CSF proteomic fingerprints for HIV-associated cognitive impairment

Laspiur, J. Pérez; Anderson, Eric; Ciborowski, Paweł; Wojna, Valerie; Rozek, Wojciech; Duan, Fenghai; Mayo, Raúl; Jiménez, Efraín Rodríguez; Plaud-Valentín, Marinés; Rodríguez‐Orengo, José F.; Gendelman, Howard E.; Meléndez, Loyda M.

doi:10.1016/j.jneuroim.2007.08.004

Cited by 56 publications

(64 citation statements)

References 47 publications

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“…After SEC isolation, the (Lys) 6 -tagged rHbI was enzymatically digested with trypsin, and the generated peptides were identified by LC–MS/MS [37]. The analysis was performed in duplicate.…”

Section: Resultsmentioning

confidence: 99%

Molecular Cloning and Characterization of a (Lys)6-Tagged Sulfide-Reactive Hemoglobin I from Lucina pectinata

et al. 2015

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A poly-Lys tag was fused to the Lucina pectinata hemoglobin I (HbI) coding sequence and purified using an efficient and fast process. HbI is a hemeprotein that binds hydrogen sulfide (H2S) with high affinity and it has been used to understand physiologically relevant reactions of this signaling molecule. The (Lys)6-tagged rHbI construct was expressed in E. coli and purified by immobilization on a cation exchange matrix, followed by size-exclusion chromatography. The identity, structure, and function of the (Lys)6-tagged rHbI were assessed by mass spectrometry, small and wide X-ray scattering, optical spectroscopy, and kinetic analysis. The scattering and spectroscopic results showed that the (Lys)6-tagged rHbI is structurally and functionally analogous to the native protein as well as to the (His)6-tagged rHbI. Kinetics studies with H2S indicated that the association (kon) and dissociation (koff) rate constants were 1.4 × 105/M/s and 0.1 × 10−3/s, respectively. This results confirmed that the (Lys)6-tagged rHbI binds H2S with the same high affinity as its homologue.

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Section: Resultsmentioning

confidence: 99%

Molecular Cloning and Characterization of a (Lys)6-Tagged Sulfide-Reactive Hemoglobin I from Lucina pectinata

et al. 2015

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“…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. It has been established that HIV-1 transforms the monocyte plasma membrane proteome (Kadiu et al 2009) and proteomics analysis of CSF demonstrated that reduction of antioxidants enzymes such as Cu/Zn SOD and GPx, have been associated with disease severity (Laspiur et al 2007; Velazquez et al 2009; Angel et al 2012). It is quite possible that an antioxidant imbalance could promote secretion and neurotoxic activity of cathepsin B in the CNS.…”

Section: Discussionmentioning

confidence: 99%

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

Zenón

Segarra

Gonzalez

et al. 2014

J Neuroimmune Pharmacol

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Substance abuse is a risk factor for HIV infection and progression to AIDS. Recent evidence establishes that cocaine use promotes brain perivascular macrophage infiltration and microglia activation. The lysosomal protease cathepsin B is increased in monocytes from patients with HIV dementia and its secretion induces 10-15% of neurotoxicity. Here we asked if cocaine potentiates cathepsin B secretion from HIV-infected monocyte-derived macrophages (MDM) and its effect in neuronal apoptosis. Samples of plasma, CSF, and post-mortem brain tissue from HIV positive patients that used cocaine were tested for cathepsin B and its inhibitors to determine the in vivo relevance of these findings. MDM were inoculated with HIV-1ADA, exposed to cocaine, and the levels of secreted and bioactive cathepsin B and its inhibitors were measured at different time-points. Cathepsin B expression (p<0.001) and activity (p<0.05) increased in supernatants from HIV-infected cocaine treated MDM compared with HIV-infected cocaine negative controls. Increased levels of cystatin B expression was also found in supernatants from HIV-cocaine treated MDM (p<0.05). A significant increase in 30% of apoptotic neurons was obtained that decreased to 5% with the specific cathepsin B inhibitor (CA-074) or with cathepsin B antibody. Cathepsin B was significantly increased in the plasma and post-mortem brain tissue of HIV/cocaine users over non-drug users. Our results demonstrated that cocaine potentiates cathepsin B secretion in HIV-infected MDM and increase neuronal apoptosis. These findings provide new evidence that cocaine synergize with HIV-1 infection in increasing cathepsin B secretion and neurotoxicity.

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“…In this context, it is of interest that recent proteomics studies have identified lysosomal enzymes (cathepsins) and related proteinases (cystatins) to be the ones most significantly altered in the CSF of cognitively impaired HIV ϩ individuals. 42 In vitro, HIV-infected mononuclear phagocytes display similar changes in cathepsins, cystatins, and other lysosomal enzymes, 43,44 suggesting that the altered metabolism of HIV-infected macrophages and microglia is central to the pathogenesis of HIV-associated neurocognitive disorder (HAND). Significant elevations of lysosomal hydrolases and cathepsins have been found in earlier tissue-based studies HIVE and SIV encephalitis.…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor 2 Receptor Is an IFNγ-Inducible Microglial Protein that Facilitates Intracellular HIV Replication

Suh

Cosenza-Nashat

Choi

et al. 2010

The American Journal of Pathology

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Insulin-like growth factor 2 receptor (IGF2R), also known as cation-independent mannose 6-phosphate (M6P) receptor, is a transmembrane glycoprotein localized in the trans-Golgi region and is involved in targeting both M6P-bearing enzymes and IGF2 to the lysosomal compartment. During development, IGF2R plays a crucial role in removing excess growth factors from both tissue and blood. Due to the perinatal lethality of the global Igf2r knockout, the function of IGF2R in adults, particularly in the CNS, is not known. We made a novel observation that IGF2R is highly expressed in microglial nodules in human brains with HIV encephalitis. In vitro, microglial IGF2R expression was uniquely enhanced by IFN␥ among the several cytokines and TLR ligands examined. Furthermore, in several in vitro models of HIV infection, including human and murine microglia, macrophages, and nonmacrophage cells, IGF2R is repeatedly shown to be a positive regulator of HIV infection. IGF2R RNAi also down-regulated the production of the IP-10 chemokine in HIV-infected human microglia. Injection of VSVg env HIV into mouse brain induced HIV p24 expression in neurons, the only cell type normally expressing IGF2R in the adult brain. Our results demonstrate a novel role for IGF2R as an inducible microglial protein involved in regulation of HIV and chemokine expression. Mice with the Csf1r-driven Igf2r knockout should be useful for the investigation of macrophage-specific IGF2R function.

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CSF proteomic fingerprints for HIV-associated cognitive impairment

Cited by 56 publications

References 47 publications

Molecular Cloning and Characterization of a (Lys)6-Tagged Sulfide-Reactive Hemoglobin I from Lucina pectinata

Molecular Cloning and Characterization of a (Lys)6-Tagged Sulfide-Reactive Hemoglobin I from Lucina pectinata

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

Insulin-Like Growth Factor 2 Receptor Is an IFNγ-Inducible Microglial Protein that Facilitates Intracellular HIV Replication

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