The interferon-induced antiviral protein PML (TRIM19) promotes the restriction and transcriptional silencing of lentiviruses in a context-specific, isoform-specific fashion

Abstract

BackgroundThe promyelocytic leukemia (PML) protein, a type I interferon (IFN-I)-induced gene product and a member of the tripartite motif (TRIM) family, modulates the transcriptional activity of viruses belonging to various families. Whether PML has an impact on the replication of HIV-1 has not been fully addressed, but recent studies point to its possible involvement in the restriction of HIV-1 in human cells and in the maintenance of transcriptional latency in human cell lines in which HIV-1 is constitutively repressed. We investigated further the restriction of HIV-1 and a related lentivirus, SIVmac, by PML in murine cells and in a lymphocytic human cell line. In particular, we studied the relevance of PML to IFN-I-mediated inhibition and the role of individual human isoforms.ResultsWe demonstrate that both human PML (hPML) and murine PML (mPML) inhibit the early post-entry stages of the replication of HIV-1 and a related lentivirus, SIVmac. In addition, HIV-1 was transcriptionally silenced by mPML and by hPML isoforms I, II, IV and VI in MEFs. This PML-mediated transcriptional repression was attenuated in presence of the histone deacetylase inhibitor SAHA. In contrast, depletion of PML had no effect on HIV-1 gene expression in a human T cell line. PML was found to contribute to the inhibition of HIV-1 by IFN-I. Specifically, IFN-α and IFN-β treatments of MEFs enhanced the PML-dependent inhibition of HIV-1 early replication stages.ConclusionsWe show that PML can inhibit HIV-1 and other lentiviruses as part of the IFN-I-mediated response. The restriction takes place at two distinct steps, i.e. reverse transcription and transcription, and in an isoform-specific, cellular context-specific fashion. Our results support a model in which PML activates innate immune antilentiviral effectors. These data are relevant to the development of latency reversal-inducing pharmacological agents, since PML was previously proposed as a pharmacological target for such inhibitors. This study also has implications for the development of murine models of HIV-1.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0253-1) contains supplementary material, which is available to authorized users.

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

“…Interestingly, TRIM22 was found to interact with HDAC, a repressor of HIV-1 viral transcription, and this interaction was necessary for continual proviral suppression [144]. Both human and murine TRIM19 are capable of preventing HIV-1 replication by downregulating expression of the viral LTR [145,146]. This effect holds true for several isoforms of TRIM19, including I, II, IV and VI, which can be enhanced further by IFN-I stimulation [145].…”

Gene Knockout Shows That PML (TRIM19) Does Not Restrict the Early Stages of HIV-1 Infection in Human Cell Lines

“…In addition, PML inhibits HIV-1 transcription in MEFs, an effect that we did not observe in human cells (32). Thus, it is conceivable for PML to have an impact on TRIM5α-mediated restriction of HIV-1 in this specific cellular environment.…”

“…Accordingly, we previously showed that PML was important for the efficient inhibition of HIV-1 by IFN-I in MEFs (32). Although HIV-1 is also readily inhibited by IFN-I in a variety of human cell types, as illustrated in our study, we find that this effect is not affected by knocking out PML.…”

“…Retroviral vectors were prepared by cotransfection of HEK293T cells with pMIP-m(h)PMLs together with pMD-G and pCL-Eco, using polyethylenimine (PEI; Polysciences, Niles, IL) as detailed previously (32). Virus-containing supernatants were collected 2 days later, clarified by low-speed centrifugation, and kept at −80°C.…”

Tripartite motif‐containing proteins precisely and positively affect host antiviral immune response

“…A previous study showed that after herpes simplex virus (HSV) infection, the viral genomes rapidly become associated with PML‐BNs . There is another study indicated that PML downregulates the expression of the HIV‐1 LTR‐driven GFP and confers on the MEFs a restriction to HIV‐1 by affecting the reverse transcription and interfering with HIV‐1 transcription, whereas PML depletion renders human T cells susceptible to HIV‐1 and SIV . Daxx could interfere with reverse transcription and inhibit retroviral infection.…”