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Differential modulation of mitochondrial OXPHOS system during HIV-1 induced T-cell apoptosis: up regulation of Complex-IV subunit COX-II and its possible implications

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Abstract

Human Immunodeficiency Virus-1 (HIV-1) infection leads to CD4+ T cell depletion primarily by apoptosis employing both intrinsic and extrinsic pathways. Although extensive literature exists about the role of mitochondrial proteins in HIV induced T cell apoptosis, there is little understanding about the role of different components of mitochondrial oxidative phosphorylation (OXPHOS) system in apoptosis. The OXPHOS system comprises of five enzyme complexes (Complex I, II, III, IV, V), subunits of which have been implicated in various functions in addition to their primary role in energy generating process. Here using differential gene expression analysis, we report that Cytochrome Oxidase-II (COX-II), a subunit of Complex-IV is induced in HIV infected apoptotic T-cells. We also observe a temporal up regulation of this subunit across different T-cell lines and in human PBMCs. Further analysis indicates increase in expression of majority of Complex-IV subunits with concomitant increase in Complex-IV activity in HIV infected T cells. Silencing of COX-II expression leads to reduced apoptosis in infected T-cells, indicating its importance in apoptosis. Furthermore, our results also show that the activities of enzyme complexes I, II and III are decreased while those of Complex IV and V are increased at the time of acute infection and apoptosis. This differential regulation in activities of OXPHOS system complexes indicate a complex modulation of host cell energy generating system during HIV infection that ultimately leads to T cell apoptosis.

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Abbreviations

OXPHOS:

Oxidative phosphorylation

BN-PAGE:

Blue native page

ADP:

Adenosine 5′-diphosphate

ATP:

Adenosine 5′-triphosphate

AZT:

Azidothymidine

MOI:

Multiplicity of infection

MTT:

3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide

PBMC:

Peripheral blood mononuclear cells

ROS:

Reactive oxygen species

MOMP:

Mitochondrial outer membrane potential

CcO:

Cytochrome c Oxidase

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Acknowledgements

We are thankful to Dr. G. C. Mishra, Director, NCCS for his support and constant encouragement. We thank J. S. Ladha, M. Kumar and Md. Zulfazal Ahmed for their technical help and the NCCS FACS core facility. We thank Dr. Islam Khan, NCL Pune for his help in spectrophotometric studies. This work was supported by Department of Biotechnology, Government of India. MKT is a Senior Research Fellow of Council of Scientific and Industrial Research (CSIR), Government of India.

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  1. National Centre for Cell Science, Ganeshkhind, Pune, 411007, India

    Manoj Kumar Tripathy & Debashis Mitra

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Correspondence to Debashis Mitra.

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Tripathy, M.K., Mitra, D. Differential modulation of mitochondrial OXPHOS system during HIV-1 induced T-cell apoptosis: up regulation of Complex-IV subunit COX-II and its possible implications. Apoptosis 15, 28–40 (2010). https://doi.org/10.1007/s10495-009-0408-9

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