Abstract
HIV-associated neurocognitive disorders (HAND) are prevalent despite combined antiretroviral therapy (cART), affecting 52% of people living with HIV. Our laboratory has demonstrated increased expression of cathepsin B (CATB) in postmortem brain tissue with HAND. Increased secretion of CATB from in vitro HIV-infected monocyte-derived macrophages (MDM) induces neurotoxicity. Activation of cannabinoid receptor type 2 (CB2R) inhibits HIV-1 replication in macrophages and the neurotoxicity induced by viral proteins. However, it is unknown if CB2R agonists affect CATB secretion and neurotoxicity in HIV-infected MDM. We hypothesized that HIV-infected MDM exposed to CB2R agonists decrease CATB secretion and neurotoxicity. Primary MDM were inoculated with HIV-1ADA and treated with selective CB2R agonists JWH-133 and HU-308. HIV-1 p24 and CATB levels were determined from supernatants using ELISA. MDM were pre-treated with a selective CB2R antagonist SR144528 before JWH-133 treatment to determine if CB2R activation is responsible for the effects. Neuronal apoptosis was assessed using a TUNEL assay. Results show that both agonists reduce HIV-1 replication and CATB secretion from MDM in a time and dose-dependent manner and that CB2R activation is responsible for these effects. Finally, JWH-133 decreased HIV/MDM-CATB induced neuronal apoptosis. Our results suggest that agonists of CB2R represent a potential therapeutic strategy against HIV/MDM-induced neurotoxicity.
Highlights
Neurocognitive disorders in HIV-positive people are still prevalent in the combined antiretroviral therapy (cART) era, affecting approximately 52% of this population[1]
Increased secretion of cathepsin B (CATB) from in vitro HIV-infected monocyte-derived macrophages (MDM) and microglia leads to neuronal apoptosis, and it can be prevented by the specific CATB inhibitor CA074 or an a ntibody[5,7,8,9,10,11]
We demonstrated that CB2R agonist JWH-133 decreased HIV/MDM-induced neuronal death and CATB neurotoxic potential by decreasing CATB secretion from HIV-infected MDM
Summary
Neurocognitive disorders in HIV-positive people are still prevalent in the cART era, affecting approximately 52% of this population[1]. The mechanisms by which cART-treated patients still develop these disorders are not completely understood Immune cells such as macrophages play a major role in the neuroinflammation promoted by HIV infection[2,3,4]. In search of mechanisms of CATB-induced neurotoxicity using quantitative proteomics, we recently found that HIV/MDM-derived CATB and SAPC complex trigger apoptosis in neurons using common mechanisms, which include Tubulin 1A and nuclear Lamin A protein expression deregulation (Zenon et al, in press)[13]. Some studies have shown increased expression of CB2R in in vitro HIV-infected macrophages and microglia and in postmortem brain tissues of HIVE and HAND p atients[23,24]. The role of CB2R agonists in HIV/MDM-induced neuronal death and CATB neurotoxic potential has not been previously studied. Our results indicate that CB2R agonist JWH-133 reduces CATB secretion and neurotoxicity induced by HIV-infected macrophages
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