Delta-9-Tetrahydrocannabinol Enhances Release of Herpes Simplex Virus Type 2

Abstract

SUMMARYThis study was undertaken to determine the effect of micromolar concentrations of delta-9-tetrahydrocannabinol (Delta-9-THC) on herpes simplex virus type 2 (HSV-2) replication in vitro. Virus-infected Vero cells pretreated for 24 h with 10 -5 M-or 10 -6 MDelta-9-THC yielded 100-fold increases in infectious extracellular virus. Transmission electron microscopy of drug-treated cells revealed plasma membrane dissolution, distension of the smooth and rough endoplasmic reticulum, and the appearance of macrovacuoles in the cytoplasm containing aggregates of virus. These results suggest that Delta-9-THC enhances the release of HSV-2 by perturbing cellular membranes in virus-infected cells.

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.…”

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

“…Furthermore, l 0-7 to l O-' M A9-THC treatment of c1: l l s did not affect the total yield of infectious virus ( 18). The paradox of drug-induced suppression of virus-specified, cell-associated glycoprotein concomitant with unaltered amounts of infectious virus may be resolved by proposing that A9-THC differentially targets cellular surface and cytoplasmic membranes.…”

“…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 exposure may facilitate virus release in the infected host as a result of drug-induced membrane alteration and vacuolization ( 18). This enhanced release coupled with diminished expression of virus-specified cell surface glycoproteins which normally account for induction of cellular and humoral immunity (24) could contribute to diminished host resistance to herpes sequelae.…”