Category Archives: HIV/AIDS

Cannabinoids shift the basal ganglia microRNA m6A methylation profile towards an anti-inflammatory phenotype in SIV-infected rhesus macaques

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“Epitranscriptomic modifications [N6-methyladenosine (m6A)] regulate various diseases, including cancer and inflammation. Despite their functional relevance in neural development and differentiation, the role of m6A modifications in HIV neuropathogenesis is unknown. Using anti-N6-methyladenosine (m6A) antibody-immunoprecipitation and microarray profiling, we identified m6A modifications in miRNAs in basal ganglia (BG) of uninfected (VEH) and SIV-infected Rhesus macaques (RMs) on combination anti-retroviral therapy (ART) and either VEH-treated (VEH/SIV/ART) or THC:CBD-treated (THC:CBD/SIV/ART).

HIV/SIV infection promoted an overall hypomethylated miRNA m6A profile. While THC:CBD did not significantly impact the overall hypomethylated m6A profile, specific miRNAs predicted to target proinflammatory genes showed marked m6A hypomethylation compared to VEH-treated RMs. Additionally, specific BG m6A-modified miRNAs were detected in BG-derived extracellular vesicles. Mechanistically, the DRACH motif in the miR-194-5p seed region was significantly m6A hypomethylated in THC:CBD/SIV/ART RMs. Unlike wild-type, in-vitro transfected m6A-modified miR-194-5p mimics failed to downregulate STAT1 protein expression. Further, compared to VEH/SIV/ART RMs, THC:CBD significantly reduced m6A methylation of 44 miRNAs directly involved in regulating CNS network genes.

Our findings indicate that m6A epi-transcriptomic marks in the seed nucleotides can impair miRNA function and that cannabinoids may preserve it by reducing m6A methylation levels, thus providing a mechanistic explanation underlying their anti-neuroinflammatory effects in HIV/SIV infection.”

https://pubmed.ncbi.nlm.nih.gov/41286161

https://www.nature.com/articles/s42003-025-09049-w

Cannabis use is associated with alterations in NLRP3 inflammasome related gene expression in monocyte-derived macrophages from people living with HIV

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“Introduction: Human immunodeficiency virus (HIV) infection is often associated with chronic inflammation and cognitive dysfunction in people living with HIV (PWH). The nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome plays a crucial role in the secretion of pro-inflammatory cytokines, specifically interleukin (IL)-18 and IL-1β.

Cannabis use and certain phytocannabinoids, such as cannabidiol (CBD), may provide therapeutic benefits in conditions associated with chronic inflammation.

Methods: In this cross-sectional study, we investigated the relationship between cannabis use and NLRP3-related gene expression in monocyte-derived macrophages (MDMs) from PWH (n = 43) and people without HIV (PWoH; n = 22). Participants were categorized as naïve, moderate, or daily cannabis users. Donor-derived MDMs were treated with CBD (30 μM), IL-1β (20 ng/mL), or CBD + IL-1β for 24 hours to examine effects on NLRP3-related gene expression. Gene expression data were analyzed using one-way and two-way ANOVA with Holm-Sidak’s multiple comparisons tests. Correlations between gene expression and clinical parameters were assessed using Pearson’s correlation coefficient. Statistical significance was determined at p < 0.05.

Results: MDMs without treatment from PWH exhibited 83% higher NLRP3 mRNA expression compared to MDMs from PWoH. Furthermore, MDMs without treatment from moderate cannabis users expressed 61% less IL1β mRNA compared to naïve users, and MDMs from daily users expressed a 64% increase in IL18 expression compared to moderate users. Additionally, MDMs treated with CBD and IL-1β showed a 22% decrease in NLRP3 mRNA expression compared to IL-1β treated MDMs. When treated with CBD and IL-1β, we observed a significant increase in both IL1β (3-fold, p < 0.01) and IL18 (2-fold, p < 0.01) expression compared to vehicle. The relationship between NLRP3 mRNA expression in MDMs and global deficit scores in PWH not using cannabis was inverse to that relationship in PWH using cannabis.

Discussion: Overall, these findings suggest that CBD, as consumed through cannabis use, may mitigate NLRP3 activation in PWH, potentially offering therapeutic benefits for chronic inflammation. However, the unexpected effects on downstream cytokine mRNA expression, combined with product heterogeneity, underscore the need for future mechanistic studies to fully delineate cannabinoid-inflammasome interactions in the context of HIV.”

https://pubmed.ncbi.nlm.nih.gov/41280902

“Given the need for effective strategies to address neuroinflammation in PWH, these findings support further exploration of NLRP3 inhibitors, including cannabinoids like CBD, to mitigate chronic inflammation and improve cognitive outcomes.”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1634203/full

Liposomal-Cannabidiol Nanoformulation to Suppress HIV Replication and Reduce Oxidative Stress in Infected Microglia

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“The advent of antiretroviral therapy has significantly reduced HIV-related morbidity and mortality. However, persistent HIV infection in the central nervous system continues to drive HIV-associated neurocognitive disorders (HAND).

Cannabidiol (CBD), a nonpsychoactive cannabinoid with antioxidant and anti-inflammatory properties, has shown promise in clinical trials as a candidate to address cognitive impairments.

Despite this potential, further research is required to elucidate CBD’s molecular mechanisms in HIV infection and to improve its brain bioavailability. To overcome these challenges, we investigated CBD’s effects on oxidative stress pathways and developed a liposomal nanoformulation (NF) to enhance its delivery and efficacy in brain cells.

CBD treatment significantly upregulated APOE3 gene and protein expression while reducing HIV long terminal repeat (LTR) gene expression in infected microglia. The NF was characterized by hydrodynamic size, polydispersity index, zeta potential, encapsulation efficiency, cellular uptake, HIV infection levels, and APOE3 secretion. Successful CBD encapsulation was confirmed by liquid chromatography-mass/mass spectrometry.

Importantly, the CBD-loaded NF reduced p24 antigen levels and LTR expression, increased APOE secretion, and attenuated mitochondrial reactive oxygen species production more rapidly than free CBD.

This liposomal CBD NF enhances the pharmacological profile of CBD, offering a promising nanotherapeutic strategy to suppress HIV replication, reduce oxidative stress, and mitigate neurocognitive dysfunction associated with HAND.”

https://pubmed.ncbi.nlm.nih.gov/41222925/

https://pubs.acs.org/doi/10.1021/acsbiomaterials.5c01218

Sex differences in the capacity of minor phytocannabinoids to attenuate nociceptive insults in HIV-1 Tat-expressing mice

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“Objecives: Approximately 80 % of people living with HIV (PLWH) develop chronic pain and preclinical studies support the involvement of the HIV-1 regulatory protein, trans-activator of transcription (Tat). Phytocannabinoids may attenuate pain in PLWH; however, these data are controversial, and the biological mechanisms are difficult to untangle from psychosocial factors in people.

Methods: We have examined the therapeutic capacity of minor phytocannabinoids to attenuate Tat-promoted visceral hyperalgesia (acetic acid writhing assay) and reflexive nociception (warm water tail flick assay) in transgenic mice. We hypothesized that conditional expression of Tat1-86 in male and female mice [Tat(+) mice] would amplify pain responses compared to controls [Tat(-) mice], and that phytocannabinoids could ameliorate these effects.

Results: Irrespective of sex, Tat(+) mice demonstrated greater visceral pain responses than did Tat(-) controls. The phytocannabinoids, cannabigerolic acid (CBGA), cannabidiol (CBD), and cannabinol (CBN), attenuated Tat-induced visceral pain in both males and females. However, the effectiveness of these cannabinoids varied by sex with CBN being more efficacious in males, while cannabigerol (CBG) alleviated visceral pain only in Tat(+) females. Cannabidiolic acid (CBDA) and cannabidivarin (CBDV) were not effective in either sex. CBGA and CBG were also efficacious in the tail flick test among Tat(-) males and females, but demonstrated only small, sex-dependent effects to reverse Tat-induced nociception. CBD and CBN exerted little-to-no efficacy in this test.

Conclusions: These data suggest that phytocannabinoids exert analgesia for HIV-related pain, potentially aiding in the development of personalized pain management strategies.”

https://pubmed.ncbi.nlm.nih.gov/41221301/

“Overall, PLWH are more vulnerable to the development of chronic pain, resulting in physical disability and a reduced quality of life. The current pharmacological treatments for managing HIV-related pain lack efficacy and are associated with the risk of substance abuse. The medicinal use of non-psychoactive cannabis constituents for pain management might greatly benefit this population which is at a greater risk for opioid addiction and substance abuse.”

https://www.degruyterbrill.com/document/doi/10.1515/nipt-2024-0025/html

The association between cannabis use and electrocardiographic abnormalities in people living with HIV

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“Cardiovascular disease is a leading cause of morbidity and mortality among people with and without HIV. Among PWoH, cannabis has been associated with cardiovascular outcomes, including coronary artery disease, myocardial infarction (MI), and stroke. However, data on subclinical changes and other cardiovascular outcomes are limited among PWH.

In this study, we examined the association of cannabis use and HIV with electrocardiogram (ECG) findings -evidence of MI, other abnormalities, and normal findings. Data from study visits between 2007 and 2017 from the MACS/WIHS Combined Cohort Study (N=3,610) were used. Descriptive statistics were derived, and unadjusted and adjusted odds ratios were estimated via baseline logistic regression.

Most participants were PWH (n = 2272, 63%), and 28% reported cannabis use, with no significant difference in prevalence between PWH (27%) and PWoH (28%). Overall, 59% of participants had normal ECG findings.

Cannabis use was not significantly associated with evidence of ECG abnormalities in unadjusted or adjusted analyses (aOR for MI: 1.02, 95% CI: 0.82-1.26, p = 0.85; aOR for other abnormalities: 1.02, 95% CI: 0.80-1.32, p = 0.86). Abnormal findings were more common in females than males (41% vs. 35%, p = 0.0002). Among males, PWH had higher odds of evidence of non-MI abnormalities compared to PWoH (aOR = 1.35, 95% CI: 1.01 – 1.81, p = 0.0464).

While cannabis use was not independently associated with evidence of ECG abnormalities, sex and HIV status are important determinants. Future studies should explore the role of cannabis metabolites and usage patterns in cardiovascular outcomes among PWH.”

https://pubmed.ncbi.nlm.nih.gov/41129190/

https://journals.lww.com/jaids/abstract/9900/the_association_between_cannabis_use_and.735.aspx

Antiviral and Anti-inflammatory Effects of Cannabidiol in HIV/SIV Infection

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“Persistent reservoirs and chronic immune activation are hallmarks of HIV, despite the effectiveness of antiretroviral therapy (ART) in suppressing viral replication. Here, we use rhesus macaques and primary and induced pluripotent stem cell (iPSC)-derived human immune cells to evaluate the virologic and immunologic consequences of cannabidiol (CBD) exposure during HIV/SIV infection.

We show that CBD, in the absence of ART, suppresses viral replication and establishment of the viral reservoir to levels comparable with first-line therapies during acute SIV infection of rhesus macaques.

This antiviral effect of CBD extended to in vitro HIV infection of human macrophages, T cells, and microglia. Immunologically, we observe CBD slowed CD4+ T cell decline and polarization, decreased CD14+CD16+ monocyte expansion, and reduced interferon-inducible cytokine release in rhesus macaques. We identify comparable effects on cytokine production with in vitro CBD treatment of human macrophages, T cells, and microglia.

Importantly, we find CBD inhibits cytokines only when an immune response is elicited by HIV, suggesting it is not broadly immunosuppressive. Finally, we determine CBD regulates endocannabinoid receptors, modulators, and transporters and inhibits NF-κb and STAT1 activation when mediating its antiviral and anti-inflammatory effects.

These findings show beneficial effects of CBD in laboratory models of untreated HIV, thus placebo-controlled clinical trials to evaluate the safety and effectiveness of adjunctive CBD use with ART is warranted.”

https://pubmed.ncbi.nlm.nih.gov/41040324/

https://www.biorxiv.org/content/10.1101/2025.09.25.678534v1

Assessing Inflammatory Biomarkers at the Intersection of Marijuana and PrEP Use: Preliminary findings from the NCHAT-BIO study

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“Introduction: Past research has shown that inflammation is reduced among marijuana-using HIV-negative people but not those living with HIV. We take this work a step further by assessing differences based on pre-exposure prophylaxis (PrEP) use among HIV-negative individuals.

Methods: NCHAT is a nationally-representative cohort study of 3,642 adult respondents who are married or cohabiting. Their ages range from 20 to 60 years with 45% self-identifying as non-heterosexual. Biological data (n=573; CRP, IL-6, and EBV antibody levels) were collected via finger stick dried blood spots as part of NCHAT-BIO, a sub-study. Participants self-reported demographic characteristics, PrEP use, and marijuana use. Multivariable regression analyses were used to assess the relationship between these variables and each of the measured biomarkers, adjusting for known confounders.

Results: In adjusted models, neither lifetime or current PrEP use were associated with CRP, IL-6, or EBV antibody levels. Moreover, marijuana use did not differ among those who used PrEP versus those who did not. Among PrEP users, those who reported marijuana use had lower CRP than those who did not (B=-2.31; 95% CI:-4.23, -0.40). Among non-PrEP users, no association was observed between marijuana use and CRP.

Conclusion: The current preliminary data suggest inflammation is reduced among PrEP users who also use marijuana, but the same is not true among non-PrEP users. These findings may suggest that PrEP increases inflammation which is then partially mitigated by the individual cannabinoids or cannabidiols found in marijuana, although more research is needed to confirm this hypothesis.”

https://pubmed.ncbi.nlm.nih.gov/40905335/

https://journals.lww.com/jaids/abstract/9900/assessing_inflammatory_biomarkers_at_the.709.aspx

Supplementing HIV-ART with cannabinoids increases serotonin, BHB, and Ahr signaling while reducing secondary bile acids and acylcholines

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“Despite effective antiretroviral therapy (ART), people with HIV (PWH) experience persistent inflammation and metabolic dysfunction, increasing their risk for non-AIDS comorbidities. Accordingly, we evaluated the effects of long-term/low-dose Δ9-tetrahydrocannabinol (THC) supplementation in simian immunodeficiency virus (SIV)-infected, ART-treated rhesus macaques (RMs).

THC significantly increased plasma/jejunum serotonin and indole-3-propionate, enhancing gut-brain communication through up-regulation of serotonin receptors (HTR4/HTR7) and aryl hydrocarbon receptor (Ahr) signaling via a cannabinoid receptor (CBR)-2-mediated mechanism. Furthermore, THC enriched cholesterol-metabolizing Oscillibacter and reduced plasma cholesterol and toxic secondary bile acids (SBAs), thus improving cholesterol and SBA homeostasis.

Furthermore, THC increased β-hydroxybutyrate (BHB) levels via a CBR1-mediated mechanism, suggesting enhanced hepatic fatty acid oxidation for metabolic and cardiovascular health. THC restored ART/SIV-induced elevation of pro-inflammatory and cardiotoxic long-chain acylcholines to preinfection levels. THC-treated RMs maintained viral suppression despite reduced plasma ART levels, suggesting diminished ART-related toxicity.

Our findings demonstrate phytocannabinoids to be a safe adjunct therapy alongside ART to mitigate chronic inflammation and metabolic dysfunction in PWH.”

https://pubmed.ncbi.nlm.nih.gov/40901952/

“Taken as a whole, our findings uncover numerous hitherto unknown mechanisms of cannabinoid action and provide multiple lines of evidence for its utility as an effective and relatively safe adjunct therapy to ART.”

https://www.science.org/doi/10.1126/sciadv.adw4021

Cannabis Use Moderates Methamphetamine- and HIV-Related Inflammation: Evidence from Human Plasma Markers

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“Background: Methamphetamine use, which is disproportionately prevalent among people with HIV, increases risk for cardio- and neurovascular pathology through persistent immune activation and inflammation. Preclinical studies indicate that cannabinoids may reduce markers of pro-inflammatory processes, but data from people with chronic inflammatory conditions are limited. We examined potentially interacting associations of lifetime methamphetamine use disorder (MUD), recent cannabis use, and HIV with four plasma markers of immune and inflammatory functions.

Method: Participants with HIV (PWH, n = 86) and without HIV (PWoH, n = 148) provided urine and blood samples and completed neuromedical, psychiatric, and substance use assessments. Generalized linear models examined main and conditional associations of lifetime MUD, past-month cannabis use, and HIV with plasma concentrations of CXCL10/IP-10, CCL2/MCP-1, ICAM-1, and VCAM-1.

Results: PWH displayed higher CXCL10/IP-10 than PWoH. Past-month cannabis use was independently associated with lower CXCL10/IP-10 levels and conditionally lower CCL2/MCP-1, ICAM-1, and VCAM-1 levels among people with lifetime MUD, but only PWoH displayed cannabis-associated lower VCAM-1 levels.

Conclusions: Human plasma sample evidence suggests that cannabis use is associated with lower levels of immune and inflammatory molecules in the context of MUD or HIV. Cannabinoid pathways may be worthwhile clinical targets for treating sequelae of chronic inflammatory conditions.”

https://pubmed.ncbi.nlm.nih.gov/40872856/

“METH use disorder is highly prevalent in PWH, and both can have significant effects on immune function and pro-inflammatory processes that lead to significant central nervous system consequences, despite modern advances in anti-retroviral therapy effectiveness and tolerability. Results from this study support prior findings that METH and HIV disease confer risk for negative outcomes via their influence on chronic inflammatory processes, and we provide novel evidence from human plasma samples that cannabis use is associated with reduced levels of immune and inflammatory molecules in the context of chronic METH use or HIV infection (CCL2/MCP-1, VCAM-1, ICAM-1) and independent of METH use and HIV (CXCL10/IP-10). Associations between cannabis use and lower indices of inflammatory pathology from HIV and MUD point toward cannabinoid pathways as promising therapeutic targets that warrant further study.”

https://www.mdpi.com/1999-4915/17/8/1143

Single cell multiomic analysis of the impact of Delta-9-tetrahydrocannabinol on HIV infected CD4 T cells

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“Cannabis use is prevalent among individuals living with HIV in the United States, but the impact of cannabis exposure on the reservoir of latently infected cells that persists during antiretroviral therapy (ART) remains unclear. To address this gap, we analyzed the effect of Δ-9-tetrahydrocannabinol (THC) on primary CD4 T cells that were latently infected with HIV.

We found that THC had no detectable effect on baseline or latency reversing agent (LRA) stimulated HIV expression, or on expression of an activation marker (CD38). However, using an integrated multiomic single-cell analysis of genome-wide chromatin accessibility and gene expression, we observed altered expression of several hundred genes in HIV infected CD4 T cells after THC exposure, including transcriptional downregulation of genes involved in protein translation and antiviral pathways, indicating that THC suppresses innate immune activation in infected cells. Additionally, chromatin accessibility analysis demonstrated upregulated chromatin binding activity for the transcriptional regulator CTCF, and reduced activity for members of the ETS transcription factor family in infected cells after THC exposure.

These findings provide insights into the mechanisms by which cannabis use could influence the persistence of HIV within cellular reservoirs and the molecular phenotype of latently infected cells. Further elucidation of the underlying mechanisms involved in THC-mediated changes to HIV infected cells, will lead to an improved understanding of the impact of cannabis use on the HIV reservoir.

Importance: Cannabis use is common among individuals living with HIV, but the long-term effects of cannabis use on the HIV reservoir are not yet studied completely. We employed advanced single-cell technologies to reveal how cannabis components, specifically THC, influence HIV-infected immune cells and their pattern of gene expression. We found that, while THC doesn’t reactivate virus in latently infected cells, it alters the molecular characteristics of these infected immune cells. These findings are important because they underscore how cannabis could regulate persistent infection in people living with HIV. Understanding these cellular changes in response to THC could be helpful for successful treatment for people living with HIV.”

https://pubmed.ncbi.nlm.nih.gov/40502036/

https://www.biorxiv.org/content/10.1101/2025.06.02.657468v1

“Yes, there is growing evidence that cannabis could play a role in regulating persistent HIV infection. Studies suggest that cannabinoids, particularly THC, can alter the molecular characteristics of HIV-infected immune cells without reactivating the virus. These changes might be beneficial in reducing inflammation and improving treatment outcomes for people living with HIV.”