HIV-1 trans-activator protein dysregulates IFN-γ signaling and contributes to the suppression of autophagy induction

Li, J.; Au, Kin-yi; Fang, Juemin; Yim, Howard Chi Ho; Chow, Kin-hung; Ho, Pak‐Leung; Lau, Alan F.

doi:10.1097/qad.0b013e328340fd61

Cited by 44 publications

(31 citation statements)

References 51 publications

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“…HIV-1 Tat also suppresses STAT1 activation triggered by gamma interferon (IFN-␥) in monocytes and IFN-␥-induced autophagy in primary macrophages, suggesting that inhibition of autophagy could impair the immune defenses by blocking the antigen processing required for the recognition and killing of intracellular pathogens (34). These results are consistent with the fact that macrophages do not undergo Env-mediated apoptosis and are not subjected to depletion during HIV-1 infection.…”

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

confidence: 77%

“…Indeed, we demonstrated here that Tat can be degraded by basal constitutive autophagy and upon Env-induced autophagy. Tat was also reported to inhibit the autophagy process in uninfected cells (33,34), underlining the complex relationship between autophagy and this viral protein. This also seems to be the case for another retroviral transactivator, the human T-cell leukemia virus type 1 (HTLV-1) Tax protein.…”

Section: Discussionmentioning

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

128

130

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

confidence: 77%

Section: Discussionmentioning

confidence: 99%

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

Sagnier

Daussy

Borel

et al. 2015

J Virol

128

130

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“…41 The HIV-1 Tat protein perturbs signal transduction by IFN-␥. 42 However, it has not been known precisely how HTLV-1 evades the host immune system. In this study, we show that sHBZ inhibits the effector function of CD4 T cells via interaction with NFAT and AP-1, leading to a suppressive effect on the production of Th1 cytokines, such as IFN-␥.…”

Section: Discussionmentioning

confidence: 99%

HTLV-1 bZIP factor impairs cell-mediated immunity by suppressing production of Th1 cytokines

Sugata

Satou

Yasunaga

et al. 2012

Blood

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IntroductionHuman T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that mainly infects CD4 T cells, 1 a critical cell population for the host defense against foreign pathogens. HTLV-1 is known as the causal agent of adult T-cell leukemia (ATL), 2-4 a leukemia derived from CD4 T cells, and chronic inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis, 5,6 alveolitis, 7 and uveitis. It has also been recognized that HTLV-1 infection is complicated by opportunistic infections caused by Pneumocystis jiroveci, herpes zoster virus, cytomegalovirus, or Strongyloides stercoralis. 8 However, the mechanism by which HTLV-1 causes immune deficiency has remained unknown.Another human pathogenic retrovirus, HIV, replicates vigorously in vivo and produces a large number of virions. As a result of abundant viral production, HIV-infected CD4 T cells proceed to apoptosis, a phenomenon that eventually results in AIDS. In contrast, HTLV-1 increases its copy number primarily in the form of a provirus, by promoting the clonal proliferation of infected host CD4 T cells. 9,10 Despite this opposite effect on CD4 T-cell homeostasis compared with HIV, HTLV-1 infection and ATL are frequently accompanied by a deficiency of cellular immunity resembling that seen with AIDS.HTLV-1 encodes several regulatory and accessory genes in the viral genome. 1,11 The viral proteins expressed by the integrated provirus control viral gene transcription and induce host cell proliferation, enabling HTLV-1 to achieve persistent infection. Among the viral genes of HTLV-1, HTLV-1 bZIP factor (HBZ), which is encoded in the minus strand, 12 is a constitutively expressed viral gene. 13 It has been reported that there are 2 major transcripts of the HBZ gene: spliced HBZ (sHBZ) and unspliced HBZ (usHBZ). 14 Based on the findings that sHBZ is more abundantly expressed than usHBZ 15 and that sHBZ has a functionally stronger effect than usHBZ, 16 we focused on sHBZ in this study.Recently, we have reported that sHBZ expression increases the number of regulatory T cells (Tregs) by inducing transcription of the Foxp3 gene in transgenic mice that express the HBZ gene in CD4 T cells (HBZ-Tg mice). 17 An increase in Tregs might be implicated in the immunodeficiency observed in ATL patients. Furthermore, previous studies have reported that HBZ suppresses host cell-signaling pathways that are critical for T-cell receptor signaling in the immune response, such as the NF-B 18 and AP-1 pathways. 19 These findings led us to hypothesize that HBZ might have important roles in the dysregulation of cellular immunity associated with HTLV-1 infection.To verify this hypothesis, we used HBZ-Tg mice that express sHBZ in CD4 T cells and studied well-established infection models of 2 pathogens. The first model involves intravaginal viral infection with herpes simplex virus type-2 (HSV-2). IFN-␥ production by CD4 T cells is critical for the exclusion of HSV-2 from the host. 20,21 The other model involves infection with the Gram-positive intracellular b...

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“…Finally, in the case of retroviruses, human immunodeficiency virus type 1 (HIV-1) has been described to cause the accumulation of autophagic vacuoles in macrophages (39)(40)(41), but the effect of HIV-1 infection on autophagy in CD4 ϩ T cells is still controversial (40,42,43). It has been reported that secreted HIV-1 Tat protein can suppress the autophagy process induced by gamma interferon (IFN-␥) or rapamycin in bystander uninfected macrophages (44,45). In HIV-1-infected macrophages, the HIV-1 Nef protein has been implicated in blocking the fusion of autophagosomes with lysosomes (41), and there is also suggestive evidence that autophagy might serve to enhance HIV-1 replication (41,46,47).…”

mentioning

confidence: 99%

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

Tang

Chen

Klase

et al. 2013

J Virol

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Autophagy, a general homeostatic process for degradation of cytosolic proteins or organelles, has been reported to modulate the replication of many viruses. The role of autophagy in human T-cell leukemia virus type 1 (HTLV-1) replication has, however, been uncharacterized. Here, we report that HTLV-1 infection increases the accumulation of autophagosomes and that this accumulation increases HTLV-1 production. We found that the HTLV-1 Tax protein increases cellular autophagosome accumulation by acting to block the fusion of autophagosomes to lysosomes, preventing the degradation of the former by the latter. Interestingly, the inhibition of cellular autophagosome-lysosome fusion using bafilomycin A increased the stability of the Tax protein, suggesting that cellular degradation of Tax occurs in part through autophagy. Our current findings indicate that by interrupting the cell's autophagic process, Tax exerts a positive feedback on its own stability.

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HIV-1 trans-activator protein dysregulates IFN-γ signaling and contributes to the suppression of autophagy induction

Cited by 44 publications

References 51 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

HTLV-1 bZIP factor impairs cell-mediated immunity by suppressing production of Th1 cytokines

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

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HIV-1 trans-activator protein dysregulates IFN-γ signaling and contributes to the suppression of autophagy induction

Cited by 44 publications

References 51 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

HTLV-1 bZIP factor impairs cell-mediated immunity by suppressing production of Th1 cytokines

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

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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