Distinct inflammatory profiles in HIV-infected individuals under antiretroviral therapy using cannabis, cocaine or cannabis plus cocaine

Castro, Fernanda de Oliveira Feitosa de; Silva, Jacyelle Medeiros; Dorneles, Gilson Pires; Barros, Jéssica Barletto de Sousa; Ribeiro, Cauê; Noronha, Isaú Henrique; Barbosa, Gabriela; Souza, Luiz Carlos Silva; Guilarde, Adriana Oliveira; Pereira, Ana Joaquina Cohen Serique; Guimarães, Regyane Ferreira; Oliveira, Tiago Franco de; Eller, Sarah; Peres, Alessandra; Romão, Pedro Roosevelt Torres; Pfrimer, Irmtraut Araci Hoffmann; Fonseca, Simone Gonçalves

doi:10.1097/qad.0000000000002296

Cited by 38 publications

(27 citation statements)

References 57 publications

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“…miR-27b and other miRNAs including miR-10a, − 21, −125b, and -146a are increased in vascular tissues during inflammation and oxidative stress [ 28 ]. One factor that can promote inflammation and oxidative stress in HIV-positive subjects is cocaine abuse [ 46 , 47 ], which was prevalent in both the test and validation cohorts (50%). However, we did not detect significantly altered miRNAs with cocaine use in HIV-positive or healthy control groups in either cohort.…”

Section: Discussionmentioning

confidence: 99%

Small RNA sequencing of extracellular vesicles identifies circulating miRNAs related to inflammation and oxidative stress in HIV patients

et al. 2020

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Background Extracellular vesicles (EVs) are nano-sized particles secreted by most cells. EVs carry nucleic acids that hold promise as potential biomarkers in various diseases. Human immunodeficiency virus type 1 (HIV) infects CD4+ T cells and induces immune dysfunction, inflammation, and EV secretion, but little is known about EV small RNA cargo in relation to immune dysregulation in HIV-infected individuals. Here, we characterize small RNA carried by circulating EVs in HIV-positive subjects on antiretroviral therapy (ART) relative to uninfected controls by next-generation RNA sequencing. Results Plasma EVs isolated from HIV-positive and HIV-negative subjects in test (n = 24) and validation (n = 16) cohorts were characterized by electron microscopy, nanoparticle tracking analysis, and immunoblotting for exosome markers. EVs were more abundant in plasma from HIV-positive compared to HIV-negative subjects. Small RNA sequencing of plasma EVs in the test cohort identified diverse small RNA species including miRNA, piRNA, snRNA, snoRNA, tRNA, and rRNA, with miRNA being the most abundant. A total of 351 different miRNAs were detected in plasma EVs, with the top 50 miRNAs accounting for 90% of all miRNA reads. miR-26a-5p was the most abundant miRNA, followed by miR-21-5p and miR-148-3p. qRT-PCR analysis showed that six miRNAs (miR-10a-5p, − 21-5p, −27b-3p, − 122-5p, −146a-5p, − 423-5p) were significantly increased in plasma EVs from HIV-positive compared to HIV-negative subjects in the validation cohort. Furthermore, miR-21-5p, −27b-3p, −146a-5p, and − 423-5p correlated positively with metabolite markers of oxidative stress and negatively with anti-inflammatory polyunsaturated fatty acids. Over-representation and pathway enrichment analyses of miRNAs and their target genes predicted functional association with oxidative stress responses, interferon gamma signaling, Toll-like receptor signaling, TGF beta signaling, and Notch signaling. Conclusions HIV-positive individuals on ART have increased abundance of circulating EVs carrying diverse small RNAs, with miRNAs being the most abundant. Several miRNAs associated with inflammation and oxidative stress are increased in circulating EVs of HIV-positive individuals, representing potential biomarkers of targetable pathways that contribute to disease pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Small RNA sequencing of extracellular vesicles identifies circulating miRNAs related to inflammation and oxidative stress in HIV patients

et al. 2020

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“…Previous studies have shown that the use of cocaine enhances HIV-1 replication and undermines immune function by dysregulating gene expression on HIV-1 entry coreceptors, enhancing HIV-1 cellular toxicity, and dysregulating interleukins (IL) in the host [43,44]. Cocaine use increases the release of cytokines in immune cells and alters cytokine profile in HIV-infected individuals [45,46]. Specifically, cocaine use was positively associated with IL-4 and IL-10 [47], which likely worsens HIV severity and disease progression.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation mediates the effect of cocaine use on HIV severity

et al. 2020

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Background Cocaine use accelerates human immunodeficiency virus (HIV) progression and worsens HIV outcomes. We assessed whether DNA methylation in blood mediates the association between cocaine use and HIV severity in a veteran population. Methods We analyzed 1435 HIV-positive participants from the Veterans Aging Cohort Study Biomarker Cohort (VACS-BC). HIV severity was measured by the Veteran Aging Cohort Study (VACS) index. We assessed the effect of cocaine use on VACS index and mortality among the HIV-positive participants. We selected candidate mediators that were associated with both persistent cocaine use and VACS index by epigenome-wide association (EWA) scans at a liberal p value cutoff of 0.001. Mediation analysis of the candidate CpG sites between cocaine’s effect and the VACS index was conducted, and the joint mediation effect of multiple CpGs was estimated. A two-step epigenetic Mendelian randomization (MR) analysis was conducted as validation. Results More frequent cocaine use was significantly associated with a higher VACS index (β = 1.00, p = 2.7E−04), and cocaine use increased the risk of 10-year mortality (hazard ratio = 1.10, p = 0.011) with adjustment for confounding factors. Fifteen candidate mediator CpGs were selected from the EWA scan. Twelve of these CpGs showed significant mediation effects, with each explaining 11.3–29.5% of the variation. The mediation effects for 3 of the 12 CpGs were validated by the two-step epigenetic MR analysis. The joint mediation effect of the 12 CpGs accounted for 47.2% of cocaine’s effect on HIV severity. Genes harboring these 12 CpGs are involved in the antiviral response (IFIT3, IFITM1, NLRC5, PLSCR1, PARP9) and HIV progression (CX3CR1, MX1). Conclusions We identified 12 DNA methylation CpG sites that appear to play a mediation role in the association between cocaine use and HIV severity.

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“…Pre-clinical and human endocannabinoid system studies show that cannabinoids may mediate immunomodulatory actions that disrupt pro-inflammatory processes in HIV (Chen, Gao, Gao, Su, & Wu, 2017;Rom & Persidsky, 2013). Recent evidence has demonstrated associations between current cannabis use and reduced systemic inflammation among PWH, as indexed by lower levels of activated and inflammatory monocyte frequencies, and in plasma, lower levels of macrophage inflammatory protein (MIP)1α, interferongamma-inducible protein-10 (IP-10), also referred to as C-X-C motif chemokine ligand 10 (CXCL10), and tumor necrosis factor alpha (TNF-α) (Castro et al, 2019;Keen & Turner, 2015;Manuzak et al, 2018;Rizzo et al, 2018). In contrast, higher plasma levels of soluble cluster of differentiation 14 (sCD14) have been observed in cannabis-using compared to non-cannabis-using PWH (Castro et al, 2019), and many inflammatory plasma biomarkers (20 out of 21) have shown no differences by cannabis use among PWH (Manuzak et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Recent evidence has demonstrated associations between current cannabis use and reduced systemic inflammation among PWH, as indexed by lower levels of activated and inflammatory monocyte frequencies, and in plasma, lower levels of macrophage inflammatory protein (MIP)1α, interferongamma-inducible protein-10 (IP-10), also referred to as C-X-C motif chemokine ligand 10 (CXCL10), and tumor necrosis factor alpha (TNF-α) (Castro et al, 2019;Keen & Turner, 2015;Manuzak et al, 2018;Rizzo et al, 2018). In contrast, higher plasma levels of soluble cluster of differentiation 14 (sCD14) have been observed in cannabis-using compared to non-cannabis-using PWH (Castro et al, 2019), and many inflammatory plasma biomarkers (20 out of 21) have shown no differences by cannabis use among PWH (Manuzak et al, 2018). Higher levels of plasma interleukin-1β have also been observed among daily cannabis using PWH and HIV− individuals compared to non-users, with no differences in many inflammatory plasma biomarkers (23 out of 24) by cannabis use after controlling for multiple comparisons (Krsak et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Daily Cannabis Use is Associated With Lower CNS Inflammation in People With HIV

Watson

Campbell

Sun-Suslow

et al. 2021

J Int Neuropsychol Soc

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Objective:Recent cannabis exposure has been associated with lower rates of neurocognitive impairment in people with HIV (PWH). Cannabis’s anti-inflammatory properties may underlie this relationship by reducing chronic neuroinflammation in PWH. This study examined relations between cannabis use and inflammatory biomarkers in cerebrospinal fluid (CSF) and plasma, and cognitive correlates of these biomarkers within a community-based sample of PWH.Methods:263 individuals were categorized into four groups: HIV− non-cannabis users (n = 65), HIV+ non-cannabis users (n = 105), HIV+ moderate cannabis users (n = 62), and HIV+ daily cannabis users (n = 31). Differences in pro-inflammatory biomarkers (IL-6, MCP-1/CCL2, IP-10/CXCL10, sCD14, sTNFR-II, TNF-α) by study group were determined by Kruskal–Wallis tests. Multivariable linear regressions examined relationships between biomarkers and seven cognitive domains, adjusting for age, sex/gender, race, education, and current CD4 count.Results:HIV+ daily cannabis users showed lower MCP-1 and IP-10 levels in CSF compared to HIV+ non-cannabis users (p = .015; p = .039) and were similar to HIV− non-cannabis users. Plasma biomarkers showed no differences by cannabis use. Among PWH, lower CSF MCP-1 and lower CSF IP-10 were associated with better learning performance (all ps < .05).Conclusions:Current daily cannabis use was associated with lower levels of pro-inflammatory chemokines implicated in HIV pathogenesis and these chemokines were linked to the cognitive domain of learning which is commonly impaired in PWH. Cannabinoid-related reductions of MCP-1 and IP-10, if confirmed, suggest a role for medicinal cannabis in the mitigation of persistent inflammation and cognitive impacts of HIV.

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Distinct inflammatory profiles in HIV-infected individuals under antiretroviral therapy using cannabis, cocaine or cannabis plus cocaine

Cited by 38 publications

References 57 publications

Small RNA sequencing of extracellular vesicles identifies circulating miRNAs related to inflammation and oxidative stress in HIV patients

Small RNA sequencing of extracellular vesicles identifies circulating miRNAs related to inflammation and oxidative stress in HIV patients

DNA methylation mediates the effect of cocaine use on HIV severity

Daily Cannabis Use is Associated With Lower CNS Inflammation in People With HIV

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