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Characterization of the HIV-1 transcription profile after romidepsin administration in ART-suppressed individuals.

ABSTRACT: OBJECTIVES:Reversing HIV-1 latency has been suggested as a strategy to eradicate HIV-1. We investigated the effect of romidepsin on the HIV transcription profile in participants from the REDUC part B clinical trial. DESIGN:Seventeen participants on suppressive antiretroviral therapy were vaccinated with six doses of the therapeutic vaccine Vacc-4x followed by treatment with three doses of romidepsin. Samples from nine study participants were available for HIV transcription profile analysis. METHODS:Read-through, total (TAR), elongated (longLTR), polyadenylated (polyA) and multiply-spliced (Tat-Rev) HIV transcripts and total HIV DNA were quantified at baseline (visit 1) and 4?h after the second (visit 10b) and third (visit 11b) romidepsin infusions. RESULTS:Read-through, total, elongated, and polyadenylated HIV transcripts increased after romidepsin infusion (P?=?0.020, P?=?0.0078, P?=?0.0039, P?=?0.027, respectively), but no changes were observed in multiply-spliced HIV RNA or HIV DNA. No change was observed in the ratio of read-through/total HIV transcripts. The ratio of elongated/total HIV RNA increased after romidepsin (P?=?0.016), whereas the ratio of polyadenylated/elongated HIV decreased. Both elongated HIV transcripts and total HIV DNA correlated negatively with the time to viral rebound after interruption of ART. CONCLUSIONS:In these patients, romidepsin increased early events in HIV transcription (initiation and especially elongation), but had less effect on later stages (completion, multiple splicing) that may be required for comprehensive latency reversal and cell killing. Without cell death, increased HIV transcription before or after latency reversal may hasten viral rebound after therapy interruption.

SUBMITTER: Moron-Lopez S

PROVIDER: S-EPMC6374101 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Characterization of the HIV-1 transcription profile after romidepsin administration in ART-suppressed individuals.

Moron-Lopez Sara S Kim Peggy P Søgaard Ole S OS Tolstrup Martin M Wong Joseph K JK Yukl Steven A SA

AIDS (London, England) 20190301 3

<h4>Objectives</h4>Reversing HIV-1 latency has been suggested as a strategy to eradicate HIV-1. We investigated the effect of romidepsin on the HIV transcription profile in participants from the REDUC part B clinical trial.<h4>Design</h4>Seventeen participants on suppressive antiretroviral therapy were vaccinated with six doses of the therapeutic vaccine Vacc-4x followed by treatment with three doses of romidepsin. Samples from nine study participants were available for HIV transcription profile ...[more]

PMID: 30531314

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Project description:Background. HIV-infected individuals on antiretroviral therapy (HIV/ART) experience higher levels of non-AIDS morbidity than uninfected people, which is believed to be driven by inflammation that persists despite viral suppression. Elevations in plasma cytokines, coagulation markers and both innate and adaptive immune cell activation during untreated infection are often incompletely reversed by ART and associated with these morbidities. Monocytes/macrophages play a central role in many of these complications including neurocognitive and cardiovascular disease. Results. We investigated monocyte surface markers, gene expression and plasma cytokines in 11 HIV-infected older individuals (median age 53 years) who started therapy with low CD4 counts (median 129 cells/ul), with elevated hsCRP (≥2mg/L) despite long-term ART (median 7.4 years), along with age, gender, race and smoking status-matched controls. Major monocyte subsets (based on CD14/CD16/CD163) were not different from controls, but surface levels differed for CD163 (p=0.022), PD1 (p=0.015) and a trend for tissue factor (p=0.098). As a group, HIV/ART subjects had elevated levels of plasma CCL2 (MCP-1; p=0.0001), CXCL9 (MIG; p=0.04) and sIL2R (p=0.015), which were highly correlated, whereas sCD14 and several other markers were not significantly elevated. However, principal component analysis of soluble markers revealed that about half of HIV/ART subjects clustered with controls, whereas the remainder were distinct, driven by IL-10, CCL11, CXCL10, CXCL11 as well as CCL2, CXCL9 and sIL2R. Outlier subjects were significantly older than those who clustered with controls. Gene expression analysis unexpectedly revealed downregulation in HIV/ART monocytes of multiple genes linked to immune functions including inflammation, immune cell development and cell-cell signaling. Conclusions. These results reveal a novel pattern of immune dysregulation involving both aberrant inflammation and monocyte dysfunction, which suggests complex mechanisms linking monocytes and HIV/ART comorbidities.

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Characterization of the HIV-1 transcription profile after romidepsin administration in ART-suppressed individuals.

Publications

Characterization of the HIV-1 transcription profile after romidepsin administration in ART-suppressed individuals.

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