Dominguez-Molina, BeatrizTarancon-Diez, LauraHua, StephaneAbad-Molina, CristinaRodriguez-Gallego, EstherMachmach, KawtharVidal, FrancescTural, CristinaMoreno, SantiagoGoni, Maria JoseRamirez-de-Arellano, Elenadel-Val, MargaritaGonzalez-Escribano, Maria FranciscaDel-Romero, JorgeRodriguez, CarmenCapa, LauraViciana, PompeyoAlcami, JoseYu, Xu G.Walker, Bruce D.Leal, ManuelLichterfeld, MathiasRuiz-Mateos, Ezequiel2023-02-122023-02-122017-03-01Dominguez-Molina B, Tarancon-Diez L, Hua S, Abad-Molina C, Rodriguez-Gallego E, Machmach K, et al. HLA-B*57 and IFNL4-related polymorphisms are associated with protection against HIV-1 disease progression in controllers. Clin Infect Dis. 2017 Mar 1;64(5):621-628.1058-4838http://hdl.handle.net/10668/18938Human immunodeficiency virus type 1 ( 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. Methods .We analyzed the association of interferon-lambda 4 (IFNL4)–related polymorphisms and human leukocyte antigen (HLA)-B haplotypes within long-term nonprogressor HIV-1 controllers (LTNP-Cs; defined by maintaining CD4+ T-cells counts >500 cells /mm3 for more than 7 years after HIV-1 diagnosis ) vs non-LTNP-Cs who developed CD4+ T-cell 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 analyzed.Results. HLA-B *57 was independently associated with the LTNP-C phenotype ( odds ratio [OR], 3.056 [1.029–9.069]; P = .044 and OR, 1.924 [1.252–2.957]; P = .003) while IFNL4 genotypes represented independent factors for becoming non-LTNP-C (TT/TT, ss469415590; OR, 0.401 [0.171–0.942]; P = .036 or A/A, rs12980275; OR, 0.637 [0.434–0.934]; P = .021) in the Spanish and validation cohorts, respectively, after adjusting for sex , age at HIV-1 diagnosis , IFNL4-related polymorphisms, and different HLA-B haplotypes . LTNP-Cs showed lower plasma induced protein 10 (P = .019) and higher IFN-γ (P = .02) levels than the HIV-1 controllers with diminished CD4+ T-cell numbers. Moreover, LTNP-Cs exhibited higher quantities of interleukin (IL)2+CD57- and IFN-γ +CD57- HIV-1 –specific CD8+ T cells (P = .002 and .041, respectively) than non-LTNP-Cs.Conclusions.We 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.enHIV controllersprogressionHLA-B(star)57IFNL4Plasmacytoid dendritic cellsEliteIl28bClearanceTherapyCytokinesInterleukin-2HaplotypesViremiaInterferon LambdaInterleukinsHIV Seropositivityresearch articleRestricted AccessLinfocitos TAntígenos HLA-BHaplotiposInterferón lambdaViremia10.1093/cid/ciw8331537-6591https://academic.oup.com/cid/article-pdf/64/5/621/24254783/ciw833.pdf397303400012