Δ9-Tetrahydrocannabinol Treatment During Human Monocyte Differentiation Reduces Macrophage Susceptibility to HIV-1 Infection
- 520 Downloads
The major psychoactive component of marijuana, Δ9-tetrahydrocannabinol (THC), also acts to suppress inflammatory responses. Receptors for THC, CB1, CB2, and GPR55, are differentially expressed on multiple cell types including monocytes and macrophages, which are important modulators of inflammation in vivo and target cells for HIV-1 infection. Use of recreational and medicinal marijuana is increasing, but the consequences of marijuana exposure on HIV-1 infection are unclear. Ex vivo studies were designed to investigate effects on HIV-1 infection in macrophages exposed to THC during or following differentiation. THC treatment of primary human monocytes during differentiation reduced HIV-1 infection of subsequent macrophages by replication competent or single cycle CCR5 using viruses. In contrast, treatment of macrophages with THC immediately prior to or continuously following HIV-1 exposure failed to alter infection. Specific receptor agonists indicated that the THC effect during monocyte differentiation was mediated primarily through CB2. THC reduced the number of p24 positive cells with little to no effect on virus production per infected cell, while quantitation of intracellular viral gag pinpointed the THC effect to an early event in the viral life cycle. Cells treated during differentiation with THC displayed reduced expression of CD14, CD16, and CD163 and donor dependent increases in mRNA expression of selected viral restriction factors, suggesting a fundamental alteration in phenotype. Ultimately, the mechanism of THC suppression of HIV-1 infection was traced to a reduction in cell surface HIV receptor (CD4, CCR5 and CXCR4) expression that diminished entry efficiency.
KeywordsMacrophage THC Cannabinoid receptor HIV Differentiation
We would like to acknowledge Daniel Rodriguez, Chris Little, and Steve Pomeroy for technical assistance and thank Dr. Mark Wallet for helpful comments and critical review of the manuscript. We would also like to thank the University of Florida Interdisciplinary Center for Biotechnology Research cellomics core facility for providing flow cytometers and genomics core facility for Sanger sequencing and access to the ABI 7500 FAST instrument. This study was supported in part by HHS funding from the National Institute for Drug Abuse [DA031017] and by Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) supported by the National Institutes of Child Health and Development [HD40533 and HD40474]. JCW is supported by the Laura McClamma Fellowship at the University of Florida. SA is supported by the University of Florida Alumni graduate fellowship and the Linton E. Grinter fellowship. Additional support was provided by the Robert A. Good endowed Chair in Immunology (University of South Florida), Stephany W. Holloway University Chair for AIDS Research (University of Florida), Center for Research in Pediatric Immune Deficiency and Inflammation, and University of Florida Health Cancer Center.
Conflict of Interest
The authors declare that we have no conflict of interest.
- Bouaboula M, Poinot-Chazel C, Marchand J, Canat X, Bourrié B, Rinaldi-Carmona M, Calandra B, Le Fur G, Casellas P (1996) Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression. Eur J Biochem 237:704–711PubMedCrossRefGoogle Scholar
- Johnston SH, Lobritz MA, Nguyen S, Lassen K, Delair S, Posta F, Bryson YJ, Arts EJ, Chou T, Lee B (2009) A quantitative affinity-profiling system that reveals distinct CD4/CCR5 usage patterns among human immunodeficiency virus type 1 and simian immunodeficiency virus strains. J Virol 83:11016–11026PubMedCentralPubMedCrossRefGoogle Scholar
- Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, Sun C, Grayson T, Wang S, Li H, Wei X, Jiang C, Kirchherr JL, Gao F, Anderson JA, Ping LH, Swanstrom R, Tomaras GD, Blattner WA, Goepfert PA, Kilby JM, Saag MS, Delwart EL, Busch MP, Cohen MS, Montefiori DC, Haynes BF, Gaschen B, Athreya GS, Lee HY, Wood N, Seoighe C, Perelson AS, Bhattacharya T, Korber BT, Hahn BH, Shaw GM (2008) Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A 105:7552–7557PubMedCentralPubMedCrossRefGoogle Scholar
- National Institute on Drug Abuse (2012) Research Report Series: Marijuana abuse. In: NIoD (ed) Abuse. National Institutes of HealthGoogle Scholar
- Nichols S, Lowe A, Zhange X, Garvie P, Thornton S, Goldberger B, Hou W, Goodenow M, Sleasman J (2014) Concordance between self-reported substance use and toxicoogy among HIV-infected and unifected at risk youth. Drug Alcohol Depend 134:376–382Google Scholar
- O’Connell O, Repik A, Reeves JD, Gonzalez-Perez MP, Quitadamo B, Anton ED, Duenas-Decamp M, Peters P, Lin R, Zolla-Pazner S, Corti D, Wallace A, Wang S, Kong XP, Lu S, Clapham PR (2013) Efficiency of bridging-sheet recruitment explains HIV-1 R5 envelope glycoprotein sensitivity to soluble CD4 and macrophage tropism. J Virol 87:187–198PubMedCentralPubMedCrossRefGoogle Scholar
- Surdo M, Balestra E, Saccomandi P, Di Santo F, Montano M, Di Carlo D, Sarmati L, Aquaro S, Andreoni M, Svicher V, Perno CF, Ceccherini-Silberstein F (2013) Inhibition of dual/mixed tropic HIV-1 isolates by CCR5-inhibitors in primary lymphocytes and macrophages. PLoS One 8:e68076PubMedCentralPubMedCrossRefGoogle Scholar
- Theodore TS, Englund G, Buckler-White A, Buckler CE, Martin MA, Peden KW (1996) Construction and characterization of a stable full-length macrophage-tropic HIV type 1 molecular clone that directs the production of high titers of progeny virions. AIDS Res Hum Retrovir 12:191–194PubMedCrossRefGoogle Scholar
- Tuttle DL, Anders CB, Aquino-De Jesus MJ, Poole PP, Lamers SL, Briggs DR, Pomeroy SM, Alexander L, Peden KW, Andiman WA, Sleasman JW, Goodenow MM (2002) Increased replication of non-syncytium-inducing HIV type 1 isolates in monocyte-derived macrophages is linked to advanced disease in infected children. AIDS Res Hum Retrovir 18:353–362PubMedCrossRefGoogle Scholar