In Vivo Study of THC-induced Immune-genome Changes at Single Cell Solution in HIV-infected Humans

In this study, the investigators hypothesize that THC alters the immunogenome in a cell type-specific fashion and alters cytokine production via epigenetic regulatory mechanisms and that these alterations differ between HIV-infected and HIV-uninfected host genomes.

Study Overview

• Status: Recruiting
• Conditions: HIV Infections; Healthy
• Intervention / Treatment: Drug: Active Delta-9-THC

Detailed Description

In this study, the investigators hypothesize that THC alters the immunogenome in a cell type-specific fashion and alters cytokine production via epigenetic regulatory mechanisms and that these alterations differ between HIV-infected and HIV-uninfected host genomes. To test these hypotheses, the investigators propose defining the epigenomic and transcriptomic alterations at single cell resolution in peripheral blood mononuclear cells by administering THC to humans with and without HIV infection. The THC-associated epigenomic/transcriptomic alterations will be linked to genomic variants to understand the causal effects of THC response in immune cells.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Brooklyn A Bradley, BS; Phone Number: 4495 203-932-5711; Email: bb889@yale.edu
• Study Contact Backup: Name: Heather R Garrett, BS; Phone Number: 2406 203-932-5711; Email: heather.garrett@yale.edu

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • Recruiting
      • VA Connecticut Healthcare System
      • Contact: Deepak C D'Souza, MD; Phone Number: 2594 203-932-5711; Email: deepak.dsouza@yale.edu
      • Contact: Brooklyn A Bradley, BS; Phone Number: 4495 203-932-5711; Email: bb889@yale.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria (HIV-infected group):

• HIV-positive
• Good medication adherence
• Negative urine toxicology for drugs of abuse (including cannabis)
• Good mental and physical health (other than HIV) as determined by history, psychiatric interview, collateral information, physical and laboratory examinations, ECG, and vital signs.

Inclusion Criteria (HIV-uninfected group):

• HIV-negative
• Negative urine toxicology for drugs of abuse (including cannabis)
• Good mental and physical health as determined by history, psychiatric interview, collateral information, physical and laboratory examinations, ECG, and vital signs.

Exclusion Criteria (common to both groups):

• Major medical conditions, e.g., myocardial infarction, hypertension, etc.
• Positive pregnancy test and lactation;
• Weight greater than 166 kg (365 lbs)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active Delta-9-THC; Active Delta-9-THC (0.03 mg/kg) administered intravenously.	Drug: Active Delta-9-THC; Active Delta-9-THC (0.03 mg/kg) administered intravenously.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Gene Expression Alteration	Quantity of each gene is measured via sequence transcriptome, and significant differences of quantified gene pre- and post-THC infusion will be identified as THC-induced gene expression alteration.	Blood samples will be collected to measure changes in gene expression altered by THC before study drug infusion and at 70, 140, and 300 minutes after study drug infusion.
Change in Cytokine Profile	Cytokine profile will be measured using Luminex Performance Human Cytokine Discovery panel before and after study drug infusion. The 45 cytokines selected based on their established role in immune functioning are: CCL2/MCP-1, CCL3/MIP-1a, CCL4/MIP-1b, CCL5/RANTES, CCL11/Eotaxin, CCL19/MIP-3b, CCL20/MIP-3a, TNFSF5, CX3CL1/Fractalkine, CXCL1/GROa, CXCL2/GROb, CXCL10/IP-10, EGF, FGF2, FLT3L, G-CSF, GM-CSF, Granzyme B, IFN-a2, IFN-b, IFN-g, IL-1a, IL-1b, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8/CXCL8, IL-10, IL-12 p70, IL-13, IL-15, IL-17A, IL-17E, IL-33, PD-L1, PDGF-AA, PDGF-AB/BB, TGF-a, TNF-a, TNFSF10, VEGF.	Blood samples will be collected to measure changes in cytokine profile before study drug infusion and at 70, 140, and 300 minutes after study drug infusion.
Change in Gene Expression Alteration by THC between HIV-positive and HIV-negative Groups	Quantity of each gene is measured via sequence transcriptome, and significant differences of quantified gene pre- and post-THC infusion are identified as THC-induced gene expression alteration. Results will be compared between HIV-positive and HIV-negative subjects.	Blood samples will be collected to measure change in gene expression altered by THC before study drug infusion and at 70, 140, and 300 minutes after study drug infusion.
Change in Cytokine Profile by THC between HIV-positive and HIV-negative Groups	Cytokine profile will be measured using Luminex Performance Human Cytokine Discovery panel before and after study drug infusion. Results will be compared between HIV-positive and HIV-negative subjects. The 45 cytokines selected based on their established role in immune functioning are: CCL2/MCP-1, CCL3/MIP-1a, CCL4/MIP-1b, CCL5/RANTES, CCL11/Eotaxin, CCL19/MIP-3b, CCL20/MIP-3a, TNFSF5, CX3CL1/Fractalkine, CXCL1/GROa, CXCL2/GROb, CXCL10/IP-10, EGF, FGF2, FLT3L, G-CSF, GM-CSF, Granzyme B, IFN-a2, IFN-b, IFN-g, IL-1a, IL-1b, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8/CXCL8, IL-10, IL-12 p70, IL-13, IL-15, IL-17A, IL-17E, IL-33, PD-L1, PDGF-AA, PDGF-AB/BB, TGF-a, TNF-a, TNFSF10, VEGF.	Blood samples will be collected to measure changes in cytokine profile by THC before study drug infusion and at 70, 140, and 300 minutes after study drug infusion.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Perceptual Alterations	Perceptual alterations will be measured using scales such as the Clinician Administered Dissociative Symptoms Scale (CADSS), a scale consisting of 19 self-report items and 8 clinician-rated items (0 = not at all, 4 = extremely) that we have shown to be sensitive to THC effects. The scale captures alterations in environmental/time/body perception, feelings of unreality, and memory impairment.	Perceptual alterations will be measured before study drug infusion and 70, 140, and 300 minutes after study drug infusion.
Cannabis Subjective Effects	Various feeling states associated with cannabis intoxication will be measured using a self-reported visual analog scale of feeling states ("high", "calm and relaxed", and "tired") associated with cannabis effects. Subjects will be asked to score the perceived intensity of these feeling states at that moment on a 100 mm line (0 = not at all, 100 = extremely). These data will be captured to validate that the experiment is relevant to cannabis effects.	Cannabis subjective effects will be measured before study drug infusion and 70, 140, and 300 minutes after study drug infusion.
Cannabinoid Relevant Molecules	Blood will be sampled for cannabinoid relevant molecules before and after study drug infusion. Cannabinoid relevant molecules will include THC and THC-COOH levels.	Blood will be collected before study drug infusion and at 70, 140, and 300 minutes after study drug infusion.
Change in total immediate recall on the RAVLT.	Memory, attention, and executive function will be measured before and after study drug administration using the Rey Auditory Verbal Learning Task (RAVLT).	The RAVLT will be administered prior to study drug administration at approximately 25 minutes after study drug administration.

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Deepak C D'Souza, MD, Yale University Professor of Psychiatry

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2022
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: May 17, 2021
• First Submitted That Met QC Criteria: June 3, 2021
• First Posted (Actual): June 10, 2021

Study Record Updates

• Last Update Posted (Estimated): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Psychotropic Drugs; Hallucinogens; Cannabinoid Receptor Agonists; Cannabinoid Receptor Modulators; Dronabinol
• Other Study ID Numbers: 2000030067; R01DA052846 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No