Interferon lambda rs368234815 ΔG/ΔG is associated with higher CD4⁺:CD8⁺ T-cell ratio in treated HIV-1 infection

The objectives of this study were to investigate the relationships between polymorphisms at the interferon lambda (IFNL) locus and CD4⁺:CD8⁺ ratio normalisation in people living with HIV (PLWH) on effective antiretroviral therapy (ART); and to examine whether these polymorphisms influence the composition of T lymphocyte compartments in long-term treated HIV-1 infection.

A cross-sectional study in PLWH enrolled into the Mater Immunology study. We performed IFNL genotyping on stored samples and evaluated the association of IFNL single-nucleotide polymorphisms (rs368234815 and rs12979860) with CD4⁺:CD8⁺ ratio normalization (> 1) and expanded CD4⁺ and CD8⁺ T-cell subsets; CD45RO⁺CD62L⁺ (central-memory), CD45RO⁺ CD62L^-(effector-memory) and CD45RO^-CD62L⁺ (naïve), using logistic and linear regression models, respectively.

190 ambulatory PLWH recruited to the main study, 143 were included in the analysis (38 had no stored DNA and 9 no T-lymphocyte subpopulation). Of 143 included, the median age (IQR) was 45(39-48) years, 64% were male and 66% were of Caucasian ethnicity. Heterosexual-contact (36%), injecting drug-use (33%) and men who have sex with men (24%) were the most presented HIV-transmission risk groups. The majority of subjects (90.2%) were on ART with 79% of the cohort having an undetectable HIV-RNA (< 40 copies/ml) and the time since ART initiation was 7.5 (3.7-10.4) year. rs368234815 and rs12979860 displayed similar allelic frequencies, with minor alleles ΔG and T representing 39% and 42%, respectively, of circulating alleles. rs368234815 ΔG/ΔG minor homozygotes were significantly associated with increased odds for attaining a normalised CD4⁺:CD8⁺ ratio compared to rs368234815 T/T major homozygotes in PLWH virologically suppressed on effective ART (OR = 3.11; 95% CI [1.01:9.56]). rs368234815 ΔG/ΔG homozygosity was also significantly associated with lower levels of CD4⁺ effector memory T-cells (regression coefficient: - 7.1%, p = 0.04) and CD8⁺ naïve T-cell subsets were significantly higher in HIV-1 mono-infected PLWH with rs368234815 ΔG/ΔG (regression coefficient: + 7.2%, p = 0.04).

In virally-suppressed, long-term ART-treated PLWH, rs368234815 ΔG/ΔG homozygotes were more likely to have attained normalisation of their CD4⁺:CD8⁺ ratio, displayed lower CD4⁺ effector memory and higher naive CD8⁺ T-cells. Further studies are needed to replicate our findings in other, larger and more diverse cohorts and to determine the impact of IFNL genetic-variation on CD4⁺:CD8⁺ ratio normalisation and clinical outcomes in PLWH.