Chronic human immunodeficiency virus type one (HIV-1) infection leads to a spectrum of neurological and cognitive abnormalities, known collectively as HIV-associated neurocognitive disorders (HAND). HAND remains prevalent, particularly in its milder forms, despite effective combination antiretroviral therapy (cART). The pathogenesis of HAND is involves HIV-infected perivascular macrophages and microglia, whose activation leads to the release of pro-inflammatory cytokines and other soluble factors toxic to neurons. One factor that may be involved in macrophage-mediated HIV neurotoxicity is cathepsin B, a cysteine protease. We recently demonstrated that monocyte-derived macrophages (MDM) secreted, cathepsin B has increased neurotoxic activity in vitro. In studies of our Hispanic women cohort, we observed increased expression of both cathepsin B and cystatin B in monocytes of women with HAD on cART with no comorbid conditions. Studies are needed to determine the role of monocyte cathepsin B, cystatins B and C, as potential biomarkers for HAND by flow cytometry. A pilot study of limited samples post-mortem brain tissue indicated that cathepsin B is also upregulated in the CNS of patients with HAND [1]. New preliminary studies of MDM secreted interactome demonstrate that cathepsin B interacts with MMP-9 in uninfected cells but this interaction disappears in HIV infection and develops a new interaction with serum amyloid P component (SAPC), related to amyloid deposition in Alzheimer's disease (AD). Studies in the literature also suggest that cathepsin B might be involved in amyloid-beta (A)- related inflammatory response, which results in neuronal death. This new role of cathepsin B in HIV infection deserves further studies. Our long-term goal is to determine the potential of the cathepsin B system as a diagnostic tool and therapeutic target for HAND and the mechanisms whereby cathepsin B dysregulation causes neuronal cell dysfunction and death. Our central hypothesis is that increased secretion of monocyte-derived cathepsin B after HIV infection causes neuronal dysfunction and death, and contributes to the pathogenesis of HAND. The proposed research is conceptually innovative because the role of the cathepsin B as a potential early blood biomarker of HAND has not been explored. Understanding how dysregulation of the cathepsin B interacting proteins in the HIV-infected MDM secretome contributes to neurotoxicity using primary human neurons could elucidate novel targets for therapy.
The specific aims are: 1) Create a longitudinal expression profile of cathepsin B and cystatins B and C in CD14+ monocytes from HAND patients. 2) Characterize of the interactome of MDM-secreted cathepsin B and its involvement in HIV-induced neuronal death; 3) Determine the translational significance of cathepsin B interactome in human post-mortem brain tissue. The proposed studies will significantly advance the HIV field by providing new clinical diagnostic tools, new pathways, and possible complementary therapies against HAND.
The proposed research will explore the role of neurotoxic proteins from macrophages in the development of HIV-neurotoxicity and their expression in in patients treated with combined antiretroviral therapy or cART. Defining the mechanisms of HIV-induced neurotoxicity may lead to the discovery of protein candidates for early diagnosis and novel targets for drug development, and thereby are improve the health of patients living with HIV.
| Rosario-Rodríguez, Lester J; Colón, Krystal; Borges-Vélez, Gabriel et al. (2018) Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages. J Neuroimmune Pharmacol : |
| Rosas-Vidal, Luis E; Lozada-Miranda, Valeria; Cantres-Rosario, Yisel et al. (2018) Alteration of BDNF in the medial prefrontal cortex and the ventral hippocampus impairs extinction of avoidance. Neuropsychopharmacology 43:2636-2644 |
| Cantres-Rosario, Yisel M; Acevedo-Mariani, Frances M; Pérez-Laspiur, Juliana et al. (2017) Microwave & magnetic proteomics of macrophages from patients with HIV-associated cognitive impairment. PLoS One 12:e0181779 |
| Cantres-Rosario, Yisel M; Hernandez, Natalia; Negron, Karla et al. (2015) Interacting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis. AIDS 29:2081-92 |
| Zenón, Frances; Cantres-Rosario, Yisel; Adiga, Radhika et al. (2015) HIV-infected microglia mediate cathepsin B-induced neurotoxicity. J Neurovirol 21:544-58 |
