Informacja

Drogi użytkowniku, aplikacja do prawidłowego działania wymaga obsługi JavaScript. Proszę włącz obsługę JavaScript w Twojej przeglądarce.

Tytuł pozycji:

Impact of the HIV-1 genetic background and HIV-1 population size on the evolution of raltegravir resistance

Tytuł:
Impact of the HIV-1 genetic background and HIV-1 population size on the evolution of raltegravir resistance
Autorzy:
Axel Fun
Thomas Leitner
Linos Vandekerckhove
Martin Däumer
Alexander Thielen
Bernd Buchholz
Andy I. M. Hoepelman
Elizabeth H. Gisolf
Pauline J. Schipper
Annemarie M. J. Wensing
Monique Nijhuis
Temat:
Immunologic diseases. Allergy
RC581-607
Źródło:
Retrovirology, Vol 15, Iss 1, Pp 1-13 (2018)
Wydawca:
BMC, 2018.
Rok publikacji:
2018
Kolekcja:
LCC:Immunologic diseases. Allergy
Typ dokumentu:
article
Opis pliku:
electronic resource
Język:
English
ISSN:
1742-4690
Relacje:
http://link.springer.com/article/10.1186/s12977-017-0384-z; https://doaj.org/toc/1742-4690
DOI:
10.1186/s12977-017-0384-z
Dostęp URL:
https://doaj.org/article/475a8646434341b186207350901f7945  Link otwiera się w nowym oknie
Numer akcesji:
edsdoj.475a8646434341b186207350901f7945
Czasopismo naukowe
Abstract Background Emergence of resistance against integrase inhibitor raltegravir in human immunodeficiency virus type 1 (HIV-1) patients is generally associated with selection of one of three signature mutations: Y143C/R, Q148K/H/R or N155H, representing three distinct resistance pathways. The mechanisms that drive selection of a specific pathway are still poorly understood. We investigated the impact of the HIV-1 genetic background and population dynamics on the emergence of raltegravir resistance. Using deep sequencing we analyzed the integrase coding sequence (CDS) in longitudinal samples from five patients who initiated raltegravir plus optimized background therapy at viral loads > 5000 copies/ml. To investigate the role of the HIV-1 genetic background we created recombinant viruses containing the viral integrase coding region from pre-raltegravir samples from two patients in whom raltegravir resistance developed through different pathways. The in vitro selections performed with these recombinant viruses were designed to mimic natural population bottlenecks. Results Deep sequencing analysis of the viral integrase CDS revealed that the virological response to raltegravir containing therapy inversely correlated with the relative amount of unique sequence variants that emerged suggesting diversifying selection during drug pressure. In 4/5 patients multiple signature mutations representing different resistance pathways were observed. Interestingly, the resistant population can consist of a single resistant variant that completely dominates the population but also of multiple variants from different resistance pathways that coexist in the viral population. We also found evidence for increased diversification after stronger bottlenecks. In vitro selections with low viral titers, mimicking population bottlenecks, revealed that both recombinant viruses and HXB2 reference virus were able to select mutations from different resistance pathways, although typically only one resistance pathway emerged in each individual culture. Conclusions The generation of a specific raltegravir resistant variant is not predisposed in the genetic background of the viral integrase CDS. Typically, in the early phases of therapy failure the sequence space is explored and multiple resistance pathways emerge and then compete for dominance which frequently results in a switch of the dominant population over time towards the fittest variant or even multiple variants of similar fitness that can coexist in the viral population.
Zaloguj się, aby uzyskać dostęp do pełnego tekstu.

Ta witryna wykorzystuje pliki cookies do przechowywania informacji na Twoim komputerze. Pliki cookies stosujemy w celu świadczenia usług na najwyższym poziomie, w tym w sposób dostosowany do indywidualnych potrzeb. Korzystanie z witryny bez zmiany ustawień dotyczących cookies oznacza, że będą one zamieszczane w Twoim komputerze. W każdym momencie możesz dokonać zmiany ustawień dotyczących cookies