title: Identification of Siglec-1 null individuals infected with HIV-1.
abstract: Siglec-1/CD169 is a myeloid-cell surface receptor critical for HIV-1 capture and infection of bystander target cells. To dissect the role of SIGLEC1 in natura, we scan a large population genetic database and identify a loss-of-function variant (Glu88Ter) that is found in ∼1% of healthy people. Exome analysis and direct genotyping of 4,233 HIV-1-infected individuals reveals two Glu88Ter homozygous and 97 heterozygous subjects, allowing the analysis of ex vivo and in vivo consequences of SIGLEC1 loss-of-function. Cells from these individuals are functionally null or haploinsufficient for Siglec-1 activity in HIV-1 capture and trans-infection ex vivo. However, Siglec-1 protein truncation does not have a measurable impact on HIV-1 acquisition or AIDS outcomes in vivo. This result contrasts with the known in vitro functional role of Siglec-1 in HIV-1 trans-infection. Thus, it provides evidence that the classical HIV-1 infectious routes may compensate for the lack of Siglec-1 in fuelling HIV-1 dissemination within infected individuals.
authors: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.|University of Vic-Central University of Catalonia (UVic-UCC), 08500 Vic, Barcelona, Spain.
authors: Javier
authors: J
authors: Martinez-Picado
authors: National HIV and Retrovirology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada R3E 0W3.|Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada R3E 0J9.
authors: Paul J
authors: PJ
authors: McLaren
authors: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain.
authors: Itziar
authors: I
authors: Erkizia
authors: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
authors: Maureen P
authors: MP
authors: Martin
authors: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain.
authors: Susana
authors: S
authors: Benet
authors: Institute of Microbiology, University Hospital Center and University of Lausanne, 1011 Lausanne, Switzerland.
authors: Margalida
authors: M
authors: Rotger
authors: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain.
authors: Judith
authors: J
authors: Dalmau
authors: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain.
authors: Dan
authors: D
authors: Ouchi
authors: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors: Steven M
authors: SM
authors: Wolinsky
authors: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors: Sudhir
authors: S
authors: Penugonda
authors: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.|Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland.
authors: Huldrych F
authors: HF
authors: Günthard
authors: School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.|Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors: Jacques
authors: 0000-0002-8240-939X
authors: J
authors: Fellay
authors: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.|Ragon Institute for MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA.
authors: Mary
authors: M
authors: Carrington
authors: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain.
authors: Nuria
authors: N
authors: Izquierdo-Useros
authors: Genomic Medicine, J. Craig Venter Institute, La Jolla, California 12037, USA.
authors: Amalio
authors: 0000-0001-6290-7677
authors: A
authors: Telenti
mesh_terms: D000328:Adult; D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D019070:Cell Lineage; D003713:Dendritic Cells / Q000378:metabolism; D018450:Disease Progression; D059472:Exome; D005091:Exons; D005260:Female; D005828:Genetics, Population; D005838:Genotype; D015658:HIV Infections / Q000235:genetics*; D015497:HIV-1; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000235:genetics*; D013557:Switzerland; D014481:United States
chemical_list: C571166:SIGLEC1 protein, human; D063267:Sialic Acid Binding Ig-like Lectin 1