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PMID: 22718199 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans.

Human molecular genetics ·Vol. 21 ·No. 19 ·2012-10-01 ·Pages 4334-47

McLaren PJ, Ripke S, Pelak K, Weintrob AC, Patsopoulos NA, Jia X, Erlich RL, Lennon NJ, Kadie CM, Heckerman D, Gupta N, Haas DW, Deeks SG, Pereyra F, Walker BD, de Bakker PI, International HIV Controllers Study

Abstract

A small proportion of human immunodeficiency virus-1 (HIV-1) infected individuals, termed HIV-1 controllers, suppress viral replication to very low levels in the absence of therapy. Genetic investigations of this phenotype have strongly implicated variation in the class I major histocompatibility complex (MHC) region as key to HIV-1 control. We collected sequence-based classical class I HLA genotypes at 4-digit resolution in HIV-1-infected African American controllers and progressors (n = 1107), and tested them for association with host control using genome-wide single nucleotide polymorphism data to account for population structure. Several classical alleles at HLA-B were associated with host control, including B*57:03 [odds ratio (OR) = 5.1; P= 3.4 × 10(-18)] and B*81:01 (OR = 4.8; P= 1.3 × 10(-9)). Analysis of variable amino acid positions demonstrates that HLA-B position 97 is the most significant association with host control in African Americans (omnibus P = 1.2 × 10(-21)) and explains the signal of several HLA-B alleles, including B*57:03. Within HLA-B, we also identified independent effects at position 116 (omnibus P= 2.8 × 10(-15)) in the canonical F pocket, position 63 in the B pocket (P= 1.5 × 10(-3)) and the non-pocket position 245 (P= 8.8 × 10(-10)), which is thought to influence CD8-binding kinetics. Adjusting for these HLA-B effects, there is evidence for residual association in the MHC region. These results underscore the key role of HLA-B in affecting HIV-1 replication, likely through the molecular interaction between HLA-B and viral peptides presented by infected cells, and suggest that sites outside the peptide-binding pocket also influence HIV-1 control.

MeSH Terms
African Americans/genetics Disease Resistance Genetic Variation HIV Infections/genetics,immunology,virology HIV-1/physiology HLA Antigens/genetics,immunology HLA-B Antigens/genetics,immunology Humans Polymorphism, Single Nucleotide
Chemicals
HLA Antigens HLA-B Antigens
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
McLaren Paul J
Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ripke Stephan
Pelak Kimberly
Weintrob Amy C
Patsopoulos Nikolaos A
Jia Xiaoming
Erlich Rachel L
Lennon Niall J
Kadie Carl M
Heckerman David
Gupta Namrata
Haas David W
Deeks Steven G
Pereyra Florencia
Walker Bruce D
de Bakker Paul I W
International HIV Controllers Study
Investigators
249 investigators, click to expand
Addo Marylyn M
Agan Brian
Agarwal Shanu
Ahern Richard L
Allen Brady L
Altidor Sherly
Altschuler Eric L
Ambardar Sujata
Anastos Kathryn
Anderson Val
Andrady Ushan
Antoniskis Diana
Bangsberg David
Barbaro Daniel
Barrie William
Bartczak J
Barton Simon
Basden Patricia
Basgoz Nesli
Bellos Nicholaos C
Berger Judith
Bernard Nicole F
Bernard Annette M
Bodner Stanley J
Bolan Robert K
Boudreaux Emilie T
Braun James F
Brndjar Jon E
Brown J
Brown Sheldon T
Burack Jedidiah
Bush Larry M
Cafaro Virginia
Campbell John
Carlson Robert H
Carmichael J Kevin
Casey Kathleen K
Cavacuiti Chris
Celestin Gregory
Chambers Steven T
Chez Nancy
Chirch Lisa M
Cimoch Paul J
Cohen Daniel
Cohn Lillian E
Conway Brian
Cooper David A
Cornelson Brian
Cox David T
Cristofano Michael V
Cuchural George
Czartoski Julie L
Dahman Joseph M
Daly Jennifer S
Davis Benjamin T
Davis Kristine
Davod Sheila M
DeJesus Edwin
Dietz Craig A
Dunham Eleanor
Dunn Michael E
Ellerin Todd B
Eron Joseph J
Fangman John J W
Ferlazzo Helen
Fidler Sarah
Fleenor-Ford Anita
Frankel Renee
Freedberg Kenneth A
French Neel K
Fuchs Jonathan D
Fuller Jon D
Gaberman Jonna
Gallant Joel E
Gandhi Rajesh T
Garcia Efrain
Garmon Donald
Gathe Joseph C
Gaultier Cyril R
Gebre Wondwoosen
Gilman Frank D
Gilson Ian
Goepfert Paul A
Gottlieb Michael S
Goulston Claudia
Groger Richard K
Gurley T Douglas
Haber Stuart
Hardwicke Robin
Hardy W David
Harrigan P Richard
Hawkins Trevor N
Heath Sonya
Hecht Frederick M
Henry W Keith
Hladek Melissa
Hoffman Robert P
Horton James M
Hsu Ricky K
Huhn Gregory D
Hunt Peter
Illeman Mark L
Jaeger Hans
Jellinger Robert M
John Mina
Johnson Jennifer A
Johnson Kristin L
Johnson Heather
Johnson Kay
Joly Jennifer
Jordan Wilbert C
Kauffman Carol A
Khanlou Homayoon
Kim Arthur Y
Kim David D
Kinder Clifford A
Kogelman Laura
Kojic Erna Milunka
Korthuis P Todd
Kurisu Wayne
Kwon Douglas S
LaMar Melissa
Lampiris Harry
Lederman Michael M
Lee David M
Lee Marah J
Lee Edward T Y
Lemoine Janice
Levy Jay A
Llibre Josep M
Liguori Michael A
Little Susan J
Liu Anne Y
Lopez Alvaro J
Loutfy Mono R
Loy Dawn
Mohammed Debbie Y
Man Alan
Mansour Michael K
Marconi Vincent C
Markowitz Martin
Martin Jeffrey N
Martin Harold L
Mayer Kenneth Hugh
McElrath M Juliana
McGhee Theresa A
McGovern Barbara H
McGowan Katherine
McIntyre Dawn
McLeod Gavin X
Menezes Prema
Mesa Greg
Metroka Craig E
Meyer-Olson Dirk
Miller Andy O
Montgomery Kate
Mounzer Karam C
Nagin Iris
Nahass Ronald G
Nielsen Craig
Norene David L
O'Connor David H
Okulicz Jason
Oldfield Edward C
Olender Susan A
Ostrowski Mario
Owen William F
Parsonnet Jeffrey
Pavlatos Andrew M
Piechocka-Trocha Alicja
Perlmutter Aaron M
Pincus Jonathan M
Pisani Leandro
Price Lawrence Jay
Proia Laurie
Prokesch Richard C
Pujet Heather Calderon
Ramgopal Moti
Rausch Michael
Ravishankar J
Rhame Frank S
Richards Constance Shamuyarira
Richman Douglas D
Robbins Gregory K
Rodes Berta
Rodriguez Milagros
Rose Richard C
Rosenberg Eric S
Rosenthal Daniel
Ross Polly E
Rubin David S
Rumbaugh Elease
Saenz Luis
Salvaggio Michelle R
Sanchez William C
Sanjana Veeraf M
Santiago Steven
Schmidt Wolfgang
Schuitemaker Hanneke
Sestak Philip M
Shalit Peter
Shay William
Shirvani Vivian N
Silebi Vanessa I
Sizemore James M
Skolnik Paul R
Sokol-Anderson Marcia
Sosman James M
Stabile Paul
Stapleton Jack T
Stein Francine
Stellbrink Hans-Jurgen
Sterman F Lisa
Stone Valerie E
Stone David R
Tambussi Giuseppe
Taplitz Randy A
Tedaldi Ellen M
Telenti Amalio
Torres Richard
Tosiello Lorraine
Tremblay Cecile
Tribble Marc A
Trinh Phuong D
Vaccaro Anthony
Valadas Emilia
Vanig Thanes J
Vecino Isabel
Veikley Wenoah
Wade Barbara H
Walworth Charles
Wanidworanun Chingchai
Ward Douglas J
Weber Robert D
Webster Duncan
Weis Steve
Wheeler David A
White David J
Wilkins Ed
Winston Alan
Wlodaver Clifford G
van't Wout Angelique
Wright David P
Yang Otto O
Yurdin David L
Zabukovic Brandon W
Zachary Kimon C
Zeeman Beth
Zhao Meng
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Article Info
Journal
Human molecular genetics
Abbr.
Hum Mol Genet
ISSN
1460-2083
DOI
10.1093/hmg/dds226
Published
2012-10-01
Epub
2012-00-19
Pages
4334-47
Language
English
Region
England
NLM ID
9208958
PMCID
PMC3441117
Subset
IM
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PubMed source DOI: 10.1093/hmg/dds226 PMC Full Text View journal details
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