Macrophage Derived Cystatin B/Cathepsin B in HIV Replication and Neuropathogenesis

Abstract

Mononuclear phagocytes including monocytes and macrophages, are important defense components of innate immunity, but can be detrimental in HIV-1 infection by serving as the principal reservoirs of virus in brain and triggering a strong immune response. These viral reservoirs represent a challenge to HIV-1 eradication since they continue producing virus in tissue despite antiretroviral therapy. HIV-1 associated neurocognitive disorders (HAND) involve alterations to the blood-brain barrier and migration of activated HIV-1 infected monocytes to the brain with subsequent induced immune activation response. Our group recently showed that HIV replication in monocyte-derived macrophages is associated with increased cystatin B. This cysteine protease inhibitor also inhibits the interferon-induced antiviral response by decreasing levels of tyrosine phosphorylated STAT-1. These recent discoveries reveal novel mechanisms of HIV persistence that could be targeted by new therapeutic approaches to eliminate HIV in macrophage reservoirs. However, cystatin B has been also associated with neuroprotection. Cystatin B is an inhibitor of the cysteine protease cathepsin B, a potent neurotoxin. During HIV-1 infection cystatin B and cathepsin B are upregulated in macrophages. Reduction in cystatin/cathepsin interactions in infected macrophages leads to increased cathepsin B secretion and activity which contributes to neuronal apoptosis. Increased intracellular expression of both proteins was recently found in monocytes from Hispanic women with HAND. These findings provide new evidence for the role of cathepsin /cystatin system in the neuropathogenesis induced by HIV-infected macrophages. We summarize recent research on cystatin B and one of its substrates, cathepsin B, in HIV replication in macrophages and neuropathogenesis.

HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity

“…Thus, it is important to maintain the homeostasis of those enzymes or lysosomal exocytosis. Consistent with our findings, increased cathepsin B release has recently been linked to HIV infectionassociated neuronal death and neurocognitive deficits (76,77). Taken together, these findings suggest important roles of lysosomal exocytosis and cathepsins in neurodegenerative diseases, including HIV/neuroAIDS, and may provide new strategies for development of therapeutics for those diseases.…”

Cocaine Potentiates Cathepsin B Secretion and Neuronal Apoptosis from HIV-Infected Macrophages

“…We observed a significant increase in the levels of cathepsin B secretion and activity in plasma of HIV-infected cocaine users compared with non-drug users. This increased cathepsin B in HIV-1 infected cocaine users parallels to previous clinical findings from studies of plasma samples of patients with HIV associated neurocognitive disorders (HAND) (Rivera et al 2014). Similar results were obtained in the CSF of HAND patients and in HIV seropositive patients that are cocaine users where cathepsin B secretion and activity remained at the same levels between experimental and control groups.…”

Interacting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis

“…Cathepsin B, a lysosomal cysteine protease, is up-regulated and secreted from HIV-infected macrophages [7–9]. The interaction of cathepsin B with its endogenous inhibitors cystatins B and C is disrupted by HIV infection [7–9].…”

“…The interaction of cathepsin B with its endogenous inhibitors cystatins B and C is disrupted by HIV infection [7–9]. Notably, cathepsin B present in macrophage-conditioned medium (MCM) contributes to 10–20% of neuronal apoptosis [7].…”