Translating HIV Sequences into Quantitative Fitness Landscapes Predicts Viral Vulnerabilities for Rational Immunogen Design

被引：172

作者：

Ferguson, Andrew L. ^{[1
,2
,3
]}

Mann, Jaclyn K. ^{[4
,5
]}

Omarjee, Saleha ^{[4
,5
]}

Ndung'u, Thumbi ^{[2
,3
,4
,5
]}

Walker, Bruce D. ^{[2
,3
,6
]}

Chakraborty, Arup K. ^{[1
,2
,3
,7
,8
,9
]}

机构：

[1] MIT, Dept Chem Engn, Cambridge, MA 02139 USA

[2] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02129 USA

[3] Harvard Univ, Boston, MA 02129 USA

[4] Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, ZA-4013 Durban, South Africa

[5] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV K RITH, ZA-4013 Durban, South Africa

[6] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[7] MIT, Dept Chem, Cambridge, MA 02139 USA

[8] MIT, Dept Phys, Cambridge, MA 02139 USA

[9] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA

来源：

IMMUNITY | 2013年 / 38卷 / 03期

基金：

美国国家卫生研究院; 新加坡国家研究基金会;

关键词：

IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL RESPONSES; REPLICATION CAPACITY; CLASS-I; ELITE CONTROLLERS; LYMPHOCYTE ESCAPE; VACCINE DESIGN; HLA ALLELES; P24; GAG; INFECTION;

D O I：

10.1016/j.immuni.2012.11.022

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

A prophylactic or therapeutic vaccine offers the best hope to curb the HIV-AIDS epidemic gripping sub-Saharan Africa, but it remains elusive. A major challenge is the extreme viral sequence variability among strains. Systematic means to guide immunogen design for highly variable pathogens like HIV are not available. Using computational models, we have developed an approach to translate available viral sequence data into quantitative landscapes of viral fitness as a function of the amino acid sequences of its constituent proteins. Predictions emerging from our computationally defined landscapes for the proteins of HIV-1 clade B Gag were positively tested against new in vitro fitness measurements and were consistent with previously defined in vitro measurements and clinical observations. These landscapes chart the peaks and valleys of viral fitness as protein sequences change and inform the design of immunogens and therapies that can target regions of the virus most vulnerable to selection pressure.

引用

页码：606 / 617

页数：12

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