A systems analysis of mutational effects in HIV-1 protease and reverse transcriptase

被引：135

作者：

Hinkley, Trevor ^{[1
]}

Martins, Joao ^{[1
]}

Chappey, Colombe ^{[2
]}

Haddad, Mojgan ^{[2
]}

Stawiski, Eric ^{[2
]}

Whitcomb, Jeannette M. ^{[2
]}

Petropoulos, Christos J. ^{[2
]}

Bonhoeffer, Sebastian ^{[1
]}

机构：

[1] ETH, Inst Integrat Biol, Zurich, Switzerland

[2] Monogram Biosci, San Francisco, CA USA

来源：

NATURE GENETICS | 2011年 / 43卷 / 05期

基金：

瑞士国家科学基金会;

关键词：

IMMUNODEFICIENCY-VIRUS TYPE-1; DRUG-RESISTANCE; FITNESS; EPISTASIS; EVOLUTION; INHIBITORS; LANDSCAPE;

D O I：

10.1038/ng.795

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The development of a quantitative understanding of viral evolution and the fitness landscape in HIV-1 drug resistance is a formidable challenge given the large number of available drugs and drug resistance mutations. We analyzed a dataset measuring the in vitro fitness of 70,081 virus samples isolated from HIV-1 subtype B infected individuals undergoing routine drug resistance testing. We assayed virus samples for in vitro replicative capacity in the absence of drugs as well as in the presence of 15 individual drugs. We employed a generalized kernel ridge regression to estimate main fitness effects and epistatic interactions of 1,859 single amino acid variants found within the HIV-1 protease and reverse transcriptase sequences. Models including epistatic interactions predict an average of 54.8% of the variance in replicative capacity across the 16 different environments and substantially outperform models based on main fitness effects only. We find that the fitness landscape of HIV-1 protease and reverse transcriptase is characterized by strong epistasis.

引用

页码：487 / +

页数：4

共 32 条

[1] Drug Resistance Mutations for Surveillance of Transmitted HIV-1 Drug-Resistance: 2009 Update [J].

Bennett, Diane E. ;

Camacho, Ricardo J. ;

Otelea, Dan ;

Kuritzkes, Daniel R. ;

Fleury, Herve ;

Kiuchi, Mark ;

Heneine, Walid ;

Kantor, Rami ;

Jordan, Michael R. ;

Schapiro, Jonathan M. ;

Vandamme, Anne-Mieke ;

Sandstrom, Paul ;

Boucher, Charles A. B. ;

van de Vijver, David ;

Rhee, Soo-Yon ;

Liu, Tommy F. ;

Pillay, Deenan ;

Shafer, Robert W. .

PLOS ONE, 2009, 4 (03)

[2] Robustness-epistasis link shapes the fitness landscape of a randomly drifting protein [J].

Bershtein, Shimon ;

Segal, Michal ;

Bekerman, Roy ;

Tokuriki, Nobuhiko ;

Tawfik, Dan S. .

NATURE, 2006, 444 (7121) :929-932

[3] Evidence for positive epistasis in HIV-1 [J].

Bonhoeffer, S ;

Chappey, C ;

Parkin, NT ;

Whitcomb, JM ;

Petropoulos, CJ .

SCIENCE, 2004, 306 (5701) :1547-1550

[4]

Candes E, 2007, ANN STAT, V35, P2313, DOI 10.1214/009053606000001523

[5] Positive selection detection in 40,000 human immunodeficiency virus (HIV) type 1 sequences automatically identifies drug resistance and positive fitness mutations in HIV protease and reverse transcriptase [J].

Chen, LM ;

Perlina, A ;

Lee, CJ .

JOURNAL OF VIROLOGY, 2004, 78 (07) :3722-3732

[6]

Clavel F, 2004, NEW ENGL J MED, V350, P1023, DOI 10.1056/NEJM2ra025195

[7] The Genetic Landscape of a Cell [J].

Costanzo, Michael ;

Baryshnikova, Anastasia ;

Bellay, Jeremy ;

Kim, Yungil ;

Spear, Eric D. ;

Sevier, Carolyn S. ;

Ding, Huiming ;

Koh, Judice L. Y. ;

Toufighi, Kiana ;

Mostafavi, Sara ;

Prinz, Jeany ;

Onge, Robert P. St. ;

VanderSluis, Benjamin ;

Makhnevych, Taras ;

Vizeacoumar, Franco J. ;

Alizadeh, Solmaz ;

Bahr, Sondra ;

Brost, Renee L. ;

Chen, Yiqun ;

Cokol, Murat ;

Deshpande, Raamesh ;

Li, Zhijian ;

Lin, Zhen-Yuan ;

Liang, Wendy ;

Marback, Michaela ;

Paw, Jadine ;

Luis, Bryan-Joseph San ;

Shuteriqi, Ermira ;

Tong, Amy Hin Yan ;

van Dyk, Nydia ;

Wallace, Iain M. ;

Whitney, Joseph A. ;

Weirauch, Matthew T. ;

Zhong, Guoqing ;

Zhu, Hongwei ;

Houry, Walid A. ;

Brudno, Michael ;

Ragibizadeh, Sasan ;

Papp, Balazs ;

Pal, Csaba ;

Roth, Frederick P. ;

Giaever, Guri ;

Nislow, Corey ;

Troyanskaya, Olga G. ;

Bussey, Howard ;

Bader, Gary D. ;

Gingras, Anne-Claude ;

Morris, Quaid D. ;

Kim, Philip M. ;

Kaiser, Chris A. .

SCIENCE, 2010, 327 (5964) :425-431

[8] Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors [J].

Croteau, G ;

Doyon, L ;

Thibeault, D ;

McKercher, G ;

Pilote, L ;

Lamarre, D .

JOURNAL OF VIROLOGY, 1997, 71 (02) :1089-1096

[9] Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV [J].

De Clercq, Erik .

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, 2009, 33 (04) :307-320

[10] The evolution of sex: empirical insights into the roles of epistasis and drift [J].

de Visser, J. Arjan G. M. ;

Elena, Santiago F. .

NATURE REVIEWS GENETICS, 2007, 8 (02) :139-149

← 1 2 3 4 →