Abstract Body

Background:

Telmisartan, an angiotensin II receptor antagonist, is known to reduce inflammation. In a randomized trial, we examined whether 48 weeks of sustained adjunctive telmisartan initiated with antiretroviral therapy (ART) in acute HIV infection (AHI) would modify HIV’s impact on the central nervous system (CNS). While we observed no significant changes in soluble makers of CNS inflammation or injury markers due to telmisartan, we did not evaluate its effects on CNS cells. Hence, we investigated whether telmisartan modified epigenetic states in cerebrospinal fluid (CSF) cells.

Methods:

We utilized a new ultra-low DNA input assay to measure genome-wide DNA methylation (DNAm) epigenetic profiles in CSF cells at 48 and 72 weeks from 21 participants with AHI that were randomized 2:1 to initiate treatment with ART +/- telmisartan for 48 weeks. We used R statistical software to analyze DNA methylation data and identify differentially methylated loci using a linear model with FDR correction.

Results:

The median age of participants was 29 years (IQR: 24-34), pre-ART median log10 plasma viral load was 5.95 copies/mL (5.36-6.48), pre-ART median CSF HIV RNA was 2.82 copies/mL (2.17-4.36), and pre-ART CD4+ T Cell count was 479 cells/mm3 (95-688). Age, Fiebig stage, pre-ART plasma and CSF viral loads, and pre-ART CD4+ T cell count did not significantly differ between participants randomly assigned to ART+ telmisartan versus ART only groups. Comparing the DNAm states of CSF cells at Week 48 in participants receiving 48 weeks of ART+telmisartan versus ART, we identified 11,433 differentially methylated loci (DML) at a mean difference in DNAm of 10% or greater. Notably, DNAm levels of marker of proliferation Ki-67 MKI67, inflammatory gene IL1B, immune checkpoint receptor gene LAG3, central regulator of stress response gene CRH, and interferon stimulated gene IFI27 were significantly altered in CSF cells of participants receiving ART+ telmisartan versus ART only for 48 weeks. We examined the durability of telmisartan-associated changes in CSF cells at week 72 in participants who stopped telmisartan and continued ART only. We found that only 5.46% of DML identified at week 72 overlapped with changes observed at week 48.

Conclusions:

Telmisartan initiated during AHI affects epigenetic states of genes related to inflammation, immune response, and cellular proliferation in CSF cells. Telmisartan’s effects on long-term epigenetic reprogramming of CNS cells and CNS outcomes warrant further investigation.