Nicotinamide activates latent HIV-1 ex vivo in ART suppressed individuals, revealing higher potency than the association of two methyltransferase inhibitors, chaetocin and BIX01294

Samer, Sadia; Arif, Muhammad Shoaib; Giron, Leila B.; Zukurov, Jean; Hunter, James R.; Santillo, Bruna Teresa; Namiyama, Gislene Mitsue; Galinskas, Juliana; Komninakis, Shirley Vasconcelos; Oshiro, Telma Miyuki; Sucupira, Maria Cecília Araripe; Janini, Luiz Mário; Diaz, Ricardo Sobhie

doi:10.1016/j.bjid.2020.01.005

Cited by 16 publications

(13 citation statements)

References 37 publications

(45 reference statements)

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“…Moreover, these observations may shed new light on the previously reported contribution of nicotinamide to proviral escape from latency (Samer et al, 2020) and viability of HIV-1-infected cells (Savarino et al, 1997).…”

Section: Discussionmentioning

confidence: 53%

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

Shytaj

Procopio

Tarek

et al. 2020

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HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic and metabolomic analysis, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+/NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, the antioxidant NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a “shock and kill effect” decreasing proviral DNA in cells from people-living-with-HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies.

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Section: Discussionmentioning

confidence: 53%

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

Shytaj

Procopio

Tarek

et al. 2020

Preprint

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“…Similarly, plasma metabolites have been investigated as diagnostic and prognostic biomarkers in several diseases such as heart disease, Alzheimer’s disease, and cancer 17 – 19 . Similar to plasma glycans, plasma metabolites are biologically active molecules that can regulate immunological responses, including inflammatory responses 20 , 21 .…”

Section: Introductionmentioning

confidence: 99%

Non-invasive plasma glycomic and metabolic biomarkers of post-treatment control of HIV

et al. 2021

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Non-invasive biomarkers that predict HIV remission after antiretroviral therapy (ART) interruption are urgently needed. Such biomarkers can improve the safety of analytic treatment interruption (ATI) and provide mechanistic insights into the host pathways involved in post-ART HIV control. Here we report plasma glycomic and metabolic signatures of time-to-viral-rebound and probability-of-viral-remission using samples from two independent cohorts. These samples include a large number of post-treatment controllers, a rare population demonstrating sustained virologic suppression after ART-cessation. These signatures remain significant after adjusting for key demographic and clinical confounders. We also report mechanistic links between some of these biomarkers and HIV latency reactivation and/or myeloid inflammation in vitro. Finally, machine learning algorithms, based on selected sets of these biomarkers, predict time-to-viral-rebound with 74% capacity and probability-of-viral-remission with 97.5% capacity. In summary, we report non-invasive plasma biomarkers, with potential functional significance, that predict both the duration and probability of HIV remission after treatment interruption.

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“…Given these premises, we designed and tested a personalized MDDCT using autologous HIV Gag peptides from patients undergoing long-term suppressive ART to decrease the reservoir of HIV-infected cells. This MDDCT was administered in the context of a larger clinical trial (clinicaltrials.gov ID: NCT02961829) which also examined the effects of a conditioning regimen consisting of aurano n to decrease the central memory T-cell pool encompassing the viral reservoir (39)(40)(41)) and nicotinamide, favoring HIV escape from latency to facilitate recognition of the HIV-infected cells (42,43). To assess the immunogenicity of our personalized MDDCT strategy and help guide the choice of analytical treatment interruption (ATI) in a larger planned trial, we performed an interim analysis of immunologic parameters in the MDDCT recipients.…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity of Personalized Dendritic-cell Therapy in HIV-1 Infected Individuals Under Suppressive Antiretroviral Treatment: Interim Analysis From a Phase II Clinical Trial.

Batista¹,

Silva²,

Samer³

et al. 2021

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BackgroundWe developed a personalized Monocyte-Derived Dendritic Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses.MethodsPBMCs were obtained from 10 HIV+ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-α and GM-CSF. After sequencing each patient’s HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients’ cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-γ) production were measured in CD4+ and CD8+ T-cells. ResultsThe protocol of ex-vivo treatment with IFN-α and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4+ and CD8+ T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-γ expression was significantly increased in CD4+ T-cells. The number of candidates that increased in vitro the cytokine levels in CD4+ and CD8+ T cells upon stimulation with Gag peptides from baseline to days 15 and from baseline to days 30 and days 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. ConclusionsMDDC has a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment.NCT02961829: (Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure, https://www.clinicaltrials.gov/ct2/show/NCT02961829, posted November 11th, 2016).

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Nicotinamide activates latent HIV-1 ex vivo in ART suppressed individuals, revealing higher potency than the association of two methyltransferase inhibitors, chaetocin and BIX01294

Cited by 16 publications

References 37 publications

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

Non-invasive plasma glycomic and metabolic biomarkers of post-treatment control of HIV

Immunogenicity of Personalized Dendritic-cell Therapy in HIV-1 Infected Individuals Under Suppressive Antiretroviral Treatment: Interim Analysis From a Phase II Clinical Trial.

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