Effect of micromolar concentrations of delta—9—tetrahydrocannabinol on herpes simplex virus type 2 replication in vitro

Abstract

The effect of micromolar concentrations of delta-9-tetrahydrocannabinol (delta-9-THC) on the in vitro replication and biosynthesis of herpes simplex virus type 2 (HSV2) was determined. A 100-fold increase in extracellular virus was recorded for infected Vero cells pretreated with 10(-6) M or 10(-5) M drug when compared to infected vehicle-treated controls. However, no significant differences were observed in the production of total infectious virus for any of the vehicle or drug-treated cultures. Immunofluorescence of virus-infected cells revealed that delta-9-THC did not alter the intracellular compartmentalization of virus-specified proteins. Analytical sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography of isotopically labeled, cell-associated virus-specified proteins revealed that delta-9-THC had no major effect on the production of early nonstructural proteins but decreased the synthesis of late structural proteins. Scanning electron microscopy and light microscopy revealed blebs on the surface and macrovacuoles in the cytoplasm of both infected and uninfected cells treated with drug. These results suggest that delta-9-THC at micromolar concentrations selectively targets the host cell with the consequence of perturbation of cellular membranes. The alteration of cellular membranes may account for the enhanced virus release and for the decreased expression of virus-specified, cell-associated late structural proteins.

Immunoregulatory Role of Cannabinoids during Infectious Disease

“…During SIV infection, the activity of NK cells is inhibited [68], resulting in increased host mortality [63,65,66], and, in an influenza virus infection, the viral load is also increased [77]. In the studies in vitro, different cannabinoids increased HCV [59] and HSV replication [60,61]. On the other hand, the use of cannabinoids during an infection with Theiler's virus, an experimental model of MS, showed that cannabinoid agents such as WIN 5,212-2, ACEA, and JWH-015 may be good therapeutic targets for treating MS due to the fact that they promote remyelination [81].…”

“…Based on this, Cabral et al [60,61] evaluated the effect of THC on HSV-2 infections. Their studies in vitro, using virus-infected Vero cells pretreated for 24 h with THC, showed a higher extracellular incidence of the virus that correlated with the dissolution of the cellular membrane, and inhibited the synthesis, maturation, and cellular transport of specific HSV-2 glycoproteins [62] and macrovacuoles in the cytoplasm that contained virus aggregates.…”

Cannabinoids and COVID-19

“…Arachidonyl-2-chloroethanolamide, a relatively selective agonist of CB1, leads to facilitation of hepatitis C viral replication in hepatocyte cultures in vitro in association with CB1 overexpression and higher 2-AG levels [29]. Concerning THC, it has been associated with the presence of increased extracellular herpes simplex virus in vitro [30, 31] and an increased mortality in mice [32] and guinea pigs [33] with vaginal herpes simplex virus infection. THC has also been associated with increased HIV replication and influenza virus load in animal models.…”

Inhibition of Cell-Associated Herpes Simplex Virus Type 2 Glycoproteins by 9-Tetrahydrocannabinol

“…A9-THC has been shown to be highly lipophilic (3 1, 32), to impart increased fluidity to membranes (33,34), and to disrupt cell surface and intracytoplasmic membranes (7,18,35). A9-THC, also, was shown in the present investigation to induce vacuolization, first at the outer periphery of the cytoplasm, and then extending into the inner cytoplasm to a degree depending on drug concentration and duration of exposure.…”

“…A9-THC also inhibits macromolecular synthesis in a diverse number of cell culture systems (4)(5)(6). This laboratory has previously reported that A9-THC at micromolar levels inhibits the synthesis of herpes simplex virus type 2 (HSV2) cell-associated structural proteins (7). The drug doses which effected this macromolecular inhibition, however, did not significantly alter the total production of infectious HSV2.…”