Human 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.

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.

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.

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.