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HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution

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Abstract

With the advent of the combination antiretroviral therapy era (cART), the development of AIDS has been largely limited in the USA. Unfortunately, despite the development of efficacious treatments, HIV-1-associated neurocognitive disorders (HAND) can still develop, and as many HIV-1 positive individuals age, the prevalence of HAND is likely to rise because HAND manifests in the brain with very low levels of virus. However, the mechanism producing this viral disorder is still debated. Interestingly, HIV-1 infection exposes neurons to proteins including Tat, Nef, and Vpr which can drastically alter mitochondrial properties. Mitochondrial dysfunction has been posited to be a cornerstone of the development of numerous neurodegenerative diseases. Therefore, we investigated mitochondria in an animal model of HAND. Using an HIV-1 transgenic rat model expressing seven of the nine HIV-1 viral proteins, mitochondrial functional and proteomic analysis were performed on a subset of mitochondria that are particularly sensitive to cellular changes, the neuronal synaptic mitochondria. Quantitative mass spectroscopic studies followed by statistical analysis revealed extensive proteome alteration in this model paralleling mitochondrial abnormalities identified in HIV-1 animal models and HIV-1-infected humans. Novel mitochondrial protein changes were discovered in the electron transport chain (ETC), the glycolytic pathways, mitochondrial trafficking proteins, and proteins involved in various energy pathways, and these findings correlated well with the function of the mitochondria as assessed by a mitochondrial coupling and flux assay. By targeting these proteins and proteins upstream in the same pathway, we may be able to limit the development of HAND.

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Acknowledgments

We would like to thank the Proteomics Core Facility members at the University of Nebraska Medical Center, under the direction of Dr. Pawel Ciborowski, for all their support and aid in the proteomics experiments.

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Authors and Affiliations

  1. Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center-DRC1 3008, Omaha, NE, 68198-5800, USA

    Lance M. Villeneuve, Phillip R. Purnell, Kelly L. Stauch, Shannon E. Callen, Shilpa J. Buch & Howard S. Fox

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  1. Lance M. Villeneuve
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  2. Phillip R. Purnell
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  3. Kelly L. Stauch
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  4. Shannon E. Callen
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Correspondence to Howard S. Fox.

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Conflict of interest

Lance M. Villeneuve, Phillip R. Purnell, Kelly L. Stauch, Shannon E. Callen, Shilpa J. Buch, and Howard S. Fox report no conflict of interest.

Funding sources

This work was funded by the National Institute of Health (NIH) grants P30MH062261, R01DA027729, R01DA033150, R01DA36157, and R01MH73490.

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Supplementary file 1: Table S1

List of select proteins with significantly altered expression profiles in the HIV-1 Tg rat brain synaptic mitochondria. Proteomic data was analyzed through CyberT (http://cybert.ics.uci.edu/). A Bayesian analysis of the data was performed using a Bayesian coefficient of 12. Multiple testing corrections were applied. For significance, p < 0.05 and cumulative posterior probability of differential expression (Cum PPDE) > 0.95. (XLS 126 kb)

Supplementary file 2: Fig. S1

Histograms demonstrating sample reproducibility. Area under curve data obtained from mass spectrometry was used to generate histograms comparing samples against one another within each experimental group. Pearson’s r coefficient was generated for each comparison. (TIFF 16456 kb)

Supplementary file 3: Fig. S2

Gene Ontology (GO) biological process analysis. Data from the mass spectrometry analysis were uploaded into the Panther classification system (http://www.pantherdb.org/) to determine which biological processes were most represented in our samples. (TIFF 667 kb)

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Villeneuve, L.M., Purnell, P.R., Stauch, K.L. et al. HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution. J. Neurovirol. 22, 564–574 (2016). https://doi.org/10.1007/s13365-016-0424-9

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