24 Hours in the Life of HIV-1 in a T Cell Line

Mohammadi, Pejman; Desfarges, Sébastien; Bartha, István; Joos, Béda; Zangger, Nadine; Muñoz, Miguel; Günthard, Huldrych F.; Beerenwinkel, Niko; Telenti, Amalio; Ciuffi, Angela

doi:10.1371/journal.ppat.1003161

Cited by 139 publications

(175 citation statements)

References 31 publications

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“…As shown in Fig. 4A, autophagy was rapidly induced in read-out cells upon coculture with MOLT-X4, with a peak around 4 h corresponding to the early phase of HIV-1 infection (19). Autophagy was then negatively regulated and finally completely inhibited after 24 h of coculture, a step corresponding to the late phases of HIV-1 infection.…”

Section: Autophagy Is Induced By Hiv-1 Envelope Glycoproteins (Env) Amentioning

confidence: 86%

“…After the integration step, the viral transactivator Tat enables the transcription of the viral DNA, leading to the production of the viral components necessary to synthesize new infectious particles that are released from the infected cells. The HIV-1 replication cycle can thus be divided in two phases: the early phase, from viral entry to provirus integration, and the late phase, from transcription of viral genes to the release of new viral particles (18,19).…”

Section: Human Immunodeficiency Virus Type 1 (Hiv-1) Infects Immune Cmentioning

confidence: 99%

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Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 ⁺ T Lymphocytes

Sagnier

Daussy

Borel

et al. 2015

J Virol

126

121

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Autophagy is a ubiquitous mechanism involved in the lysosomal-mediated degradation of cellular components when they are engulfed in vacuoles called autophagosomes. Autophagy is also recognized as an important regulator of the innate and adaptive immune responses against numerous pathogens, which have, therefore, developed strategies to block or use the autophagy machinery to their own benefit. Upon human immunodeficiency virus type 1 (HIV-1) infection, viral envelope (Env) glycoproteins induce autophagy-dependent apoptosis of uninfected bystander CD4؉ T lymphocytes, a mechanism likely contributing to the loss of CD4 ؉ T cells. In contrast, in productively infected CD4 ؉ T cells, HIV-1 is able to block Env-induced autophagy in order to avoid its antiviral effect. To date, nothing is known about how autophagy restricts HIV-1 infection in CD4 ؉ T lymphocytes. Here, we report that autophagy selectively degrades the HIV-1 transactivator Tat, a protein essential for viral transcription and virion production. We demonstrated that this selective autophagy-mediated degradation of Tat relies on its ubiquitin-independent interaction with the p62/SQSTM1 adaptor. Taken together, our results provide evidence that the anti-HIV effect of autophagy is specifically due to the degradation of the viral transactivator Tat but that this process is rapidly counteracted by the virus to favor its replication and spread. IMPORTANCE Autophagy is recognized as one of the most ancient and conserved mechanisms of cellular defense against invading pathogens.Cross talk between HIV-1 and autophagy has been demonstrated depending on the virally challenged cell type, and HIV-1 has evolved strategies to block this process to replicate efficiently. However, the mechanisms by which autophagy restricts HIV-1 infection remain to be elucidated. Here, we report that the HIV-1 transactivator Tat, a protein essential for viral replication, is specifically degraded by autophagy in CD4 ؉ T lymphocytes. Both Tat present in infected cells and incoming Tat secreted from infected cells are targeted for autophagy degradation through a ubiquitin-independent interaction with the autophagy receptor p62/SQSTM1. This study is the first to demonstrate that selective autophagy can be an antiviral process by degrading a viral transactivator. In addition, the results could help in the design of new therapies against HIV-1 by specifically targeting this mechanism. M acroautophagy, herein referred to as autophagy, is a major cellular catabolic pathway highly regulated in eukaryotes. It is involved in the degradation of cytoplasmic material after its sequestration in vacuoles called autophagosomes. The autophagosomes fuse with lysosomes to form autolysosomes in which the sequestered material is degraded and then recycled (1). Since the discovery of the Atg genes that regulate this process, autophagy has been found to be involved in a number of important cellular functions, including cellular homeostasis, development, aging, or innate and adaptive immune responses (2...

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Section: Autophagy Is Induced By Hiv-1 Envelope Glycoproteins (Env) Amentioning

confidence: 86%

Section: Human Immunodeficiency Virus Type 1 (Hiv-1) Infects Immune Cmentioning

confidence: 99%

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 ⁺ T Lymphocytes

Sagnier

Daussy

Borel

et al. 2015

J Virol

126

121

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“…The start of protein production in HIV-infected Jurkat cells was also highly variable and seemed to negatively correlate with the level of produced viral protein, which has been linked to the position of the integration site within the nucleus (14). Details of the steps in HIV provirus transcription and translation leading to virus production in the SupT1 cell line during the first 24 h of infection have also been recently studied (16). However, the impact of viral protein production on cell death could not be seen in the immortalized cell lines, and it is not clear whether these observed dynamics of virus production and cell death are consistent with the dynamics found in primary cell infection.…”

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confidence: 99%

Intracellular Dynamics of HIV Infection

Petravic

Ellenberg

Chan

et al. 2014

J Virol

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dEarly studies of HIV infection dynamics suggested that virus-producing HIV-infected cells had an average half-life of approximately 1 day. However, whether this average behavior is reflective of the dynamics of individual infected cells is unclear. Here, we use HIV-enhanced green fluorescent protein (EGFP) constructs and flow cytometry sorting to explore the dynamics of cell infection, viral protein production, and cell death in vitro. By following the numbers of productively infected cells expressing EGFP over time, we show that infected cell death slows down over time. Although infected cell death in vivo could be very different, our results suggest that the constant decay of cell numbers observed in vivo during antiretroviral treatment could reflect a balance of cell death and delayed viral protein production. We observe no correlation between viral protein production and death rate of productively infected cells, showing that viral protein production is not likely to be the sole determinant of the death of HIV-infected cells. Finally, we show that all observed features can be reproduced by a simple model in which infected cells have broad distributions of productive life spans, times to start viral protein production, and viral protein production rates. This broad spectrum of the level and timing of viral protein production provides new insights into the behavior and characteristics of HIV-infected cells.

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“…Furthermore, the life cycle of HIV-1 from infection of a cell to the release of virus particles can be divided into cell populations with different transcriptional activity [26]. We took both of these important characteristics into account in our model that consists of 12 subpopulations of cells that can be stratified according to their HIV-1 DNA and RNA content (Figure 3 and Methods).…”

Section: Resultsmentioning

confidence: 99%

Quantifying the turnover of transcriptional subclasses of HIV-1-infected cells

Althaus

Joos

Perelson

et al. 2013

Preprint

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HIV-1-infected cells in peripheral blood can be grouped into different transcriptional subclasses. Quantifying the turnover of these cellular subclasses can provide important insights into the viral life cycle and the generation and maintenance of latently infected cells. We used previously published data from five patients chronically infected with HIV-1 that initiated combination antiretroviral therapy (cART).Patient-matched PCR for unspliced and multiply spliced viral RNAs combined with limiting dilution analysis provided measurements of transcriptional profiles at the single cell level. Furthermore, measurement of intracellular transcripts and extracellular virion-enclosed HIV-1 RNA allowed us to distinguish productive from non-productive cells. We developed a mathematical model describing the dynamics of plasma virus and the transcriptional subclasses of HIV-1-infected cells. Fitting the model to the data allowed us to better understand the phenotype of different transcriptional subclasses and their contribution to the overall turnover of HIV-1 before and during cART. The average number of virus-producing cells in peripheral blood is small during chronic infection (25.7 cells ml −1 ). We find that 14.0%, 0.3% and 21.2% of infected cells become defectively, latently and persistently infected cells, respectively. Assuming that the infection is homogenous throughout the body, we estimate an average in vivo viral burst size of 2.1 × 10 4 virions per cell. Our study provides novel quantitative insights into the turnover and develop-

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24 Hours in the Life of HIV-1 in a T Cell Line

Cited by 139 publications

References 31 publications

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 ⁺ T Lymphocytes

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 ⁺ T Lymphocytes

Intracellular Dynamics of HIV Infection

Quantifying the turnover of transcriptional subclasses of HIV-1-infected cells

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24 Hours in the Life of HIV-1 in a T Cell Line

Cited by 139 publications

References 31 publications

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 + T Lymphocytes

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 + T Lymphocytes

Intracellular Dynamics of HIV Infection

Quantifying the turnover of transcriptional subclasses of HIV-1-infected cells

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Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 ⁺ T Lymphocytes

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 ⁺ T Lymphocytes