Mutacije povezane s rezistencijom virusa ljudske imunodeficijencije tipa 1 na antiretrovirusne lijekove

doctoral thesis

• Title (english): Mutations associated with antiviral drug resistance in hiv-1
• Author: Ana Planinić
• Mentor: Snježana Židovec Lepej (mentor)
• Committee member: Dijana Škorić (član povjerenstva)
• Committee member: Maja Šantak (član povjerenstva); MBZ: 229111
• Committee member: Andreja Ambriović Ristov (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2014, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology
• Universal decimal classification (UDC): 577 - Biochemistry. Molecular biology. Biophysics

Abstract

Cilj ovog istraživanja bio je odrediti prevalenciju rezistencije virusa ljudske imunodeficijencije tipa 1 (Human immunodeficiency virus type 1, HIV-1) na antiretrovirusne lijekove u liječenih zaraženih osoba primjenom dvije metode (analiza u jednoj vremenskoj točki i metoda kumulativne rezistencije), analizirati učestalost pojave klinički značajnih mutacija povezanih s rezistencijom na antiretrovirusne lijekove, odrediti distribuciju subtipova HIV-a, te na odabranim uzorcima usporediti metodu ˝ultra-deep˝-sekvenciranja (UDS) sa standardnom metodom sekvenciranja. Prevalencija rezistencije HIV-a na lijekove i subtipove HIV-a odredila se analizom dijela regije pol genoma virusa i različitim intepretativnim algoritmima u osoba s virološkim neuspjehom u periodu od 2008. do kraja 2012. Mutacije povezane s rezistencijom HIV-a na antiretrovirusne lijekove detektirane su u 50% uzoraka, od kojih je najzastupljenija M184V (26.7% uzoraka). Rezistencija na nukleozidne inhibitore reverzne transkriptaze dokazana je u 39.5%, na nenukleozidne inhibitore reverzne transkriptaze u 42%, a na inhibitore proteaze u 5.8% uzoraka. Većina ispitanika (71%) bila je zaražena subtipom B HIV-1. Značajna razlika između dviju metoda za procjenu prevalencije rezistencije nije opažena za ispitivanu skupinu. UDS je detektiralo 65 od 85 (77.3%) mutacija koje nisu otkrivene standardnom metodom sekvenciranja. Ovim istraživanjem po prvi se put procijenila prevalencija rezistencije HIV-a na antiretrovirusne lijekove u liječenih bolesnika iz Hrvatske te analizirali obrasci mutacija u uvjetima selektivnog pritiska antiretrovirusnih lijekova. UDS je pokazalo prisutnost mutacija niske prevalencije koje su mogući uzrok neuspjeha terapije bolesnika te pružilo dodatne informacije o genetičkoj raznolikosti virusa.

Abstract (english)

The aim of this study was to: determine the prevalence of Human immunodeficiency virus type 1 (HIV-1) resistance to antiretroviral drugs in treatment-experienced patients using two methods (single-point analysis, cumulative model), the distribution of HIV subtypes, analyze frequency of clinicaly relevant resistance mutations, and to compare results of ultra-deep sequencing (UDS) with standard sequencing method on selected samples. The prevalence of resistance and viral subtypes were determined by analyzing HIV pol genomic region and by applying different resistance interpretation algorithms in persons with treatment failure in the period 2008-2012. Resistance mutations were detected in 50% of samples and the most frequent was M184V (26.7% of samples). The resistance to nucleoside analogues reverse transcriptase inhibitors was found in 39.5%, to non-nucleoside analogues reverse transcriptase inhibitors in 42% and to protease inhibitors in 5.8% of samples. The majority of patients were infected with HIV-1 subtype B (71%). No significant difference was found between two methods when estimating the prevalence of resistance to drugs. A total of 65 out of 85 (77.3%) mutations revealed by UDS were not identified by standard sequencing method. For the first time in Croatia, this study showed the prevalence of HIV-resistance to antiretroviral drugs in patients subjected to treatment and analyzed the patterns of mutations in an enviroment under drug presure. UDS identified minor drug-resistance variants which may be the reason of treatment failure and revealed additional information about genetic variability of the virus.

• Keywords: HIV tipa 1; antiretrovirusno liječenje; subtip HIV-a tipa 1; ultra-deepsekvenciranje
• Keywords (english): HIV type 1; antiretroviral treatment; HIV-1 subtype; ultra-deep sequencing
• Language: croatian
• URN:NBN: urn:nbn:hr:217:752606
• Study programme: Title: Biology; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija (doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2017-05-18 10:43:28