Project Summary
Approximately, 50% of HIV-positive people develop HIV-associated neurocognitive disorders (HAND), despite
being under combined antiretroviral therapy (cART). HAND is an inflammatory neurodegenerative disease
characterized by increased macrophage infiltration and persistent HIV replication in the brain of affected
individuals. There are no effective therapies available against HAND. Our laboratory has found increased
expression of cathepsin B, a pro-inflammatory lysosomal enzyme, in postmortem brain tissues of individuals with
HAND. In addition, after HIV-1 infection of monocyte-derived macrophages (MDM), secreted cathepsin B
changes interactions with other proteins such as serum amyloid P component (SAPC) and promotes
neurotoxicity. Thus, targeting cathepsin B represents a potential strategy against HAND. In search for new
therapies, it was demonstrated that activation of cannabinoid receptor type 2 (CB2R) inhibits HIV-1 replication
in macrophages, reduces blood-brain barrier (BBB) permeability, decreases neurotoxicity to HIV-1 viral proteins,
and diminishes pro-inflammatory cytokines release. Nonetheless, studies have shown increased expression of
CB2R in in vitro HIV-infected macrophages, and in post-mortem brain tissues of HAND patients. Therefore, this
receptor represents a promising target for treatment against HAND. However, the role of CB2R activation in
cathepsin B secretion and neurotoxicity has not been studied previously. The overall objective of this proposal
is to understand the mechanisms of CB2R activation in cathepsin B secretion and neurotoxicity from HIV-infected
macrophages. Our central hypothesis is that CB2R activation will prevent cathepsin B secretion and neurotoxicity
from HIV-infected macrophages by attenuating intracellular inflammation pathways in MDM and preventing
cathepsin B interactions with SAPC. Our hypothesis was formulated based on results that show a significant
decrease in cathepsin B secretion and neurotoxicity from HIV-infected MDM treated with a CB2R agonist. We
will test our central hypothesis and, thereby, accomplish the objective of this proposal by pursuing the following
specific aims: 1) Determine the effect of CB2R activation in cathepsin B secretion and neurotoxicity from HIV-
infected macrophages. 2) Explore the intracellular pathways and characterize cathepsin B interactome in
supernatants from HIV-infected macrophages after CB2R activation. 3) Understand the mechanisms of chronic
inflammation in HAND. The rationale for this proposed research is that understanding the role of CB2R activation
in cathepsin B secretion and interactions will permit the development of strategies against HIV-induced cathepsin
B neurotoxicity. This contribution is significant because it will provide new knowledge about the mechanisms of
CB2R modulation in cathepsin B-induced neurotoxicity from HIV-infected macrophages, and will contribute to
the development of new strategies against HAND.
