Candidate host epigenetic marks predictive for HIV reservoir size, responsiveness to latency reversal, and viral rebound

Abstract

Objective: This study aimed to identify candidate host epigenetic biomarkers predicting latency reversal agents (LRA) efficacy and HIV-1 rebound kinetics during analytical treatment interruption (ATI).Design: Retrospective longitudinal epigenetic profiling study from 13 people with HIV (PWH) on virologically suppressive antiretroviral therapy (ART) that participated in a LRA (HDAC inhibitor) clinical trial (NCT01680094) and a subsequent optional ATI to monitor for viral recrudescence after ART cessation.Methods: Genome-wide DNA methylation (DNAm) in purified CD4 þ T cells was measured at single-nucleotide resolution using the Infinium MethylationEPIC array. HIV-1 DNA and RNA measures were previously assessed by PCR-based methods and the association of DNAm levels at regulatory sites of the human genome were examined with reservoir size, responsiveness to LRA, and time to viral rebound following ATI.Results: A distinct set of 15 candidate DNAm sites in purified CD4 þ T cells at baseline pre-LRA and pre-ATI significantly correlated with time to viral rebound. Eight of these DNAm sites occurred in genes linked to HIV-1 replication dynamics including (SEP-SECS, cg19113954), (MALT1, cg15968021), (CPT1C, cg14318858), (CRTAM, cg10977115), (B4GALNT4, cg04663285), (IL10, cg16284789), (TFPI2, cg19645693), and (LIFR, cg26437306); with the remaining sites at intergenic regions containing regulatory elements. Moreover, baseline DNAm states related to total HIV-1 DNA levels and the fold change in unspliced cell-associated HIV RNA following LRA treatment. Conclusion:Preexisting host epigenetic states may determine HIV-1 rebound kinetics and reservoir maintenance. These findings suggest integrating a suite of DNA methylation markers to improve optimal participant selection and drug regimen in future HIV cure clinical trials.

Epigenetic landscape in the kick-and-kill therapeutic vaccine BCN02 clinical trial is associated with antiretroviral treatment interruption (ATI) outcome

“…Furthermore, a recent study has associated specific DNA methylation marks with the size of the viral reservoir and the time to viral rebound during an ATI in a clinical trial administrating a latent reactivation agent (NCT01680094). 61 The potential of epigenome studies in the identification of correlates of control of HIV-1 infection is also in line with a previous report from our group showing that differential capacity to control HIV infection in the absence of ART was associated with a differential methylation profile of genes involved in antiviral response and T-cell immunity. 16 , 62 Finally, different DNA methylation in CD4 T cells has been associated with distinct viral progression and can be impacted by cART treatment initiation, 17 again suggesting that epigenetic profiling, even in early stages of HIV infection, may have predictive power for post-treatment control.…”

Cellular resistance to an oncolytic virus is driven by chronic activation of innate immunity

“… 48 , 86 Microtubule-associated protein 1A ( Map1a ) and carnitine palmitoyltransferase 1C ( Cpt1c ) promote HIV-1 routing to the nucleus and viral replication. 87 , 88 Carbonyl Reductase 1 ( Cbr1 ) is an anti-inflammatory mediator, 89 Phosphoinositide-3-Kinase regulatory subunit 5 ( Pik2r5 ) is an inflammation-related gene with a prognostic value for lung adenocarcinoma, 90 , 91 and cardiotrophin 1 ( Ctf1 ) an immune-related gene belonging to the IL-6 family. 92 However, none of these genes has been described to participate in the VSV infection cycle, or has been associated with oncolytic virus infection outcomes.…”

Proteomic Signature of HIV-Associated Subclinical Left Atrial Remodeling and Incident Heart Failure

“…45 Measures of CRTAM expression have previously been shown to associate with positive HIV serostatus, HIV viral reservoir size, and viral rebound kinetics. 46,47 It is also believed critical to shaping the gut microbiome and Th17 responses at the mucosa, 48 increased permeability of which is a consequence of Th17 HIV-susceptibility and a contributor to chronic inflammation among PLWH. 49 CRTAM was not associated with LAVi or incident HF among older PWOH in MESA, consistent with our hypothesis that it is an HIV-specific contributor to CVD.…”