Pharmacological Inhibition of PPAR&lt;sub&gt;y&lt;/sub&gt; Boosts HIV Reactivation and Th17 Effector Functions, while Preventing Progeny Virion Release and &lt;i&gt;de novo&lt;/i&gt; Infection

Planas, Delphine; Fert, Augustine; Zhang, Yuwei; Goulet, Jean-Philippe; Richard, Jonathan; Uchil, Pradeep D.; Ruiz, María Julia; Marchand, Laurence Raymond; Chatterjee, Debashree; Chen, Huicheng; Salinas, Tomas Raul Wiche; Gosselin, Annie; Cohen, Éric A.; Routy, Jean Pierre; Chomont, Nicolas; Ancuța, Petronela

doi:10.20411/pai.v5i1.348

Cited by 15 publications

(16 citation statements)

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“…2a). The size of transcriptionally-competent HIV reservoirs, quantified by RT-PCR as cell-associated (CA) unspliced (US) HIV-RNA ex vivo [65], revealed no statistically significant changes in response to metformin (Fig. 2b).…”

Section: Effects Of Metformin On Hiv Reservoir Markers In Blood Cd4 + T-cellsmentioning

confidence: 99%

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LILAC pilot study: Effects of metformin on mTOR activation and HIV reservoir persistence during antiretroviral therapy

et al. 2021

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Background: Chronic inflammation and residual HIV transcription persist in people living with HIV (PLWH) receiving antiretroviral therapy (ART), thus increasing the risk of developing non-AIDS co-morbidities. The mechanistic target of rapamycin (mTOR) is a key regulator of cellular metabolism and HIV transcription, and therefore represents an interesting novel therapeutic target. Methods: The LILAC pilot clinical trial, performed on non-diabetic ART-treated PLWH with CD4 + /CD8 + T-cell ratios <0.8, evaluated the effects of metformin (12 weeks oral administration; 500-850 mg twice daily), an indirect mTOR inhibitor, on the dynamics of immunological/virological markers and changes in mTOR activation/phosphorylation in blood collected at Baseline, Week 12, and 12 weeks after metformin discontinuation (Week 24) and sigmoid colon biopsies (SCB) collected at Baseline and Week 12. Findings: CD4 + T-cell counts, CD4 + /CD8 + T-cell ratios, plasma markers of inflammation/gut damage, as well as levels of cell-associated integrated HIV-DNA and HIV-RNA, and transcriptionally-inducible HIV reservoirs, underwent minor variations in the blood in response to metformin. The highest levels of mTOR activation/ phosphorylation were observed in SCB at Baseline. Consistently, metformin significantly decreased CD4 + Tcell infiltration in the colon, as well as mTOR activation/phosphorylation, especially in CD4 + T-cells expressing the Th17 marker CCR6. Also, metformin decreased the HIV-RNA/HIV-DNA ratios, a surrogate marker of viral transcription, in colon-infiltrating CD4 + T-cells of 8/13 participants.

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Section: Effects Of Metformin On Hiv Reservoir Markers In Blood Cd4 + T-cellsmentioning

confidence: 99%

“…Total DNA and RNA were dually extracted from colon memory CD4 + T-cells using the AllPrep DNA/RNA Mini Kit (Qiagen), according to the manufacturer's instructions, as we reported [65]. Cell-associated HIV-RNA and HIV-DNA extracted from each sample were quantified as described above.…”

Section: Quantification Of Ca Us Hiv-rna In Colon Memory Cd4 + T-cellsmentioning

confidence: 99%

LILAC pilot study: Effects of metformin on mTOR activation and HIV reservoir persistence during antiretroviral therapy

et al. 2021

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“…Both these genes are found in immune pathways, and impact T cells and innate lymphoid cell type 2. Specifically, TMEM229B was found to be down regulated in memory CCR6+ T cells in an HIV study [37]. The CCR6+ T cells direct Th17 cells to effector mucosal sites [38, 39], where they secrete cytokines.…”

Section: Discussionmentioning

confidence: 99%

Genomic regions associated withMycoplasma ovipneumoniaepresence in nasal secretions of domestic sheep

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et al. 2021

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Mycoplasma ovipneumoniae contributes to polymicrobial pneumonia in domestic sheep. Elucidation of host genetic components to M. ovipneumoniae nasal detection would have the potential to reduce the incidence of pneumonia. Nasal mucosal secretions were collected from 647 sheep from a large US sheep flock. Ewes of three breeds (Polypay n=222, Rambouillet n=321, and Suffolk n=104) ranging in age from one to seven years, were sampled at three different times of the production cycle (February, April, and September/October) over four years (2015 to 2018). The presence and quantity of M. ovipneumoniae was determined using a species-specific qPCR with 3 to 10 sampling times per sheep. Breed (P<0.001), age (P<0.024), sampling time (P<0.001), and year (P<0.001) of collection affected log 10 transformed M. ovipneumoniae DNA copy number, where Rambouillet had the lowest (P<0.0001) compared with both Polypay and Suffolk demonstrating a possible genetic component to detection. Samples from yearlings, April, and 2018 had the highest (P<0.046) detected DNA copy number mean. Sheep genomic DNA was genotyped with the Illumina OvineHD BeadChip. Principal component analysis identified most of the variation in the dataset was associated with breed. Therefore, genome wide association analysis was conducted with a mixed model (EMMAX), with principle components 1 to 6 as fixed and a kinship matrix as random effects. Genome-wide significant (P<9x10 -8 ) SNPs were identified on chromosomes 6 and 7 in the all-breed analysis. Individual breed analysis had genome-wide significant (P<9x10 -8 ) SNPs on chromosomes 3, 4, 7, 9, 10, 15, 17, and 22. Annotated genes near these SNPs are part of immune ( ANAPC7 , CUL5 , TMEM229B , PTPN13 ), gene translation ( PIWIL4 ), and chromatin organization ( KDM2B ) pathways. Immune genes are expected to have increased expression when leukocytes encounter M. ovipneumoniae which would lead to chromatin reorganization. Work is underway to narrow the range of these associated regions to identify the underlying causal mutations.

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“…Both these genes are found in immune pathways, and impact T cells and innate lymphoid cell type 2. Specifically, TMEM229B was found to be down regulated in memory CCR6+ T cells in an HIV study [ 45 ]. The CCR6+ T cells direct Th17 cells to effector mucosal sites [ 46 , 47 ], where they secrete cytokines.…”

Section: Discussionmentioning

confidence: 99%

Genes involved in immune, gene translation and chromatin organization pathways associated with Mycoplasma ovipneumoniae presence in nasal secretions of domestic sheep

et al. 2021

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Mycoplasma ovipneumoniae contributes to polymicrobial pneumonia in domestic sheep. Elucidation of host genetic influences of M. ovipneumoniae nasal detection has the potential to reduce the incidence of polymicrobial pneumonia in sheep through implementation of selective breeding strategies. Nasal mucosal secretions were collected from 647 sheep from a large US sheep flock. Ewes of three breeds (Polypay n = 222, Rambouillet n = 321, and Suffolk n = 104) ranging in age from one to seven years, were sampled at three different times in the production cycle (February, April, and September/October) over four years (2015 to 2018). The presence and DNA copy number of M. ovipneumoniae was determined using a newly developed species-specific qPCR. Breed (P<0.001), age (P<0.024), sampling time (P<0.001), and year (P<0.001) of collection affected log10 transformed M. ovipneumoniae DNA copy number, where Rambouillet had the lowest (P<0.0001) compared with both Polypay and Suffolk demonstrating a possible genetic component to detection. Samples from yearlings, April, and 2018 had the highest (P<0.046) detected DNA copy number mean. Sheep genomic DNA was genotyped with the Illumina OvineHD BeadChip. Principal component analysis identified most of the variation in the dataset was associated with breed. Therefore, genome wide association analysis was conducted with a mixed model (EMMAX), with principal components 1 to 6 as fixed and a kinship matrix as random effects. Genome-wide significant (P<9x10-8) SNPs were identified on chromosomes 6 and 7 in the all-breed analysis. Individual breed analysis had genome-wide significant (P<9x10-8) SNPs on chromosomes 3, 4, 7, 9, 10, 15, 17, and 22. Annotated genes near these SNPs are part of immune (ANAPC7, CUL5, TMEM229B, PTPN13), gene translation (PIWIL4), and chromatin organization (KDM2B) pathways. Immune genes are expected to have increased expression when leukocytes encounter M. ovipneumoniae which would lead to chromatin reorganization. Work is underway to narrow the range of these associated regions to identify the underlying causal mutations.

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Pharmacological Inhibition of PPAR<sub>y</sub> Boosts HIV Reactivation and Th17 Effector Functions, while Preventing Progeny Virion Release and <i>de novo</i> Infection

Cited by 15 publications

References 96 publications

LILAC pilot study: Effects of metformin on mTOR activation and HIV reservoir persistence during antiretroviral therapy

LILAC pilot study: Effects of metformin on mTOR activation and HIV reservoir persistence during antiretroviral therapy

Genomic regions associated withMycoplasma ovipneumoniaepresence in nasal secretions of domestic sheep

Genes involved in immune, gene translation and chromatin organization pathways associated with Mycoplasma ovipneumoniae presence in nasal secretions of domestic sheep

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