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Modulation of HIVGP120 Antigen-Specific Immune Responses In Vivo by Δ9-Tetrahydrocannabinol

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Abstract

Approximately 25 % of HIV patients use marijuana for its putative therapeutic benefit; however, it is unknown how cannabinoids affect the immune status of HIV patients. Previously, a surrogate in vitro mouse model was established, which induced CD8+ T cell proliferation and gp120-specific IFNγ production. ∆9-Tetrahydrocannabinol (THC), the predominant psychoactive compound in marijuana, suppressed or enhanced the responses depending on the magnitude of cellular activation. The purpose of the current study was to investigate whether THC produced similar effects in vivo and therefore a mouse model to induce HIVgp120-specific immune responses was established. A gp120-expressing plasmid, pVRCgp120, or a vector plasmid, pVRC2000, was injected intramuscularly into mice, which were also dosed with THC orally. The gp120-specific IFNγ and IL-2 responses were detected when splenocytes were restimulated with gp120-derived peptide 81 (IIGDIRQAHCNISRA), which was identified as being immunodominant. Various cellular populations were activated in response to pVRCgp120 stimulation followed by peptide restimulation, as evidenced by increased expression levels of activation markers (e.g., CD69, CD80, and major histocompatibility complex II [MHC II]). The IFNγ response and cellular activation were enhanced by THC in C57Bl/6 wild type (WT) mice but suppressed or not affected by THC in cannabinoid receptor 1 (CB1) and 2 (CB2) knockout (CB1 −/−CB2 −/−) mice. Furthermore, CB1 −/−CB2 −/− mice exhibited augmented IFNγ production when compared to WT mice in the absence of THC. Collectively, our findings demonstrate that under certain conditions, THC enhances HIV antigen-specific immune responses, which occurs through CB1/CB2-dependent and -independent mechanisms.

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Abbreviations

AC:

Adenylyl cyclase

AP-1:

Activator protein-1

APC:

Antigen presenting cell

BCS:

Bovine calf serum

cAMP:

Cyclic adenosine 3′,5′-monophosphate

CB1 :

Cannabinoid receptor 1

CB2 :

Cannabinoid receptor 2

CB1 −/−CB2 −/− :

CB1 and CB2 null

CO:

Corn oil

CTL:

Cytotoxic T lymphocytes

DC:

Dendritic cell

DMSO:

Dimethyl sulfoxide

FcRs:

Fragment cystallizable receptors

GPCR:

G protein-coupled receptor

i.m.:

Intramuscular

KV :

Voltage-gated potassium channels

MCP-1:

Monocyte chemotactic protein-1

MFI:

Mean fluorescence intensity

NA:

Naïve

NFAT:

Nuclear factor of activated T cells

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NT:

No treatment

PBS:

Phosphate buffered saline

SIV:

Simian immunodeficiency virus

THC:

Δ9-tetrahydrocannabinol

TRP:

Transient receptor potential

VH:

Vehicle

WT:

Wild type

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Acknowledgments

The authors thank Jose Suarez and Natalia Kovalova for technical support during the study, and Kimberly Hambleton for assistance with submission of the manuscript.

Funding

This study was funded by National Institutes of Health (grant number DA007908).

Conflict of Interests

The authors declare that they have no conflict of interest.

Authorship Contributions

• W Chen, BLF Kaplan, and NE Kaminski participated in research design

• W Chen and RB Crawford conducted experiments

• W Chen performed data analysis

• W Chen wrote the paper

Author information

Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA

    Weimin Chen

  2. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA

    Barbara L. F. Kaplan & Norbert E. Kaminski

  3. Center for Integrative Toxicology, Michigan State University, 315 Food Safety and Toxicology Building, 1129 Farm Lane, East Lansing, MI, 48824, USA

    Weimin Chen, Robert B. Crawford, Barbara L. F. Kaplan & Norbert E. Kaminski

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  1. Weimin Chen
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  2. Robert B. Crawford
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  3. Barbara L. F. Kaplan
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  4. Norbert E. Kaminski
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Correspondence to Norbert E. Kaminski.

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Chen, W., Crawford, R.B., Kaplan, B.L.F. et al. Modulation of HIVGP120 Antigen-Specific Immune Responses In Vivo by Δ9-Tetrahydrocannabinol. J Neuroimmune Pharmacol 10, 344–355 (2015). https://doi.org/10.1007/s11481-015-9597-x

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