Intracellular expression of Tat alters mitochondrial functions in T cells: a potential mechanism to understand mitochondrial damage during HIV-1 replication.

Sara Rodríguez-Mora,Daniel Luque,Mayte Coiras,María Carmen Terrón,Elena Mateos,José Alcamí,Enrique Calvo,María Moran,Miguel Ángel Martín,Delphine Muriaux,María Rosa López-Huertas,Juan Antonio López

doi:10.1186/s12977-015-0203-3

Abstract

BackgroundHIV-1 replication results in mitochondrial damage that is enhanced during antiretroviral therapy (ART). The onset of HIV-1 replication is regulated by viral protein Tat, a 101-residue protein codified by two exons that elongates viral transcripts. Although the first exon of Tat (aa 1–72) forms itself an active protein, the presence of the second exon (aa 73–101) results in a more competent transcriptional protein with additional functions.ResultsMitochondrial overall functions were analyzed in Jurkat cells stably expressing full-length Tat (Tat101) or one-exon Tat (Tat72). Representative results were confirmed in PBLs transiently expressing Tat101 and in HIV-infected Jurkat cells. The intracellular expression of Tat101 induced the deregulation of metabolism and cytoskeletal proteins which remodeled the function and distribution of mitochondria. Tat101 reduced the transcription of the mtDNA, resulting in low ATP production. The total amount of mitochondria increased likely to counteract their functional impairment. These effects were enhanced when Tat second exon was expressed.ConclusionsIntracellular Tat altered mtDNA transcription, mitochondrial content and distribution in CD4+ T cells. The importance of Tat second exon in non-transcriptional functions was confirmed. Tat101 may be responsible for mitochondrial dysfunctions found in HIV-1 infected patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0203-3) contains supplementary material, which is available to authorized users.

Highlights

Human immunodeficiency virus type 1 (HIV-1) replication results in mitochondrial damage that is enhanced during antiretroviral therapy (ART)
Tat101 deregulated the expression of cellular proteins related to metabolism and oxidative stress To describe the role of Tat on mitochondria, Jurkat cells stably expressing Tat72 (Jurkat-Tat72) or Tat101 (JurkatTat101) protein were used as a proper model of CD4+ T lymphocytes as previously shown [15]
A comparative analysis of the liquid chromatography–mass spectrometry (LC–MS)/MS proteome showed that the intracellular expression of Tat101 deregulated the expression of 19 cellular proteins involved in metabolism and control of oxidative stress (Table 1)

Summary

Introduction

HIV-1 replication results in mitochondrial damage that is enhanced during antiretroviral therapy (ART). The onset of HIV-1 replication is regulated by viral protein Tat, a 101-residue protein codified by two exons that elon‐ gates viral transcripts. The first exon of Tat (aa 1–72) forms itself an active protein, the presence of the second exon (aa 73–101) results in a more competent transcriptional protein with additional functions. HIV-1 Tat is a 101-residue protein codified by two exons that promotes the efficient elongation of the viral transcripts through the binding to RNA polymerase II (RNAPII) complex and the recruitment of cellular elongation factors [12]. The second exon is codified by amino acids 73–101 and its expression within the protein results in a more competent transcriptional protein with additional functions independent of transcription such as control of apoptosis [14, 15]. Our group showed that intracellular Tat deregulated the expression of proteins required for mitochondrial membrane stabilization as HSP and Prohibitin [15]

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