Abstract
BackgroundThe 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.MethodsA 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.Results190 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).ConclusionsIn 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.
Highlights
With advances in antiretroviral therapy (ART), Human immunodeficiency viruses (HIV)-infection has become a chronic, manageable condition.For the majority of individuals, infection with HIV-1 results in inversion of the normal CD4+:CD8+ ratio and, despite effective antiret‐ roviral therapy (ART), only about 30% of subjects on ART for more than 5 years achieve normalisation of their CD4+:CD8+ T-cell ratios to > 1 [1]
Initiation of ART early after HIV acquisition or at higher CD4+ T-cell counts is associated with higher subsequent CD4+:CD8+ ratios [4–6], and ART containing the non-nucleoside reverse transcriptase inhibitor efavirenz [7] or integrase strand transfer inhibitors (InSTI)
The objectives of the present study were to: (i) investigate relationships between polymorphisms at the inter‐ feron lambda (IFNL) locus and CD4+:CD8+ ratio normalisation in people living with HIV (PLWH) on effective ART; and (ii) examine whether these polymorphisms influence the composition of T lymphocyte compartments in long-term treated HIV-1 infection
Summary
For the majority of individuals, infection with HIV-1 results in inversion of the normal CD4+:CD8+ ratio and, despite effective ART, only about 30% of subjects on ART for more than 5 years achieve normalisation of their CD4+:CD8+ T-cell ratios to > 1 [1]. Attention has turned to understanding factors that influence poorer immune responses to ART, including failure to normalise the C D4+:CD8+ T-cell ratio. The role of the host immune system in determining CD4+:CD8+ T-cell ratio responses to ART have been explored. The objectives of this study were to investigate the relationships between polymorphisms at the inter‐ feron lambda (IFNL) locus and C D4+:CD8+ ratio normalisation in people living with HIV (PLWH) on effective antiret‐ roviral therapy (ART); and to examine whether these polymorphisms influence the composition of T lymphocyte compartments in long-term treated HIV-1 infection
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