Effects of Cannabidiol (CBD) on the Activation of Autophagy and Inflammation Genes, Functional Consequences in Virologically Controlled HIV-infected Patients

Autophagy and apoptosis are natural cellular mechanisms which consist for the first in a recycling and elimination process of potentially toxic cellular waste, and for the second in a process of cellular suicide when it becomes abnormal and "not" repairable, notably by autophagy. A deficit in autophagic function at the cellular level can lead to chronic inflammation and accelerated cellular senescence. Apoptosis is a beneficial phenomenon because it eliminates abnormal cells that could endanger the organism if it survives (e.g. karyotypic atypia). Uncontrolled, it can be deleterious if apoptosis is hypo or hyperactive.

The Centre of Molecular Biology of the CNRS in Orléans has developed for many years an expertise concerning apoptosis via the discovery of the GALIG gene. This pro-apoptotic gene produces two proteins, one of which, cytogaligin, interacts with several proteins involved in autophagy. Recent translational research conducted jointly by the CNRS and CHR Orléans teams have shown that PBMC from HIV-infected patients who have been on effective cART for at least 4 years show changes in the expression of certain genes involved in autophagy (BECN1, GABARAPL1, MAP1LC3B and GALIG). Gomez-Mora et al. also reported a decrease in autophagic function in CD4+ T cells of patients, with the impairment of autophagy being more important as the reconstitution of the CD4+ T compartment is incomplete. Thus, autophagy defects are more pronounced in patients whose CD4 T cell count remains low, suggesting a link between autophagy and CD4 T cell depletion.In summary, even after prolonged virological control and apparent immune reconstitution, PLWH (people living with HIV) exhibit deregulation of genes involved in autophagy. In the simian model, Δ9-tetrahydrocannabinol (Δ9-THC) cannabinoids would reduce inflammation associated with intestinal tissues, but also SIV viral load and mortality in males only. A recent review points to the potential benefit of cannabinoids on inflammation in the context of HIV. PLHIV who regularly use cannabis, and therefore potentially exposed to Δ9-THC and cannabidiol (CBD), have been the subject of a significant literature. Thus, it has been reported that in these patients, compared to non-consumers, there is a greater reduction in the HIV reservoir (HIV-DNA), a decrease in activated monocytes, the latter being linked to inflammation, as well as a reduced activation of CD4+ and CD8+ lymphocytes. A first analysis is based on 6 HIV+ patients virologically controlled for at least 4 years, having absorbed, as a dietary supplement, for 4 weeks a dose of 30 mg x2 per day of CBD duly controlled pharmacologically (Δ9-THC dosage \< 0.1%) and having declared not to use drugs. We were able to note by discriminant factor analysis (DFA): * a significant change in the expression of genes involved in autophagy. Their activation profile of genes involved in autophagy is no longer identical to that of virologically controlled HIV+ patients who did not take CBD. * a profile of serum inflammatory cytokines that is close to the profile of HIV-negative individuals, but different from that of PLWHIV who have not consumed CBD. Thus, CBD, which has no psychotropic effect, could have beneficial effects on HIV patients by reducing cellular senescence, inflammation and their consequences in terms of co-morbidities as well as the level of HIV reservoirs through an apoptotic phenomenon of cells hosting HIV in a quiescent state. Among the molecules present in the plant and in particular the species Cannabis sativa L., can be present the CBD, the Δ9 THC and a multitude of terpenes without psychotropic effects, which would be responsible for an "effect of entourage". Studies argue for a synergistic effect of these molecules to lead to the suspected effects.