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J Infect Dis. 2017 Nov 27;216(9):1063-1069. doi: 10.1093/infdis/jix470.

Evaluating the Impact of Functional Genetic Variation on HIV-1 Control.

Author information

1
JC Wilt Infectious Diseases Research Centre, National HIV and Retrovirology Laboratory, Public Health Agency of Canada.
2
Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada.
3
Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, The Netherlands.
4
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
5
Department of Medicine, University of Cambridge, United Kingdom.
6
Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Switzerland.
7
Institute for Genomic Medicine, Columbia University, New York.
8
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA.
9
Department of Infectious Diseases, University of Cambridge, United Kingdom.
10
Division of HIV and Other Retroviruses, Robert Koch Institute, Berlin, Germany.
11
Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain.
12
Department of Medicine, University of Calgary, Canada.
13
Human Immunology Laboratory, International AIDS Vaccine Initiative, Imperial College, London, United Kingdom.
14
Research Department of Infection, Division of Infection and Immunity, University College London, United Kingdom.
15
The Kirby Institute for Infection and Immunity in Society, University of New South Wales, Sydney, Australia.
16
Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
17
Department of Dermatology and Venereology, Medical University Innsbruck, Austria.
18
Kings College Hospital, London, United Kingdom.
19
Royal Sussex County Hospital, Brighton, United Kingdom.
20
Department of Medicine, Vanderbilt University School of Medicine, Nashville.
21
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston.
22
Howard Hughes Medical Institute, Chevy Chase.
23
University College London, United Kingdom.
24
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands.
25
Swiss Institute of Bioinformatics, Lausanne, Switzerland.

Abstract

Background:

Previous genetic association studies of human immunodeficiency virus-1 (HIV-1) progression have focused on common human genetic variation ascertained through genome-wide genotyping.

Methods:

We sought to systematically assess the full spectrum of functional variation in protein coding gene regions on HIV-1 progression through exome sequencing of 1327 individuals. Genetic variants were tested individually and in aggregate across genes and gene sets for an influence on HIV-1 viral load.

Results:

Multiple single variants within the major histocompatibility complex (MHC) region were observed to be strongly associated with HIV-1 outcome, consistent with the known impact of classical HLA alleles. However, no single variant or gene located outside of the MHC region was significantly associated with HIV progression. Set-based association testing focusing on genes identified as being essential for HIV replication in genome-wide small interfering RNA (siRNA) and clustered regularly interspaced short palindromic repeats (CRISPR) studies did not reveal any novel associations.

Conclusions:

These results suggest that exonic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection.

KEYWORDS:

HIV host dependency factors; HIV-1 control; HIV-1 progression; exome sequencing; host genetics of infection

PMID:
28968755
PMCID:
PMC5853944
DOI:
10.1093/infdis/jix470
[Indexed for MEDLINE]
Free PMC Article

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