Category Archives: HIV/AIDS

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.”

Motor-Related Neural Dynamics are Modulated by Regular Cannabis Use Among People with HIV

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“Recent work has shown that people with HIV (PWH) exhibit deficits in cognitive control and altered brain responses in the underlying cortical networks, and that regular cannabis use has a normalizing effect on these neural responses.

However, the impact of regular cannabis use on the neural oscillatory dynamics underlying motor control deficits in PWH remains less understood. Herein, 102 control cannabis users, control nonusers, PWH who regularly use cannabis, and PWH who do not use cannabis performed a motor control task with and without interference during high-density magnetoencephalography. The resulting neural dynamics were examined using whole-brain, voxel-wise statistical analyses that examined the impact of HIV status, cannabis use, and their interaction on the neural oscillations serving motor control, spontaneous activity during the baseline period, and neurobehavioral relationships.

Our key findings revealed cannabis-by-HIV group interactions in oscillatory gamma within the prefrontal cortices, higher-order motor areas, and other regions, with the non-using PWH typically exhibiting the strongest gamma interference responses. Cannabis-by-HIV interactions were also found for oscillatory beta in the dorsal premotor cortex. Spontaneous gamma during the baseline was elevated in PWH and suppressed in cannabis users in all regions exhibiting interaction effects and the left primary motor cortex, with spontaneous levels being correlated with behavioral performance.

These findings suggest that regular cannabis use has a normalizing effect on the neural oscillations serving motor control and the abnormally elevated spontaneous gamma activity that has been widely replicated in PWH, which may suggest that cannabis has at least some therapeutic utility in PWH.”

https://pubmed.ncbi.nlm.nih.gov/40473990/

“Further, these findings corroborate multiple recent studies showing elevated spontaneous gamma activity in PWH, and that regular cannabis use is associated with a marked suppression in such spontaneous activity.”

https://link.springer.com/article/10.1007/s11481-025-10219-0

THC Reverses SIV-Induced Senescence in Astrocytes: Possible Compensatory Mechanism Against HIV Associated Brain Injury?

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“Despite effective combination antiretroviral therapy (cART), chronic neuroinflammation and glial dysfunction continues to be an important yet understudied issue with people living with HIV (PLWH).

The endocannabinoid system is increasingly recognized as a potential therapeutic target for modulating neuroimmune environments, given its role in regulating synaptic plasticity, immune responses, and neuroinflammatory cascades. However, the extent to which cannabinoids influence HIV-associated neuroinflammation remains unclear.

This study investigates the impact of Δ9-tetrahydrocannabinol (THC) on astrocyte growth characteristics, viability, and senescence-associated cytokine release following exposure to HIV Tat protein using primary mixed glial cultures derived from rhesus macaques. Real-time impedance-based cellular integrity assessments were conducted using the xCELLigence system, while morphological analyses and cytokine quantification were performed using phase-contrast microscopy and multiplex immunoassays.

Treatment of macaques with THC protected the astrocytes from virus-induced senescence.

Further, THC facilitated a rapid recovery from Tat-induced decline in astrocyte adhesion, suggesting a compensatory effect. THC promoted glial process elongation and morphological complexity, indicative of a shift toward a neuroprotective phenotype. Furthermore, THC significantly reduced inflammatory cytokine secretion, including TNF-α, IL-6, and IL-1β, in an apparently dose-dependent manner.

These findings suggest that THC may modulate neuroinflammation in PLWH by promoting astrocytic survival, suppressing inflammatory cytokine secretion, and enhancing neurotrophic signaling. However, prolonged exposure to high-dose THC may negatively impact glial survival.

The results underscore the complexity of cannabinoid signaling in the CNS and highlight the potential of cannabinoid-based interventions to mitigate HIV-associated neuroinflammation.”

https://pubmed.ncbi.nlm.nih.gov/40475423/

https://www.biorxiv.org/content/10.1101/2025.05.16.654476v1

“Senescence, in both cellular and organismal contexts, refers to the process of aging and decline.”