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Author, Editor(s)

Author(s):

Ceccherini-Silberstein, Francesca
Svicher, Valentina
Sing, Tobias
Artese, Anna
Santoro, Maria Mercedes
Forbici, Federica
Bertoli, Ada
Alcaro, Stefano
Palamara, Guido
Monforte, Antonella d'Arminio
Balzarini, Jan
Antinori, Andrea
Lengauer, Thomas
Perno, Carlo Federico

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Not MPG Author(s):

Ceccherini-Silberstein, Francesca
Svicher, Valentina
Artese, Anna
Santoro, Maria Mercedes
Forbici, Federica
Bertoli, Ada
Alcaro, Stefano
Palamara, Guido
Monforte, Antonella d'Arminio
Balzarini, Jan
Antinori, Andrea
Perno, Carlo Federico

BibTeX cite key*:

Lengauer2007r

Title

Title*:

Characterization and structural analysis of novel mutations in human immunodeficiency virus type 1 reverse transcriptase involved in the regulation of restistance to nonnucleoside inhibitors

Journal

Journal Title*:

Journal of Virology

Journal's URL:


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for the article:


Language:

English

Publisher

Publisher's
Name:

American Society for Microbiology

Publisher's URL:


Publisher's
Address:


ISSN:

0022-538X

Vol, No, pp, Date

Volume*:

81

Number:

20

Publishing Date:

October 2007

Pages*:

11507-11519

Number of
VG Pages:

13

Page Start:

11507

Page End:

11519

Sequence Number:


DOI:

10.1128/JVI.00303-07

Note, Abstract, ©

Note:


(LaTeX) Abstract:

Resistance to antivirals is a complex and dynamic phenomenon that involves more mutations than are currently known. Here, we characterize 10 additional mutations (L74V, K101Q, I135M/T, V179I, H221Y, K223E/Q, and L228H/R) in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase which are involved in the regulation of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs). These mutations are strongly associated with NNRTI failure and strongly correlate with the classical NNRTI resistance mutations in a data set of 1,904 HIV-1 B-subtype pol sequences from 758 drug-naïve patients, 592 nucleoside reverse transcriptase inhibitor (NRTI)-treated but NNRTI-naïve patients, and 554 patients treated with both NRTIs and NNRTIs. In particular, L74V and H221Y, positively correlated with Y181C, were associated with an increase in Y181C-mediated resistance to nevirapine, while I135M/T mutations, positively correlated with K103N, were associated with an increase in K103N-mediated resistance to efavirenz. In addition, the presence of the I135T polymorphism in NNRTI-naïve patients significantly correlated with the appearance of K103N in cases of NNRTI failure, suggesting that I135T may represent a crucial determinant of NNRTI resistance evolution. Molecular dynamics simulations show that I135T can contribute to the stabilization of the K103N-induced closure of the NNRTI binding pocket by reducing the distance and increasing the number of hydrogen bonds between 103N and 188Y. H221Y also showed negative correlations with type 2 thymidine analogue mutations (TAM2s); its copresence with the TAM2s was associated with a higher level of zidovudine susceptibility. Our study reinforces the complexity of NNRTI resistance and the significant interplay between NRTI- and NNRTI-selected mutations. Mutations beyond those currently known to confer resistance should be considered for a better prediction of clinical response to reverse transcriptase inhibitors and for the development of more efficient new-generation NNRTIs.

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Keywords:


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Copyright Message:

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http://journals.asm.org/subscriptions/freebackissues.shtml
08/02/08

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Access Level:

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Correlation

MPG Unit:

Max-Planck-Institut für Informatik



MPG Subunit:

Computational Biology and Applied Algorithmics

Audience:

Expert

Appearance:

MPII WWW Server, MPII FTP Server, MPG publications list, university publications list, working group publication list, Fachbeirat, VG Wort


BibTeX Entry:

@ARTICLE{Lengauer2007r,
AUTHOR = {Ceccherini-Silberstein, Francesca and Svicher, Valentina and Sing, Tobias and Artese, Anna and Santoro, Maria Mercedes and Forbici, Federica and Bertoli, Ada and Alcaro, Stefano and Palamara, Guido and Monforte, Antonella d'Arminio and Balzarini, Jan and Antinori, Andrea and Lengauer, Thomas and Perno, Carlo Federico},
TITLE = {Characterization and structural analysis of novel mutations in human immunodeficiency virus type 1 reverse transcriptase involved in the regulation of restistance to nonnucleoside inhibitors},
JOURNAL = {Journal of Virology},
PUBLISHER = {American Society for Microbiology},
YEAR = {2007},
NUMBER = {20},
VOLUME = {81},
PAGES = {11507--11519},
MONTH = {October},
ISBN = {0022-538X},
DOI = {10.1128/JVI.00303-07},
}


Entry last modified by Uwe Brahm, 02/28/2008
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Editor(s)
Ruth Schneppen-Christmann
Created
01/10/2008 11:03:07 AM
Revisions
3.
2.
1.
0.
Editor(s)
Uwe Brahm
Anja Becker
Anja Becker
Ruth Schneppen-Christmann
Edit Dates
02/28/2008 04:16:19 PM
08.02.2008 12:51:49
08.02.2008 12:51:21
10.01.2008 11:07:07