{"id":105815,"date":"2018-03-11T10:29:28","date_gmt":"2018-03-11T10:29:28","guid":{"rendered":""},"modified":"2018-03-11T10:29:28","modified_gmt":"2018-03-11T10:29:28","slug":"mecanismos-moleculares-de-resistencia-e-hipersensibilidad-a-farmacos-antirretovirales-modulados-por-deleciones-en-la-horquilla-b3-b4-de-la-retrotranscriptasa-del-virus-de-la-inmunodeficiencia-humana-t","status":"publish","type":"post","link":"https:\/\/www.deberes.net\/tesis\/sin-categoria\/mecanismos-moleculares-de-resistencia-e-hipersensibilidad-a-farmacos-antirretovirales-modulados-por-deleciones-en-la-horquilla-b3-b4-de-la-retrotranscriptasa-del-virus-de-la-inmunodeficiencia-humana-t\/","title":{"rendered":"Mecanismos moleculares de resistencia e hipersensibilidad a f\u00e1rmacos antirretovirales modulados por deleciones en la horquilla b3-b4 de la retrotranscriptasa del virus de la inmunodeficiencia humana tipo 1"},"content":{"rendered":"<h2>Tesis doctoral de <strong> Monica Kisic Aguirre <\/strong><\/h2>\n<p>The human immunodeficiency virus type 1 (hiv-1) reverse transcriptase (rt) is a  multifunctional enzyme with  rna- and dna- dependent dna polymerase, rnase h, strand  transfer and strand displacement activities. Hiv-1 rt is an heterodimer composed of two  subunits, p66 and p51, with subdomains termed fingers, palm, thumb and connection in both  subunits and an rnase h domain in the larger subunit only. The \u00edY3-\u00edY4 hairpin loop of the hiv-1  rt fingers subdomain interacts with the incoming dntp and the template overhang, and is  considered a hotspot for nucleoside analogue resistance mutations. Deletions in the \u00edY3\u00c2\u00bf\u00edY4 loop  of hiv-1 rt are associated with the emergence of multidrug resistance. Common mutational  patterns involve the deletion of asp67 (\u00c2\u00bf67) and mutations t69g and k70r, usually associated  with thymidine analogue resistance-associated mutations (tams), while the deletion of thr69  (\u00c2\u00bf69) appears together with mutations of the q151m complex. We have studied the effect of  \u00c2\u00bf69 in a multidrug-resistant sequence background (including the q151m complex and  substitutions k103n, y181c, m184v, and g190a) and in a wt sequence context, under  steady- and pre-steady-state conditions. Furthermore, we studied the effect of deleting codons  67 and 69 in rts bearing tams m41l and t215y, or k219e.  firstly, we show that the q151m complex accounts for most of the loss of susceptibility  shown by the multidrug-resistant rts, while mutation k103n generates high-level resistance to  efavirenz and other nnrtis. In addition, we  demonstrate that mutations outside the nnrti  binding pocket (e.G. A376s) can influence resistance. A376s confers low-level resistance to  nevirapine, due to a reduced affinity for the inhibitor, and affects template-primer binding.  transient kinetics have been used to demonstrate that \u00c2\u00bf69 in a wt sequence context  increases 3tc resistance through a 3tctp  versus dctp discrimination mechanism. In  comparison with the wt rt, the \u00c2\u00bf69 rt showed decreased ability to excise primers terminated  with aztmp in the presence of atp or ppi. These data support the role of the excision  mechanism in mediating azt hypersusceptibility. We also demonstrate that the deletion has no  effect on resistance to foscarnet. Furthermore, the introduction of deletion \u00c2\u00bf69 in a sequence  bearing tams m41l and t215y resulted in a lower atp-dependent phosphorolytic activity on  primers terminated with aztmp or d4tmp. Interestingly, the \u00c2\u00bf67 complex (\u00c2\u00bf67\/t69g\/k70r)  showed significant atp-mediated excision. This complex also increased excision activity on  thymidine analogue-terminated primers, when introduced in a sequence containing tams m41l  and t215y. Secondary mutations, such as k219e (a tam-2 pathway mutation) had no effect  on rescue reactions catalyzed by the  \u00c2\u00bf67 rt, while its introduction in the  \u00c2\u00bf69 rt led to a  decrease of its ppi-dependent excision activity on both azt- and d4t-terminated primers.  structural changes in the \u00edY3-\u00edY4 loop generated by these deletions can modify the accessibility  of the ppi donor to the terminating nucleotide at the 3\u00c2\u00bf end of the primer. We suggest that the  evolutionary patterns followed by \u00c2\u00bf69 and \u00c2\u00bf67 can be explained by their role in the excision  mechanism mediating resistance to nucleoside analogues.<\/p>\n<p>&nbsp;<\/p>\n<h3>Datos acad\u00e9micos de la tesis doctoral \u00ab<strong>Mecanismos moleculares de resistencia e hipersensibilidad a f\u00e1rmacos antirretovirales modulados por deleciones en la horquilla b3-b4 de la retrotranscriptasa del virus de la inmunodeficiencia humana tipo 1<\/strong>\u00ab<\/h3>\n<ul>\n<li><strong>T\u00edtulo de la tesis:<\/strong>\u00a0 Mecanismos moleculares de resistencia e hipersensibilidad a f\u00e1rmacos antirretovirales modulados por deleciones en la horquilla b3-b4 de la retrotranscriptasa del virus de la inmunodeficiencia humana tipo 1 <\/li>\n<li><strong>Autor:<\/strong>\u00a0 Monica Kisic Aguirre <\/li>\n<li><strong>Universidad:<\/strong>\u00a0 Aut\u00f3noma de Madrid<\/li>\n<li><strong>Fecha de lectura de la tesis:<\/strong>\u00a0 16\/12\/2010<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<h3>Direcci\u00f3n y tribunal<\/h3>\n<ul>\n<li><strong>Director de la tesis<\/strong>\n<ul>\n<li>Luis Menendez Arias<\/li>\n<\/ul>\n<\/li>\n<li><strong>Tribunal<\/strong>\n<ul>\n<li>Presidente del tribunal: jos\u00e9 Berenguer Carlos <\/li>\n<li>\u00e1frica Holgu\u00edn fern\u00e1ndez (vocal)<\/li>\n<li>cecilio L\u00f3pez gal\u00edndez (vocal)<\/li>\n<li>Miguel angel Mart\u00ednez de la sierra (vocal)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Tesis doctoral de Monica Kisic Aguirre The human immunodeficiency virus type 1 (hiv-1) reverse transcriptase (rt) is a multifunctional enzyme [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center 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