Differential miRNA plasma profiles associated with the spontaneous loss of HIV‐1 control: miR‐199a‐3p and its potential role as a biomarker for quick screening of elite controllers

Masip, Jenifer; Gasca-Capote, Carmen; Jiménez-León, María Reyes; Peraire, Joaquim; Pérez-Gómez, Alberto; Alba, Verónica; Malo, Ana-Irene; Leal, Lorna; Martín, Carlos González; Rallón, Norma; Viladés, Consuelo; Olona, Montserrat; Vidal, Francesc; Ruiz‐Mateos, Ezequiel; Rull, Anna

doi:10.1002/ctm2.474

Cited by 4 publications

(4 citation statements)

References 11 publications

(20 reference statements)

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“…Previous studies have focused on distinguishing both phenotypes, PC and TC, to determine the causes of the loss of the virological control and to define the best model of persistent viral remission. It is known that PCs have different immunological (5), proteomic (9), metabolomic (10), microRNA (11), and virological profiles (5) compared with TCs before losing the virological control. TCs, in comparison with PCs, are characterized by displaying a weaker HIV-specific T cell response with more limited polyfunctionality (5), a higher expression of markers associated with inflammation (9), a dysregulation of metabolic parameters (10,11) and a higher viral diversity in env and gag genes (5) even one year before losing virological control.…”

Section: Resultsmentioning

confidence: 99%

“…Participants were classified as TCs after experiencing a loss of virological control, sustained viral load above the detection limit during more than 1 year of follow up (at least 2 consecutive detectable viral loads), as previously reported (5). Using this classification, we have previously observed differences in immunological (5), proteomic (9), metabolomic (10), microRNA (11) and virological profiles (5) in PCs compared with TCs before losing virological control. Participants were classified as PCs after maintaining persistent virological control during the follow-up period.…”

Section: Methodsmentioning

confidence: 99%

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The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers

Gasca-Capote,

Lian,

Gao

et al. 2024

Journal of Clinical Investigation

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BACKGROUND. Persistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure. METHODS.The characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using nextgeneration sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq). RESULTS.PCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/ defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs.CONCLUSIONS. These results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers

Gasca-Capote,

Lian,

Gao

et al. 2024

Journal of Clinical Investigation

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“…Our study findings are in line with previous studies that reported hsa-miR-199a-3p to be downregulated in peripheral blood mononuclear cells (PBMCs) of PWH with high CD4 + T-cell counts and low viral loads, as compared with those with low CD4 + T-cell counts and/or high viral loads [ 24 ]. Furthermore, in a previous study in HIV elite controllers, an elevated plasma hsa-miR199a-3p level was predictive of subsequent loss of viral control [ 25 ]. In in-vitro studies, miR-199a-3p was upregulated in HIV-1-infected cells compared with cells infected with a Vpr/Vif-deficient HIV-1 strain [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Specific plasma microRNAs are associated with CD4+ T-cell recovery during suppressive antiretroviral therapy for HIV-1

Kroeze,

Kootstra,

van Nuenen

et al. 2024

Aids

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Objective: This study investigated the association of plasma microRNAs before and during antiretroviral therapy (ART) with poor CD4+ T-cell recovery during the first year of ART. Design: MicroRNAs were retrospectively measured in stored plasma samples from people with HIV (PWH) in sub-Saharan Africa who were enrolled in a longitudinal multicountry cohort and who had plasma viral-load less than 50 copies/ml after 12 months of ART. Methods: First, the levels of 179 microRNAs were screened in a subset of participants from the lowest and highest tertiles of CD4+ T-cell recovery (ΔCD4) (N = 12 each). Next, 11 discordant microRNAs, were validated in 113 participants (lowest tertile ΔCD4: n = 61, highest tertile ΔCD4: n = 52). For discordant microRNAs in the validation, a pathway analysis was conducted. Lastly, we compared microRNA levels of PWH to HIV-negative controls. Results: Poor CD4+ T-cell recovery was associated with higher levels of hsa-miR-199a-3p and hsa-miR-200c-3p before ART, and of hsa-miR-17-5p and hsa-miR-501-3p during ART. Signaling by VEGF and MET, and RNA polymerase II transcription pathways were identified as possible targets of hsa-miR-199a-3p, hsa-200c-3p, and hsa-miR-17-5p. Compared with HIV-negative controls, we observed lower hsa-miR-326, hsa-miR-497-5p, and hsa-miR-501-3p levels before and during ART in all PWH, and higher hsa-miR-199a-3p and hsa-miR-200c-3p levels before ART in all PWH, and during ART in PWH with poor CD4+ T-cell recovery only. Conclusion: These findings add to the understanding of pathways involved in persistent HIV-induced immune dysregulation during suppressive ART.

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“…Based on our previous works studying the loss of spontaneous HIV-1 control in ECs (transient controllers) ( 4 , 5 , 10 ), we firmly believe that the identification and quantification of small molecules, from metabolites to lipids, could provide knowledge of immunotherapeutic strategies for ART-free HIV remission ( 11 ) and aid in deciding whether ART is warranted in ECs. Thus, we aimed to define the metabolomics and lipidomics signatures underlying the long-term EC phenotype to understand the mechanisms operating for persistent viral and immunological control in LTEC patients with more than 10 years of HIV control.…”

Section: Introductionmentioning

confidence: 99%

Elevated α-Ketoglutaric Acid Concentrations and a Lipid-Balanced Signature Are the Key Factors in Long-Term HIV Control

et al. 2022

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Long-term elite controllers (LTECs) are a fascinating small subset of HIV individuals with viral and immunological HIV control in the long term that have been designated as models of an HIV functional cure. However, data on the LTEC phenotype are still scarce, and hence, the metabolomics and lipidomics signatures in the LTEC-extreme phenotype, LTECs with more than 10 years of viral and immunological HIV control, could be pivotal to finding the keys for functional HIV remission. Metabolomics and lipidomics analyses were performed using high-resolution mass spectrometry (ultra-high-performance liquid chromatography–electrospray ionization–quadrupole time of flight [UHPLC-(ESI) qTOF] in plasma samples of 13 patients defined as LTEC-extreme, a group of 20 LTECs that lost viral and/or immunological control during the follow-up study (LTEC-losing) and 9 EC patients with short-term viral and immunological control (less than 5 years; no-LTEC patients). Long-term viral and immunological HIV-1 control was found to be strongly associated with elevated tricarboxylic acid (TCA) cycle function. Interestingly, of the nine metabolites identified in the TCA cycle, α-ketoglutaric acid (p = 0.004), a metabolite implicated in the activation of the mTOR complex, a modulator of HIV latency and regulator of several biological processes, was found to be a key metabolite in the persistent control. On the other hand, a lipidomics panel combining 45 lipid species showed an optimal percentage of separation and an ability to differentiate LTEC-extreme from LTEC-losing, revealing that an elevated lipidomics plasma profile could be a predictive factor for the reignition of viral replication in LTEC individuals.

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Differential miRNA plasma profiles associated with the spontaneous loss of HIV‐1 control: miR‐199a‐3p and its potential role as a biomarker for quick screening of elite controllers

Cited by 4 publications

References 11 publications

The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers

The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers

Specific plasma microRNAs are associated with CD4+ T-cell recovery during suppressive antiretroviral therapy for HIV-1

Elevated α-Ketoglutaric Acid Concentrations and a Lipid-Balanced Signature Are the Key Factors in Long-Term HIV Control

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