The Cellular Autophagy Pathway Modulates Human T-Cell Leukemia Virus Type 1 Replication

The human T-cell leukemia virus type 1 (HTLV-1) Tax protein is considered to play a central role in the process that leads to adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 Tax IMPORTANCEOur study reveals that Tax-deregulated autophagy is a protective mechanism for DR-mediated apoptosis. The molecular mechanism of Tax-induced autophagy is also illuminated, which is different from Tax-increased c-FLIP. Tax can be degraded via manipulation of autophagy and TRAIL-induced apoptosis. These results outline a complex regulatory network between and among apoptosis, autophagy, and Tax and also present evidence that autophagy represents a new possible target for therapeutic intervention for the HTVL-1 related diseases.

Section: Discussionmentioning

confidence: 99%

“…Recently, the regulation by Tax of the autophagy pathway was also reported (41,42). However, the relationship between Tax-regulated apoptosis and autophagy is still unclear.…”

Section: Htlv-1 Tax Increases Autophagosomes Accumulationmentioning

confidence: 99%

mentioning

confidence: 96%

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Human T-Cell Leukemia Virus Type 1 Tax-Deregulated Autophagy Pathway and c-FLIP Expression Contribute to Resistance against Death Receptor-Mediated Apoptosis

Wang

Zhou

Shi

et al. 2014

“…This also seems to be the case for another retroviral transactivator, the human T-cell leukemia virus type 1 (HTLV-1) Tax protein. Indeed, it has been demonstrated that Tax is a substrate for autophagy degradation, but the underlying mechanism is still unknown (51). They also demonstrated that Tax is able to block the degradative phases of autophagy, suggesting that this viral protein could control its own stability and turnover (51).…”

Section: Discussionmentioning

confidence: 99%

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

Sagnier

Daussy

Borel

et al. 2015

127

130

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...

“…Several HTLV-1 chronically infected T-cell lines are available for in vitro studies and have been used to infect T lymphocytes (17,20,21). However, DC infection was performed using MT-2 cells only (10,22), while HTLV-1 transcytosis experiments were done using C91PL cells only (19).…”

Section: C91pl Cells Produce More Infectious Viral Particles Than Mt-mentioning

confidence: 99%

Viral Source-Independent High Susceptibility of Dendritic Cells to Human T-Cell Leukemia Virus Type 1 Infection Compared to That of T Lymphocytes

Alais

Mahieux

Dutartre

2015

109

Human T-cell leukemia virus type 1 (HTLV-1)-infected CD4؉ T cells and dendritic cells (DCs) are present in peripheral blood from HTLV-1 carriers. While T-cell infection requires cell-cell contact, DCs might be infected with cell-free virus, at least in vitro. However, a thorough comparison of the susceptibilities of the two cell types to HTLV-1 infection using cell-associated and cell-free viral sources has not been performed. We first determined that human primary monocyte-derived dendritic cells (MDDCs) were more susceptible to HTLV-1 infection than their autologous lymphocyte counterparts after contact with chronically infected cells. Next, a comparison of infection efficiency using nonconcentrated or concentrated supernatants from infected cells as well as purified viral biofilm was performed. Integrated provirus was found after exposure of MDDCs or primary lymphocytes to viral biofilm but not to a viral supernatant. Using a large series of primary cell samples (n ‫؍‬ 21), we demonstrated a higher proviral load in MDDCs exposed to viral biofilm than in lymphocytes. This higher susceptibility is correlated to a higher expression of neuropilin-1 on MDDCs than on autologous activated T lymphocytes. Moreover, we show that MDDCs infected with viral biofilm can transmit the virus to lymphocytes. In conclusion, MDDCs are more susceptible to HTLV-1 infection than autologous lymphocytes in vitro, supporting a model in which DC infection might represent an important step during primoinfection in vivo. IMPORTANCEHTLV-1 is able to infect several cell types, but viral DNA is mainly found in T lymphocytes in vivo. This supports a model in which T lymphocytes are the main target of infection. However, during the primo-infection of new individuals, incoming viruses might first encounter dendritic cells (DCs), the specialized immune cells responsible for the antiviral response of the host. HTLV-1 cell-free purified viruses can infect dendritic cells in vitro, while T-cell infection is restricted to cell-to-cell transmission. In order to understand the sequence of HTLV-1 dissemination, we undertook a direct comparison of the susceptibilities of the two cell types using cell-associated and cell-free viral sources. We report here that MDDCs are more susceptible to HTLV-1 infection than autologous lymphocytes in vitro and are able to efficiently transmit the virus to lymphocytes. Our results suggest that DCs may represent a true viral reservoir, as the first cell type to be infected in vivo.H uman T-cell leukemia virus type 1 (HTLV-1) infects 5 to 20 million people worldwide (1) and is the etiological agent of both an aggressive CD4 ϩ T-cell leukemia named adult T-cell leukemia (ATL) (2) and a neurological disease named tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) (3, 4). HTLV-1 is transmitted through contact with infected cells present in maternal milk, semen, or blood and is mainly found in CD4 ϩ T cells, but other cell types might also be infected or functionally altered in vivo and thus involv...