Macrophage derived cystatin B/cathepsin B in HIV replication and neuropathogenesis
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A Rat Model of EcoHIV Brain Infection
Published on: January 21, 2021
Linda E Rivera, Krystal Colon, Yisel M Cantres-Rosario
1Department of Microbiology and Medical Zoology, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, 00935, Puerto Rico. Loyda.melendez@upr.edu.
Insights
Mononuclear phagocytes are key HIV-1 reservoirs in the brain. Increased cystatin B and cathepsin B in these cells contribute to HIV persistence and neuroinflammation, offering potential therapeutic targets.
Area of Science:
- Immunology
- Neuroscience
- Virology
Background:
- Mononuclear phagocytes, including monocytes and macrophages, are crucial for innate immunity but serve as primary HIV-1 reservoirs in the brain.
- These viral reservoirs persist despite antiretroviral therapy, complicating HIV-1 eradication efforts.
- HIV-1 infection can lead to HIV-1-associated neurocognitive disorders (HAND) through blood-brain barrier disruption and monocyte migration.
Purpose of the Study:
- To investigate the role of cystatin B and cathepsin B in HIV-1 replication within macrophages.
- To explore the mechanisms by which these proteins contribute to HIV-1 persistence and neuropathogenesis.
- To identify potential therapeutic targets for eliminating HIV-1 in macrophage reservoirs and mitigating HAND.
Main Methods:
- Analysis of HIV-1 replication in monocyte-derived macrophages.
- Measurement of cystatin B and cathepsin B levels in infected cells.
- Investigation of the interaction between cystatin B and cathepsin B.
- Examination of protein expression in monocytes from patients with HAND.
Main Results:
- HIV-1 replication in macrophages is associated with increased cystatin B levels.
- Cystatin B inhibits the interferon-induced antiviral response by affecting STAT-1 phosphorylation.
- During HIV-1 infection, both cystatin B and cathepsin B are upregulated in macrophages.
- Reduced cystatin B/cathepsin B interaction increases cathepsin B activity, contributing to neuronal apoptosis.
- Elevated intracellular cystatin B and cathepsin B were observed in monocytes from Hispanic women with HAND.
Conclusions:
- Cystatin B and cathepsin B play significant roles in HIV-1 persistence within macrophage reservoirs.
- The cystatin B/cathepsin B system is implicated in the neuropathogenesis of HIV-1 infection.
- Targeting these proteins may offer novel therapeutic strategies for HIV-1 eradication and management of HAND.
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.
