reverse Transcription du VIH-1 : Dimerization of HIV-1 Reverse Transcriptase as a potent target to block HIV replication.

Degree: Docteur es, Biologie Santé, 2013, Université Montpellier II

URL: http://www.theses.fr/2013MON20238

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Le virus de l'immunodéficience humain de type 1 VIH-1 est un rétrovirus responsable d'une pandémie touchant actuellement 34 millions de personnes dont près de 25… (more)

▼

Le virus de l'immunodéficience humain de type 1 VIH-1 est un rétrovirus responsable d'une pandémie touchant actuellement 34 millions de personnes dont près de 25 millons en sont morts. En dépit des grands progrès réalisés dans le développement de nouveaux médicaments visant à bloquer la réplication de ce virus, l'émergence rapide de souches virales mutantes résistantes imposent l'urgence et la nécessité de développer de nouvelles stratégies thérapeutiques pour combattre ce virus. La Reverse Transcriptase (RT) duVIH-1 joue un rôle majeur dans le cycle viral puisqu'elle est responsable de convertir l'ARN génomique simple brin en ADN double afin d'intégrer l'ADN génomique de la cellule hôte. La forme biologique de la RT est un hétérodimère formé de la sous unité p66 et la sous unité p51. Les sous unités sont constituées des sous domaines fingers, palm, « connection », thumb et RNase H, ce dernier étant absent sur la sous unité p51. L'activation de la RT est un processus en deux étapes : la première étape consiste en l'association rapide des deux sous unités, suivie d'une deuxième étape plus lente, correspondant à des changements conformationnels fins à l'interface entre p66/p51.Dans l'objectif d'inhiber la fonction de la RT, nous avons proposé une nouvelle stratégie fondée sur l'utilisation des peptides interfacials courts dérivant de séquences hautement conserver de la RT, capables de cibler efficacement les interactions protéine/protéine et de bloquer la dimérisation et l'activation par maturation de la RT. La dimérisation des deux sous unités implique leur interaction part les domaines de connexion. Dans la première partie de ce travail de thèse, nous avons criblé et isolé des peptides capables d'interférer avec cette interaction impliquant un « cluster » de résidus aromatiques. Nous avons identifié un peptide court PID4, et démontré que ce peptide induit un changement de conformation de la RT, entrainant la dissociation du complexe. La maturation implique l'interaction de résidus localisés au niveau de « hot spot » dans le domaine RNase H de p66 et thumb de p51. Dans la deuxième partie de cette thèse, nous avons sélectionné un peptide court, P27, issus du domaine thumb pouvant inhiber l'étape de la « maturation » (P27). Ces deux classes de peptides bloquent la réplication virale et sont efficaces sur plusieurs souches virales et sur des mutants résistants aux NNRTIS et NRTIS.Les résultats obtenus sur nos deux classes d'inhibiteurs peptidiques, démontrent bien que la dimérisation et la maturation de la RT constituent des cibles de choix pour bloquer l'activité polymérase de la RT et ainsi stopper la prolifération virale par un nouvel concept moins exposer à l'émergence des mutation de résistance.

The human immunodeficiency virus type 1 (HIV-1) is a retrovirus responsible of a disease currently affecting 34 million people and caused the death of 25 million people from its discovery in the 1980s. Despite the great progresses made in the development of new drugs to block the replication of the virus, the rapid…

Advisors/Committee Members: Divita, Gilles (thesis director).

Subjects/Keywords: Vih-1; Reverse Transcriptase; Integrase; Inhibiteurs peptidiques; Résistance; Dimérisation et maturation du VIH; Hiv-1; Reverse Transcriptase; Integrase; Peptides inhibitors; Resistance; Dimerization and maturation of HIV

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APA (6^th Edition):

Moustapha Abba Moussa, D. (2013). Développement d'inhibiteurs de la dimérisation du complexe de la Reverse Transcription du VIH-1 : Dimerization of HIV-1 Reverse Transcriptase as a potent target to block HIV replication. (Doctoral Dissertation). Université Montpellier II. Retrieved from http://www.theses.fr/2013MON20238

Chicago Manual of Style (16^th Edition):

Moustapha Abba Moussa, Daouda. “Développement d'inhibiteurs de la dimérisation du complexe de la Reverse Transcription du VIH-1 : Dimerization of HIV-1 Reverse Transcriptase as a potent target to block HIV replication.” 2013. Doctoral Dissertation, Université Montpellier II. Accessed March 07, 2021. http://www.theses.fr/2013MON20238.

MLA Handbook (7^th Edition):

Moustapha Abba Moussa, Daouda. “Développement d'inhibiteurs de la dimérisation du complexe de la Reverse Transcription du VIH-1 : Dimerization of HIV-1 Reverse Transcriptase as a potent target to block HIV replication.” 2013. Web. 07 Mar 2021.

Vancouver:

Moustapha Abba Moussa D. Développement d'inhibiteurs de la dimérisation du complexe de la Reverse Transcription du VIH-1 : Dimerization of HIV-1 Reverse Transcriptase as a potent target to block HIV replication. [Internet] [Doctoral dissertation]. Université Montpellier II; 2013. [cited 2021 Mar 07]. Available from: http://www.theses.fr/2013MON20238.

Council of Science Editors:

Moustapha Abba Moussa D. Développement d'inhibiteurs de la dimérisation du complexe de la Reverse Transcription du VIH-1 : Dimerization of HIV-1 Reverse Transcriptase as a potent target to block HIV replication. [Doctoral Dissertation]. Université Montpellier II; 2013. Available from: http://www.theses.fr/2013MON20238

Erasmus University Rotterdam

9. Wijting, Ingeborg. HIV Treatment Strategies – The role of integrase strand transfer inhibitors.

Degree: 2019, Erasmus University Rotterdam

URL: http://hdl.handle.net/1765/112830

► markdownabstractThe studies that will be described in Chapter 2 to 8, and which resulted in this thesis, aim to evaluate the effectiveness and safety of… (more)

Subjects/Keywords: HIV; antiretroviral therapy; integrase strand transfer inhibitors

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Wijting, I. (2019). HIV Treatment Strategies – The role of integrase strand transfer inhibitors. (Doctoral Dissertation). Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/112830

Chicago Manual of Style (16^th Edition):

Wijting, Ingeborg. “HIV Treatment Strategies – The role of integrase strand transfer inhibitors.” 2019. Doctoral Dissertation, Erasmus University Rotterdam. Accessed March 07, 2021. http://hdl.handle.net/1765/112830.

MLA Handbook (7^th Edition):

Wijting, Ingeborg. “HIV Treatment Strategies – The role of integrase strand transfer inhibitors.” 2019. Web. 07 Mar 2021.

Vancouver:

Wijting I. HIV Treatment Strategies – The role of integrase strand transfer inhibitors. [Internet] [Doctoral dissertation]. Erasmus University Rotterdam; 2019. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/1765/112830.

Council of Science Editors:

Wijting I. HIV Treatment Strategies – The role of integrase strand transfer inhibitors. [Doctoral Dissertation]. Erasmus University Rotterdam; 2019. Available from: http://hdl.handle.net/1765/112830

10. Gantner, Pierre. Impact des inhibiteurs de l'intégrase sur la constitution et la compartimentalisation du réservoir viral : Impact of integrase inhibitors on HIV reservoirs dynamics and compartmentalization.

Degree: Docteur es, Virologie : aspects moléculaires et médicaux, 2018, Université de Strasbourg

URL: http://www.theses.fr/2018STRAJ018

►

L’étude de stratégies visant à diminuer la taille du reservoir viral, et notamment l’impact des traitements antirétroviraux, permettront peut-être de s’approcher des objectifs de guérison… (more)

▼

L’étude de stratégies visant à diminuer la taille du reservoir viral, et notamment l’impact des traitements antirétroviraux, permettront peut-être de s’approcher des objectifs de guérison de l’infection à VIH. Nous avons analysé la dynamique de ce réservoir chez des personnes vivant avec le VIH débutant un traitement comprenant du dolutegravir (TCD) à différents stades de l’infection. L’étude DRONE a inclus des personnes débutant et répondant à un TCD et suivies pendant 48 semaines. L’ADN-VIH dans les cellules mononucléées du sang périophérique (CMSP), l’ADN-VIH dans les sous-populations lymphocytaires TCD4+ (Effecteur mémoire, TEM; Transitionnel mémoire, TTM; Central mémoire, TCM and Naïf, TN), le séquençage à haut débit de l’ADN-VIH et des marqueurs inflammatoires (CD14s, CD163s, IL-6us and IP- 10) ont été analysés. Au total, 169 participants ont été inclus dans différents groupes: infections aiguës (AI, n=20), infections chroniques (CI, n=21), en succès virologique sous traitement (VS, n=116) et dans un contexte d’échec virologique à l’initiation du TCD (VF, n=12). L’ADN-VIH dans les CMSP et les sous-populations lymphocytaires, et les marqueurs inflammatoires ont diminué sous TCD dans les groupes AI, CI et VF mais pas dans le groupe VS. La diminution la plus prononcée a été observée dans le groupe AI. La diversité génétique du reservoir viral a, quant à elle, été modifiée rapidement après l’initiation du TCD dans tous les groupes. Un TCD efficace permet une diminution rapide du réservoir viral chez des personnes naïves de traitement mais aussi en cas d’échec virologique. L’effet du dolutegravir sur la latence virale devrait être étudié plus avant.

Strategies aimed at reducing the latent HIV reservoir size, including combined antiretroviral therapy, may enhance the probability of a possible cure. Here, we assessed the dynamics of HIV reservoir among HIV-infected adults initiating a dolutegravir-based regimen (DBR) at different stages of HIV infection. The DRONE trial enrolled individuals starting and responding to a DBR on a 48 weeks follow-up. HIV-DNA in peripheral blood mononuclear cells (PBMCs), HIV-DNA in sorted CD4+ T cell subsets (Effector memory, TEM; Transitional memory, TTM; Central memory, TCM and Naive, TN), HIV-DNA ultra-deep sequencing and serum immune activation biomarkers (sCD14, sCD163, IL-6us and IP-10) were assessed. Overall, 169 participants were allocated to different groups: acute infections (AI, n=20), chronic infections (CI, n=21), individuals in virological success on treatment (VS, n=116), and in the aftermath of virological failures at baseline (VF, n=12). HIV-DNA in PBMCs and in sorted CD4+ T cell subsets, and immune activation markers decreased on DBR in the AI, CI and VF groups but not in the VS group. Participants from the AI group experienced the most dramatic decline. Genetic diversity of the viral reservoir was also affected shortly after DBR initiation in all groups of individuals. Successful DBR produced a rapid decline in the viral reservoir in treatment-naive but also in…

Advisors/Committee Members: Fafi-Kremer, Samira (thesis director).

Subjects/Keywords: VIH; Réservoir; Inflammation; ADN-VIH; Diversité génétique; Inhibiteurs de l’intégrase; HIV; Reservoir; Immune activation; HIV-DNA; Genetic diversity; Integrase inhibitors; 579.2; 572.8; 616.91

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gantner, P. (2018). Impact des inhibiteurs de l'intégrase sur la constitution et la compartimentalisation du réservoir viral : Impact of integrase inhibitors on HIV reservoirs dynamics and compartmentalization. (Doctoral Dissertation). Université de Strasbourg. Retrieved from http://www.theses.fr/2018STRAJ018

Chicago Manual of Style (16^th Edition):

Gantner, Pierre. “Impact des inhibiteurs de l'intégrase sur la constitution et la compartimentalisation du réservoir viral : Impact of integrase inhibitors on HIV reservoirs dynamics and compartmentalization.” 2018. Doctoral Dissertation, Université de Strasbourg. Accessed March 07, 2021. http://www.theses.fr/2018STRAJ018.

MLA Handbook (7^th Edition):

Gantner, Pierre. “Impact des inhibiteurs de l'intégrase sur la constitution et la compartimentalisation du réservoir viral : Impact of integrase inhibitors on HIV reservoirs dynamics and compartmentalization.” 2018. Web. 07 Mar 2021.

Vancouver:

Gantner P. Impact des inhibiteurs de l'intégrase sur la constitution et la compartimentalisation du réservoir viral : Impact of integrase inhibitors on HIV reservoirs dynamics and compartmentalization. [Internet] [Doctoral dissertation]. Université de Strasbourg; 2018. [cited 2021 Mar 07]. Available from: http://www.theses.fr/2018STRAJ018.

Council of Science Editors:

Gantner P. Impact des inhibiteurs de l'intégrase sur la constitution et la compartimentalisation du réservoir viral : Impact of integrase inhibitors on HIV reservoirs dynamics and compartmentalization. [Doctoral Dissertation]. Université de Strasbourg; 2018. Available from: http://www.theses.fr/2018STRAJ018

University of Sydney

11. Fischer, Joshua. HIV-1 Integrase Inhibitors: A Formal Total Synthesis of Lithospermic Acid And Synthetic Studies Towards Integramycin .

Degree: 2007, University of Sydney

URL: http://hdl.handle.net/2123/2397

► This thesis describes synthetic studies towards the HIV-1 integrase inhibitory natural products lithospermic acid and integramycin, resulting in a formal total synthesis of the former.… (more)

▼ This thesis describes synthetic studies towards the HIV-1 integrase inhibitory natural products lithospermic acid and integramycin, resulting in a formal total synthesis of the former. A modular, flexible and convergent synthetic strategy to lithospermic acid was devised. In this approach, a Sonogashira coupling was used to unite the C1–C7 and C20–C27 fragments that were subsequently manipulated to then participate in the key step of the synthesis, a palladium-mediated carbonylative annulation. Reduction of the benzofuran nucleus with magnesium in methanol then provided the desired dihydrobenzofuran core of lithospermic acid. Various protecting group strategies were investigated to complete this sequence in an efficient manner. Further synthetic manipulations afforded the complete C1–C9/C19–C27 fragment, which was united with the C10–C18 fragment to deliver the entire carbon skeleton of lithospermic acid. A two step deprotection sequence was undertaken, however, complications with the final deprotective step prevented definitive proof that the total synthesis of lithospermic acid had been achieved. An alternate protecting group strategy was sought, and a formal total synthesis of lithospermic acid was achieved by intercepting an advanced intermediate from a previous total synthesis. Several strategies for the enantioselective synthesis of the dihydrobenzofuran core of lithospermic acid were evaluated, however, none proved successful. A synthetic route towards the tetramic acid subunit of integramycin was also investigated. 3- Methoxymaleimide was constructed using known chemistry, and the regioselective reduction of this ring system was developed. Attempts to further functionalise this ring system were thwarted by difficulties associated with handling. The scope of the regioselective reduction was investigated on an array of N- substituted methoxymaleimides with the procedure found to be generally high yielding and highly regioselective.

Subjects/Keywords: HIV-1 Integrase Inhibitors; Lithospermic Acid; Integramycin; Dihydrobenzofuran; Tetramic Acid

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APA (6^th Edition):

Fischer, J. (2007). HIV-1 Integrase Inhibitors: A Formal Total Synthesis of Lithospermic Acid And Synthetic Studies Towards Integramycin . (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/2397

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Fischer, Joshua. “HIV-1 Integrase Inhibitors: A Formal Total Synthesis of Lithospermic Acid And Synthetic Studies Towards Integramycin .” 2007. Thesis, University of Sydney. Accessed March 07, 2021. http://hdl.handle.net/2123/2397.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Fischer, Joshua. “HIV-1 Integrase Inhibitors: A Formal Total Synthesis of Lithospermic Acid And Synthetic Studies Towards Integramycin .” 2007. Web. 07 Mar 2021.

Vancouver:

Fischer J. HIV-1 Integrase Inhibitors: A Formal Total Synthesis of Lithospermic Acid And Synthetic Studies Towards Integramycin . [Internet] [Thesis]. University of Sydney; 2007. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/2123/2397.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Fischer J. HIV-1 Integrase Inhibitors: A Formal Total Synthesis of Lithospermic Acid And Synthetic Studies Towards Integramycin . [Thesis]. University of Sydney; 2007. Available from: http://hdl.handle.net/2123/2397

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Rockefeller University

12. Cunningham, Tshaka J. Exploring the Early Events in the HIV-1 Life Cycle: From Post-Entry Restriction to Nuclear Import.

Degree: 2005, Rockefeller University

URL: https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/46

► Early events in the viral replication cycle of the human immunodeficiency virus (HIV) determine the virus' ability to sustain a persistent infection in susceptible… (more)

▼ Early events in the viral replication cycle of the human immunodeficiency virus (HIV) determine the virus' ability to sustain a persistent infection in susceptible host species. However, many of the molecular machinations through which the virus progresses during its earliest moments in the cell's interior remain enigmatic. Similar to other virus families, HIV virions are packed with a specific assortment of viral and cellular proteins that allow them to carry out their unique program for replication inside of target cells. One such protein that is present in incoming virions, HIV-1 integrase, is an enzyme that facilitates the fusion of the viral genome and the host genomic DNA in the nucleus, thereby making HIV a permanent fixture in infected individuals. We have discovered that, in addition to its role in catalyzing integration, the HIV-1 integrase plays key part in transporting the viral DNA through the cytoplasm to the nucleus during a process known as viral nuclear import. Viral nuclear import is a key early step in the viral life cycle directly preceding integration that has to date been exploited as a target for antiretroviral therapy. Our recent studies indicate that a small stretch of sequence within the carboxyl terminus of the HIV-1 integrase protein contains a nuclear localization signal (NLS) that is indispensable for viral nuclear import and therefore absolutely required for productive HIV infection. Importantly, we have identified several mutations (NLS mutants) within this region that can disrupt nuclear import and therefore completely stall HIV infection. In addition, alignment of all the known subtypes of HIV within the region specified by our NLS mutants indicates that the virus seldom changes its sequence in this part of its genome, suggesting that this domain is a critical factor that it must preserve for optimal infection. Thus, a major focus of this thesis is to clarify the role that the HIV integrase plays in nuclear import. In turn, these analyses may provide a rational basis for the design of new experimental drug screening systems dedicated to finding inhibitors that block HIV-1 nuclear import and curtail HIV infection. A secondary aim of this work is to understand the mechanism of species-specific restriction of lentivirus infection in primates mediated by endogenous host cell restriction factors such as Lvl/TRIM5-a. Lastly, a potential role for non-pathogenic viral DNA episomal circles formed from integration-defective HIV virions as a novel platform for gene therapy based vaccines is discussed.

Subjects/Keywords: HIV-1 integrase; viral nuclear import; HIV-1 inhibitors; Life Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cunningham, T. J. (2005). Exploring the Early Events in the HIV-1 Life Cycle: From Post-Entry Restriction to Nuclear Import. (Masters Thesis). Rockefeller University. Retrieved from https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/46

Chicago Manual of Style (16^th Edition):

Cunningham, Tshaka J. “Exploring the Early Events in the HIV-1 Life Cycle: From Post-Entry Restriction to Nuclear Import.” 2005. Masters Thesis, Rockefeller University. Accessed March 07, 2021. https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/46.

MLA Handbook (7^th Edition):

Cunningham, Tshaka J. “Exploring the Early Events in the HIV-1 Life Cycle: From Post-Entry Restriction to Nuclear Import.” 2005. Web. 07 Mar 2021.

Vancouver:

Cunningham TJ. Exploring the Early Events in the HIV-1 Life Cycle: From Post-Entry Restriction to Nuclear Import. [Internet] [Masters thesis]. Rockefeller University; 2005. [cited 2021 Mar 07]. Available from: https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/46.

Council of Science Editors:

Cunningham TJ. Exploring the Early Events in the HIV-1 Life Cycle: From Post-Entry Restriction to Nuclear Import. [Masters Thesis]. Rockefeller University; 2005. Available from: https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/46

13. Nguyen, Thuy. Ultra-deep sequencing applications in virology research : Applications de séquençage haut-débit pour la recherche en virologie. Résistance de VIH-1 et de VHC aux antiviraux et caractérisation profonde des chaines de transmission de VHC.

Degree: Docteur es, Virologie, 2018, Sorbonne université

URL: http://www.theses.fr/2018SORUS282

► Les deux virus d’ARN VIH et VHC attirent beaucoup d’attention de la santé publique parce qu’ils partagent des mêmes facteurs de risque de transmission par… (more)

▼ Les deux virus d’ARN VIH et VHC attirent beaucoup d’attention de la santé publique parce qu’ils partagent des mêmes facteurs de risque de transmission par le sang et par des contacts sexuels. En plus, les maladies associées aux infections par le VIH et par le VHC sont des causes principales de mortalité et de morbidité globalement. Néanmoins, grâce à l’introduction des thérapies d’antirétroviraux pour le traitement de l’infection par le VIH et les antiviraux à action directe (AADs) pour le traitement de l’infection par le VHC, les patients infectés par ces virus constatent une amélioration significative de leur qualité de vie. Cependant, le taux de réplication élevé et l'absence de mécanisme de correction d'erreur de ces virus génèrent une population virale diversifiée appelée des quasi-espèces. Sous la pression sélective de traitement, les quasi-espèces virales sélectionnent des variants de résistance au médicament correspondant et rendent la thérapie inefficace, en particulier dans les cas où une surveillance appropriée du traitement n'est pas assurée. Afin de réserver un large choix de traitement antirétroviral tout au long de la vie chez les patients infectés par le VIH et, parallèlement, de réduire le coût de traitement des infections par le VIH et le VHC, il est fondamental de mener des recherches ciblées sur la détection, la surveillance et la transmission des mutations de résistance aux antiviraux. Dans cette thèse, nous avons utilisé les technologies de séquençage haut-débit (UDS) ou de séquençage de nouvelle génération (NGS) pour chercher des variants de résistance minoritaires (MiRVs) qui sont classiquement considérés comme représentant moins de 15%-25% de la population virale et ne sont pas trouvés par la technique de séquençage Sanger. La présence des MiRVs à baseline est responsable possiblement de l'échec de traitement et leur présence à l'échec peut limiter les options des traitements ultérieurs. Dans cette thèse, nous avons évalué la prévalence et l’impact clinique des MiRVs sur le gène de l’intégrase chez les patients infectés par le VIH qui ont été en échec d’un régime thérapeutique contenant un inhibiteur de l’intégrase. Nous avons également évalué l’impact des MiRVs chez les patients infectés par le VHC de génotype 3 et de génotype 4 et ayant échoué aux AADs. De plus, nous avons utilisé la technique UDS pour identifier et caractériser les chaines de transmission du VHC parmi une population clé d'hommes ayant des rapports sexuels avec des hommes, co-infectés par le VIH ou ayant un risque élevé d'acquisition du VIH. Nous avons également observé plusieurs cas d’infections mixtes de génotype du VHC dans cette population, probablement à cause du risque élevé de multiples expositions au VHC. Les questions sur l’avantage de l'UDS dans la recherche en virologie et l'applicabilité de cette technique en clinique ont été posées et vérifiées au travers de multiples types de projets dans cette thèse. L’UDS n’a pas été établi de manière concluante comme étant plus intéressant et bénéfique que la technique de… Advisors/Committee Members: Marcelin, Anne-Geneviève (thesis director), Todesco, Eve (thesis director).

Subjects/Keywords: Inhibiteurs de l'intégrase; Antiviraux à action directe; VHC génotype 3 et 4; Hommes ayant des rapports sexuels avec des hommes; Variants de résistance minoritaires; Integrase Strand Transfer Inhibitors; Direct-acting antivirals; HCV genotype 3 and 4,; Men having sex with men; Minority resistant variants, transmission networks; 615.7924

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Nguyen, T. (2018). Ultra-deep sequencing applications in virology research : Applications de séquençage haut-débit pour la recherche en virologie. Résistance de VIH-1 et de VHC aux antiviraux et caractérisation profonde des chaines de transmission de VHC. (Doctoral Dissertation). Sorbonne université. Retrieved from http://www.theses.fr/2018SORUS282

Chicago Manual of Style (16^th Edition):

Nguyen, Thuy. “Ultra-deep sequencing applications in virology research : Applications de séquençage haut-débit pour la recherche en virologie. Résistance de VIH-1 et de VHC aux antiviraux et caractérisation profonde des chaines de transmission de VHC.” 2018. Doctoral Dissertation, Sorbonne université. Accessed March 07, 2021. http://www.theses.fr/2018SORUS282.

MLA Handbook (7^th Edition):

Nguyen, Thuy. “Ultra-deep sequencing applications in virology research : Applications de séquençage haut-débit pour la recherche en virologie. Résistance de VIH-1 et de VHC aux antiviraux et caractérisation profonde des chaines de transmission de VHC.” 2018. Web. 07 Mar 2021.

Vancouver:

Nguyen T. Ultra-deep sequencing applications in virology research : Applications de séquençage haut-débit pour la recherche en virologie. Résistance de VIH-1 et de VHC aux antiviraux et caractérisation profonde des chaines de transmission de VHC. [Internet] [Doctoral dissertation]. Sorbonne université; 2018. [cited 2021 Mar 07]. Available from: http://www.theses.fr/2018SORUS282.

Council of Science Editors:

Nguyen T. Ultra-deep sequencing applications in virology research : Applications de séquençage haut-débit pour la recherche en virologie. Résistance de VIH-1 et de VHC aux antiviraux et caractérisation profonde des chaines de transmission de VHC. [Doctoral Dissertation]. Sorbonne université; 2018. Available from: http://www.theses.fr/2018SORUS282

Open Access Theses and Dissertations