Work

Tissue-specific effects of latency-reversing agents on HIV transcriptional blocks in gut and blood

Year: 2019

Type: article

Abstract: Methods: We studied 66 individuals (100% male; median age 34 years) in the HeatHer PHI cohort who commenced art a median of 52 days from estimated seroconversion, and 10 healthy controls (100% male; median age 35 [31-43] years).Using flow cytometry, we measured the frequency of cD4 and cD8 memory subsets from PbMcs, expression of immune checkpoint receptors (PD-1, tim-3, tIGIt), cD38 and transcription factors (t-bet and eomes).assays were performed on samples from the earliest available pre-therapy time-point (baseline) plus 1 and 3 years (for a subset of 18 individuals) after art initiation.comparisons between groups were performed using principle component analysis and nonparametric statistical tests with adjustment for multiple comparisons.Results: PHI was characterised by expansion of differentiated cD4 and cD8 t cell subsets, cD8 t cell activation (cD38 expression; p< 0.0001) and elevation of PD-1, tim-3 and tIGIt expression (all p< 0.05 on effector memory [eM] cD8 t cells).During PHI, tim-3 and cD38 expression were closely correlated with markers of clinical progression (viral load, cD4 count, cD4:cD8).Following 1 year of art there was partial, but incomplete, restoration of t cell phenotype towards that of healthy controls.this difference was driven by persistent elevation of tim-3 on memory cD4 and cD8 t cell subsets.this further reduced but had not normalised following 3 years of art.PD-1 expression was specifically elevated on eM cD4 t cells during PHI (p< 0.01) and remained unchanged following 3 years of art.PD-1 expression on other subsets and tIGIt expression was comparable to healthy controls by 1 year.Conclusions: specific immunological perturbations observed during PHI persist despite early art.In particular, tim-3 expression on memory t cells and PD-1 on eM cD4 t cells remained elevated.Persistent immune dysfunction may have implications for the pathogenesis of non-aIDs comorbidities or the efficacy of immunotherapeutic interventions to target PD-1 and tim-3 signalling.

Source: Journal of Virus Eradication

DOI: 10.1016/s2055-6640(20)31033-5