title: A regulatory polymorphism in HAVCR2 modulates susceptibility to HIV-1 infection.
abstract: The HAVCR2 gene encodes TIM-3, an immunoglobulin superfamily member expressed by exhausted CD8+ T cells during chronic viral infection. We investigated whether genetic variation at HAVCR2 modulates the susceptibility to HIV-1 acquisition; specifically we focused on a 3' UTR variant (rs4704846, A/G) that represents a natural selection target. We genotyped rs4704846 in three independent cohorts of HIV-1 exposed seronegative (HESN) individuals with different geographic origin (Italy and Spain) and distinct route of exposure to HIV-1 (sexual and injection drug use). Matched HIV-1 positive subjects and healthy controls were also analyzed. In all case-control cohorts the minor G allele at rs4704846 was more common in HIV-1 infected individuals than in HESN, with healthy controls showing intermediate frequency. Results from the three association analyses were combined through a random effect meta-analysis, which revealed no heterogeneity among samples (Cochrane's Q, p value = 0.89, I2 = 0) and yielded a p value of 6.8 ×10(-4). The minor G allele at rs4704846 was found to increase HAVCR2 expression after in vitro HIV-1 infection. Thus, a positively selected polymorphism in the 3' UTR, which modulates HAVCR2 expression, is associated with the susceptibility to HIV-1 infection. These data warrant further investigation into the role of TIM-3 in the prevention and treatment of HIV-1/AIDS.
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E. MEDEA, Bosisio Parini, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Gnudi
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E. MEDEA, Bosisio Parini, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Irma
authors.initials: I
authors.lastname: Saulle
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E. MEDEA, Bosisio Parini, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Rainone
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Trabattoni
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Micaela
authors.initials: M
authors.lastname: Garziano
authors.affiliation: Infectious Disease Unit, S. Maria Annunziata Hospital Florence, Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mazzotta
authors.affiliation: Infectious Diseases and Microbiology Clinical Unit, Valme Hospital, Seville, Spain.
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Real
authors.affiliation: Maimonides Institut for Biomedical Research (IMIBIC)-Reina Sofia Universitary Hospital-University of Cordoba, Cordoba, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rivero-Juarez
authors.affiliation: Immunogenetics Unit, Department of Experimental Biology, University of Jaen, Jaen, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Caruz
authors.affiliation: Infectious Disease Unit, S. Maria Annunziata Hospital Florence, Florence, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lo Caputo
authors.affiliation: Chair of Immunology, Department of Physiopathology and Transplantation, University of Milan, Milan, Italy; Don C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D000328:Adult; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000235:genetics* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins