Proteomics in the investigation of HIV‐1 interactions with host proteins

Li, Ming

doi:10.1002/prca.201400101

Cited by 13 publications

(13 citation statements)

References 144 publications

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“…However, lack of detection of Tat in exosomes from the infected cells in these two studies cannot simply be interpreted as absence of the protein. LC-MS/MS has not been detected Tat protein in HIV-producing CD4 T cells (Li 2015; Santos et al 2012; Saphire et al 2006) and in sera of HIV-infected patients (Donnelly and Ciborowski 2016). Only one study has detected Tat protein in purified HIV using LC-MS/MS in combination with micro-capillary reversed-phase liquid chromatography (µRPLC) (Chertova et al 2006), which has been shown to improve detection of low-abundant proteins such as Tat (Tomlinson and Chicz 2003).…”

Section: Discussionmentioning

confidence: 98%

Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein

Rahimian

2016

J. Neurovirol.

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HIV-1 Tat is an indispensible transactivator for HIV gene transcription and replication. It has been shown to exit cells as a free protein and enter neighboring cells or interact with surface receptors of neighboring cells to regulate gene expression and cell function. In this study, we report, for the first time, exosome-associated Tat release and uptake. Using a HIV-1 LTR-driven luciferase reporter-based cell assay and Western blotting or in combination with exosome inhibitor, OptiPrep gradient fractionation, and exosome depletion, we demonstrated significant presence of HIV-1 Tat in exosomes derived from Tat-expressing primary astrocytes, Tat-transfected U373.MG and 293T, and HIV-infected MT4. We further showed that exosome-associated Tat from Tat-expressing astrocytes was capable of causing neurite shortening and neuron death, further supporting that this new form of extracellular Tat is biologically active. Lastly, we constructed a Tat mutant deleted of its basic domain and determined the role of the basic domain in Tat trafficking into exosomes. Basic domain-deleted Tat exhibited no apparent effects on Tat trafficking into exosomes, while maintained its dominant-negative function in Tat-mediated LTR transactivation. Taken together, these results show a significant fraction of Tat is secreted and present in the form of exosomes and may contribute to the stability of extracellular Tat and broaden the spectrum of its target cells.

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Section: Discussionmentioning

confidence: 98%

Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein

Rahimian

2016

J. Neurovirol.

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“…Currently, antiretroviral drugs can control HIV replication and increase survival (2). However, current therapies come at substantial financial cost (3), and they are not curative. Moreover, if HIV patients are not medically compliant, drug-resistance and treatment-failure can ensue (4).…”

Section: M116066019 1447-1461 2017mentioning

confidence: 99%

Quantitative Temporal Viromics of an Inducible HIV-1 Model Yields Insight to Global Host Targets and Phospho-Dynamics Associated with Protein Vpr

Lapek

Lewinski

Wozniak

et al. 2017

Molecular & Cellular Proteomics

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The mechanisms by which human immunodeficiency virus (HIV) circumvents and coopts cellular machinery to replicate and persist in cells are not fully understood. HIV accessory proteins play key roles in the HIV life cycle by altering host pathways that are often dependent on post-translational modifications (PTMs). Thus, the identification of HIV accessory protein host targets and their PTM status is critical to fully understand how HIV invades, avoids detection and replicates to spread infection. To date, a comprehensive characterization of HIV accessory protein host targets and modulation of their PTM status does not exist. The significant gap in knowledge regarding the identity and PTMs of HIV host targets is due, in part, to technological limitations. Here, we applied current mass spectrometry techniques to define mechanisms of viral protein action by identifying host proteins whose abundance is affected by the accessory protein Vpr and the corresponding modulation of down-stream signaling pathways, specifically those regulated by phosphorylation. By utilizing a novel, inducible HIV-1 CD4+ T-cell model system expressing either the wild type or a negative viral genome, we overcame challenges associated with synchronization and infection-levels present in other models. We report identification and abundance dynamics of over 7000 proteins and 28,000 phospho-peptides. Consistent with Vpr's ability to impair cell-cycle progression, we observed Vpr-mediated modulation of spindle and centromere proteins, as well as Aurora kinase A and cyclin-dependent kinase 4 (CDK4). Unexpectedly, we observed evidence of Vpr-mediated modulation of the activity of serine/arginine-rich protein-specific kinases (SRPKs), suggesting a possible role for Vpr in the regulation of RNA splicing. This study presents a new experimental system and provides a data-resource that lays the foundation for validating host proteins and phosphorylation-pathways affected by HIV-1 and its accessory protein Vpr.

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“…Although the same protein catabolic effects in HIV infection have been recognized for a long time [ 31 - 37 ], but there are few data in the literature about infection-related amino acids and their derivatives imbalance in HIV-infected patients [ 38 - 46 ].…”

Section: Introductionmentioning

confidence: 99%

Plasma L-Carnitine and L-Lysine Concentrations in HIV-Infected Patients

Butorov¹

2017

Open Biochem J.

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Background:Virus infections are associated with significant alterations in host cells amino acids profiles that support biosynthetic demands necessary for production of viral progeny. Amino acids play an important role in the pathogenesis of all virus-related infections both as basic substrates for protein synthesis and as regulators in many metabolic pathways.Objective:Our aim was to determine the changes in plasma L-carnitine levels and its amino acid precursor (L-lysine) in HIV-infected patients.Methods:We performed a case-control study of 430 HIV-1 infected males (non-vegetarians) without any restriction in the nourishment, before highly active antiretroviral therapy (HAART) and 125 HIV-1 subjects after the introduction of HAART who were periodically monitored in the Municipal Center of HIV/AIDS prophylaxis, Surgut, Russian FederationResults:The plasma total (TC) and free (FC) L-carnitine concentrations markedly decreased with the clinical stages of HIV infection. The mean plasma TC, FC and L-lysine levels were significantly lower in asymptomatic stage (A) and advanced CDC stages (B, C) HIV-infected patients compared with our reference values. The total and free L-carnitine and its amino acid precursor concentrations mild increased in HIV-infected subjects after the introduction of HAART.Our data revealed that L-lysine amino acid and its derivative (TC) levels were negatively correlated with viral load and inversely with CD4 count lymphocytes in the total cohort.Conclusion:The study results show that there was evidence for an association between plasma L-carnitine, L-lysine and HIV-1 RNA levels, immunological markers and clinical stages of HIV infection. The obtained data indicate that level changes of these host essential nutritional elements can play an important role in the HIV life cycle. These findings are important for understanding the pathophysiology of HIV infection and must be considered in further research for the development of new approaches in the treatment of the disease.

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Proteomics in the investigation of HIV‐1 interactions with host proteins

Cited by 13 publications

References 144 publications

Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein

Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein

Quantitative Temporal Viromics of an Inducible HIV-1 Model Yields Insight to Global Host Targets and Phospho-Dynamics Associated with Protein Vpr

Plasma L-Carnitine and L-Lysine Concentrations in HIV-Infected Patients

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