title: HLA-B*57 and IFNL4-related polymorphisms are associated with protection against HIV-1 disease progression in controllers.
abstract: HIV-1-controllers maintain HIV-1 viremia at low levels (normally <2000 HIV-RNA copies/mL) without antiretroviral treatment. However, some HIV-1-controllers have evidence of immunologic progression with marked CD4+T-cell decline. We investigated host genetic factors associated with protection against CD4+T-cell loss in HIV-1-controllers.
  
  
  
  We analysed the association of interferon lambda 4 (IFNL4)-related polymorphisms and HLA-B haplotypes within Long Term Non-Progressor HIV-1-controllers ((LTNP-C), defined by maintaining CD4+T-cells counts >500 cells/mm3for more than 7 years after HIV-1 diagnosis) versus non-LTNP-C, who developed CD4+T-cells counts <500 cells/mm3Both a Spanish study cohort (n=140) and an international validation cohort (n=914) were examined. Additionally, in a subgroup of individuals HIV-1-specific T-cell responses and soluble cytokines were analysed RESULTS: HLA-B*57 was independently associated with the LTNP-C phenotype (OR=3.056 (1.029-9.069) p=0.044 and OR=1.924 (1.252-2.957) p=0.003) while IFNL4 genotypes represented independent factors for becoming non-LTNP-C (TT/TT, ss469415590, OR=0.401 (0.171-0.942) p=0.036 or A/A, rs12980275, OR=0.637 (0.434-0.934) p=0.021) in the Spanish and validation cohort, respectively, after adjusting for sex, age at HIV-1 diagnosis, IFNL4-related polymorphisms and different HLA-B haplotypes. LTNP-C showed lower plasma IP-10 (p=0.019) and higher IFN-γ (p=0.02) levels than the HIV-1-controllers with diminished CD4+T-cell numbers. Moreover, LTNP-C exhibited higher quantities of IL2+CD57-and IFN-γ+CD57-HIV-1-specific CD8+T-cells (p=0.002 and 0.041, respectively) than non-LTNP-C.
  
  
  
  We have defined genetic markers able to segregate stable HIV-1-controllers from those who experience CD4+T-cell decline. These findings allow for identification of HIV-1-controllers at risk for immunologic progression, and provide avenues for personalized therapeutic interventions and precision medicine for optimizing clinical care of these individuals.
authors.affiliation: Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Dominguez-Molina
authors.affiliation: Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Tarancon-Diez
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA Harvard Medical School, Boston, Massachusetts, USA Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts, USA Infectious Disease Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hua
authors.affiliation: Laboratoy of Immunology, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Abad-Molina
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Rodriguez-Gallego
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, Davis, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Machmach
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Vidal
authors.affiliation: Fundació Lluita Contra la Sida, Fundacio Irsicaixa, Hospital Universitari Germans Trias i Pujol, Badalona,Spain.
authors.forename: C
authors.initials: C
authors.lastname: Tural
authors.affiliation: Department of Infectious Diseases, Hospital Ramón y Cajal, Universidad de Alcalá de Henares, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Moreno
authors.affiliation: Department of Endocrinology, Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Goñi
authors.affiliation: Unidad de Inmunología Viral, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Ramírez de Arellano
authors.affiliation: Unidad de Inmunología Viral, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain.|Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Del Val
authors.affiliation: Laboratoy of Immunology, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: M F
authors.initials: MF
authors.lastname: Gonzalez-Escribano
authors.affiliation: Centro Sanitario Sandoval, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Del Romero
authors.affiliation: Centro Sanitario Sandoval, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Rodriguez
authors.affiliation: AIDS Immunopathology Unit, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Capa
authors.affiliation: Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Viciana
authors.affiliation: AIDS Immunopathology Unit, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Alcamí
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA Harvard Medical School, Boston, Massachusetts, USA Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts, USA Infectious Disease Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: X G
authors.initials: XG
authors.lastname: Yu
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA Harvard Medical School, Boston, Massachusetts, USA Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts, USA Infectious Disease Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Leal
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA Harvard Medical School, Boston, Massachusetts, USA Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts, USA Infectious Disease Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lichterfeld
authors.affiliation: Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Ruiz-Mateos
mesh_terms: D000328:Adult; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D015658:HIV Infections / Q000453:epidemiology / Q000235:genetics*; D015497:HIV-1; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult; D000095022:Interferon Lambda
chemical_list: D015235:HLA-B Antigens; D007378:Interleukins; C103707:HLA-B57 antigen; C579163:IFNL4 protein, human; D000095022:Interferon Lambda
keywords: HIV-controllers; HLA-B*57; IFNL4; progression