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Autophagy restricts HIV-1 infection by selectively degrading Tat in CD4+ T lymphocytes.

Sagnier S1, Daussy CF1, Borel S1, Robert-Hebmann V1, Faure M2, Blanchet FP1, Beaumelle B1, Biard-Piechaczyk M1, Espert L3. J Virol. 2015 Jan;89(1):615-25.

1CPBS, Université de Montpellier, UMR 5236 CNRS, Montpellier, France.

2CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France INSERM U1111, Lyon, France Ecole Normale Supérieure de Lyon, Lyon, France Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France CNRS, UMR 5308, Lyon, France.

3CPBS, Université de Montpellier, UMR 5236 CNRS, Montpellier, France Email: [email protected]


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 inCD4(+) 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.


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. BothTat 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 bydegrading a viral transactivator. In addition, the results could help in the design of new therapies against HIV-1 by specifically targeting this mechanism.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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Figure Legend

The HIV-envelope glycoproteins induce autophagy at the first steps of CD4 T cell infection. The HIV transativator Tat is a selective target of autophagy. By degrading Tat, autophagy exerts a strong anti-HIV effect and thus, this virus has evolved strategies in order to block it.


Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4+ T Lymphocytes. Global Medical Discovery