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Clin Infect Dis. 2017 Mar 1;64(5):621-628. Epub 2016 Dec 16.

HLA-B*57 and IFNL4-related polymorphisms are associated with protection against HIV-1 disease progression in controllers.

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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.
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.
Laboratoy of Immunology, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spain.
Department of Medical Microbiology and Immunology, University of California, Davis, Davis, CA, USA.
Fundació Lluita Contra la Sida, Fundacio Irsicaixa, Hospital Universitari Germans Trias i Pujol, Badalona,Spain.
Department of Infectious Diseases, Hospital Ramón y Cajal, Universidad de Alcalá de Henares, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
Department of Endocrinology, Complejo Hospitalario de Navarra, Pamplona, Spain.
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.
Centro Sanitario Sandoval, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
AIDS Immunopathology Unit, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.



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/mm3 for more than 7 years after HIV-1 diagnosis) versus non-LTNP-C, who developed CD4+T-cells counts <500 cells/mm3 Both 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.


HIV-controllers; HLA-B*57; IFNL4; progression

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