Cyclophilin A Prevents HIV-1 Restriction in Lymphocytes by Blocking Human TRIM5α Binding to the Viral Core

Selyutina, Anastasia; Persaud, Mirjana; Simons, Lacy M.; Bulnes-Ramos, Ángel; Buffone, Cindy; Martínez‐López, Alicia; Scoca, Viviana; Nunzio, Francesca Di; Hiatt, Joseph; Marson, Alexander; Krogan, Nevan J.; Hultquist, Judd F.; Díaz-Griffero, Felipe

doi:10.1016/j.celrep.2020.02.100

Cited by 76 publications

(102 citation statements)

References 65 publications

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“…Our results showing a requirement for autophagy factors in activation of these same immune pathways in response to TRIM5 over-expression suggested that autophagy factors may also contribute to TRIM5-dependent signaling in response to retroviral capsid. For these studies, we used an HIV-1 mutant with a single amino acid substitution in the capsid protein (P90A) that was recently shown to be strongly restricted by human TRIM5 in primary immune cells [ 29 , 30 ]. Additionally, P90A was previously shown to activate innate immune signaling and interferon expression [ 31 ], but this activity was not connected to TRIM5.…”

Section: Resultsmentioning

confidence: 99%

“…The ability of TRIM5 to transduce antiviral signaling is dependent on its capacity to interact with the intact retroviral core; hence human TRIM5 is activated by N-MLV but not HIV-1. In this study, we showed that an HIV-1 capsid mutant that was recently demonstrated to be bound and restricted by human TRIM5 [ 29 , 30 ] could activate TRIM5-dependent signaling in macrophage-like cells. Importantly, the ability of this virus to stimulate the expression of the key antiviral cytokine interferon β was lost in autophagy-deficient cells, again demonstrating the importance of the autophagy machinery in TRIM5 signaling ( Fig 5 ).…”

Section: Discussionmentioning

confidence: 99%

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A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α

et al. 2020

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TRIM5α is a key cross-species barrier to retroviral infection, with certain TRIM5 alleles conferring increased risk of HIV-1 infection in humans. TRIM5α is best known as a species-specific restriction factor that directly inhibits the viral life cycle. Additionally, it is also a pattern-recognition receptor (PRR) that activates inflammatory signaling. How TRIM5α carries out its multi-faceted actions in antiviral defense remains incompletely understood. Here, we show that proteins required for autophagy, a cellular self-digestion pathway, play an important role in TRIM5α’s function as a PRR. Genetic depletion of proteins involved in all stages of the autophagy pathway prevented TRIM5α-driven expression of NF-κB and AP1 responsive genes. One of these genes is the preeminent antiviral cytokine interferon β (IFN-β), whose TRIM5-dependent expression was lost in cells lacking the autophagy proteins ATG7, BECN1, and ULK1. Moreover, we found that the ability of TRIM5α to stimulate IFN-β expression in response to recognition of a TRIM5α-restricted HIV-1 capsid mutant (P90A) was abrogated in cells lacking autophagy factors. Stimulation of human macrophage-like cells with the P90A virus protected them against subsequent infection with an otherwise resistant wild type HIV-1 in a manner requiring TRIM5α, BECN1, and ULK1. Mechanistically, TRIM5α was attenuated in its ability to activate the kinase TAK1 in autophagy deficient cells, and both BECN1 and ATG7 contributed to the assembly of TRIM5α-TAK1 complexes. These data demonstrate a non-canonical role for the autophagy machinery in assembling antiviral signaling complexes and in establishing a TRIM5α-dependent antiviral state.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α

et al. 2020

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“…This molecule inhibited HIV with the following CypA-capsid lack of interaction. This is another issue which requires further research in order to explain the role of cyclosporine in HIV infection [41]. The question about its possible role in HIV infection remains open, with some evidence pointing to the possible inhibitory effect of cyclosporine on HIV replication.…”

Section: Human Immunodeficiency Virusmentioning

confidence: 99%

“…Hepatitis C [15][16][17] Influenza virus infection [28] Rotavirus infection [29,30] Human Immunodeficiency Virus infection [26,33,34] Coronavirus infection [39][40][41][42][43] Hepatitis B [10][11][12][13][14] Hepatitis D [12,20] Herpes simplex infection [26,27] Herpes Zoster Virus infection [35,36] Hepatitis E [21] Cytomegalovirus infection [19,20,22] Human Papilloma Virus infection [29,30] Human Herpesvirus-8 (Kaposi Sarcoma virus) infection [42,43] The possible beneficial effect of cyclosporine on the course of COVID-19 seems very probable. Thus, it is not justified to suggest that patients with autoimmune diseases should discontinue cyclosporine therapy solely because of the COVID-19 pandemic.…”

Section: Possible Negative Effect Of Cyclosporine On Disease Coursementioning

confidence: 99%

The Antiviral Properties of Cyclosporine. Focus on Coronavirus, Hepatitis C Virus, Influenza Virus, and Human Immunodeficiency Virus Infections

Głowacka

Rudnicka

Warszawik-Hendzel

et al. 2020

Biology

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This review updates current knowledge regarding the risk of viral infections, including COVID-19, in patients treated with cyclosporine. We also shortly refer to bacterial infections and parasitic infestations in patients treated with cyclosporin. Cyclosporine is an immunosuppressive drug, which is widely used in medicine, including in the treatment of autoimmune skin diseases in dermatology, rheumatology, ophthalmology and nephrology, and in organ transplantation. A usual concern associated with immunosuppressive treatment is the potential risk of infections. Interestingly, several data indicate a relatively low risk of infections, especially viral infections, in patients receiving cyclosporine. It was shown that cyclosporine exerts an inhibitory effect on the replication of some viruses, or may have a potentially beneficial effect on the disease course in infections. These include hepatitis C, influenza virus, rotavirus, human immunodeficiency virus and coronavirus infections. Available data indicate that cyclosporine may have a beneficial effect on COVID-19, which is caused by the coronavirus SARS-COV2.

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“…Disruption of CypA–CA interactions by either treatment with cyclosporine or its analogues (e.g., Debio 025) or by mutation within CA (e.g., G89V or P90A) decreased HIV-1 infection, by affecting uncoating or reverse transcription in certain cell types [ 34 , 35 , 36 , 37 ]. CypA has also been recently found to protect HIV-1 from TRIM5α-mediated restriction in human primary cells [ 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

Daxx Inhibits HIV-1 Reverse Transcription and Uncoating in a SUMO-Dependent Manner

Maillet

Fernandez

Decourcelle

et al. 2020

Viruses

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Death domain-associated protein 6 (Daxx) is a multifunctional, ubiquitously expressed and highly conserved chaperone protein involved in numerous cellular processes, including apoptosis, transcriptional repression, and carcinogenesis. In 2015, we identified Daxx as an antiretroviral factor that interfered with HIV-1 replication by inhibiting the reverse transcription step. In the present study, we sought to unravel the molecular mechanism of Daxx-mediated restriction and, in particular, to identify the protein(s) that Daxx targets in order to achieve its antiviral activity. First, we show that the SUMO-interacting motif (SIM) located at the C-terminus of the protein is strictly required for Daxx to inhibit HIV-1 reverse transcription. By performing a quantitative proteomic screen combined with classical biochemical analyses, we found that Daxx associated with incoming HIV-1 cores through a SIM-dependent interaction with cyclophilin A (CypA) and capsid (CA). Daxx was found to reside within a multiprotein complex associated with viral capsids, also containing TNPO3, TRIM5α, and TRIM34. Given the well-known influence of these cellular factors on the stability of HIV-1 cores, we investigated the effect of Daxx on the cytoplasmic fate of incoming cores and found that Daxx prevented HIV-1 uncoating in a SIM-dependent manner. Altogether, our findings suggest that, by recruiting TNPO3, TRIM5α, and TRIM34 and possibly other proteins onto incoming HIV-1 cores through a SIM-dependent interaction with CA-bound CypA, Daxx increases their stability, thus preventing uncoating and reverse transcription. Our study uncovers a previously unknown function of Daxx in the early steps of HIV-1 infection and further illustrates how reverse transcription and uncoating are two tightly interdependent processes.

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Cyclophilin A Prevents HIV-1 Restriction in Lymphocytes by Blocking Human TRIM5α Binding to the Viral Core

Cited by 76 publications

References 65 publications

A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α

A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α

The Antiviral Properties of Cyclosporine. Focus on Coronavirus, Hepatitis C Virus, Influenza Virus, and Human Immunodeficiency Virus Infections

Daxx Inhibits HIV-1 Reverse Transcription and Uncoating in a SUMO-Dependent Manner

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