Letter | Published:

Stimulating the RIG-I pathway to kill cells in the latent HIV reservoir following viral reactivation

Nature Medicine volume 22, pages 807811 (2016) | Download Citation

Abstract

The persistence of latent HIV proviruses in long-lived CD4+ T cells despite antiretroviral therapy (ART)1,2,3 is a major obstacle to viral eradication4,5,6. Because current candidate latency-reversing agents (LRAs) induce HIV transcription, but fail to clear these cellular reservoirs7,8, new approaches for killing these reactivated latent HIV reservoir cells are urgently needed. HIV latency depends upon the transcriptional quiescence of the integrated provirus and the circumvention of immune defense mechanisms4,5,6,9. These defenses include cell-intrinsic innate responses that use pattern-recognition receptors (PRRs) to detect viral pathogens, and that subsequently induce apoptosis of the infected cell10. Retinoic acid (RA)-inducible gene I (RIG-I, encoded by DDX58) forms one class of PRRs that mediates apoptosis and the elimination of infected cells after recognition of viral RNA11,12,13,14. Here we show that acitretin, an RA derivative approved by the US Food and Drug Administration (FDA), enhances RIG-I signaling ex vivo, increases HIV transcription, and induces preferential apoptosis of HIV-infected cells. These effects are abrogated by DDX58 knockdown. Acitretin also decreases proviral DNA levels in CD4+ T cells from HIV-positive subjects on suppressive ART, an effect that is amplified when combined with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. Pharmacological enhancement of an innate cellular-defense network could provide a means by which to eliminate reactivated cells in the latent HIV reservoir.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 1291–1295 (1997).

  2. 2.

    et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997).

  3. 3.

    et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA 94, 13193–13197 (1997).

  4. 4.

    , & The end of AIDS: HIV infection as a chronic disease. Lancet 382, 1525–1533 (2013).

  5. 5.

    & HIV cure research: advances and prospects. Virology 454–455, 340–352 (2014).

  6. 6.

    & An integrated overview of HIV-1 latency. Cell 155, 519–529 (2013).

  7. 7.

    et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 487, 482–485 (2012).

  8. 8.

    et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517, 381–385 (2015).

  9. 9.

    , , & Altering cell death pathways as an approach to cure HIV infection. Cell Death Dis. 4, e718 (2013).

  10. 10.

    & RIG-I in RNA virus recognition. Virology 479–480, 110–121 (2015).

  11. 11.

    , , & Cloning and characterization of a novel retinoid-inducible gene 1 (RIG1) deriving from human gastric cancer cells. Mol. Cell. Endocrinol. 159, 15–24 (2000).

  12. 12.

    et al. Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′ diphosphates. Nature 514, 372–375 (2014).

  13. 13.

    et al. Viral apoptosis is induced by IRF-3-mediated activation of BAX. EMBO J. 29, 1762–1773 (2010).

  14. 14.

    & Newly described pattern recognition receptors team up against intracellular pathogens. Nat. Rev. Immunol. 13, 551–565 (2013).

  15. 15.

    Master sensors of pathogenic RNA—RIG-I like receptors. Immunobiology 218, 1322–1335 (2013).

  16. 16.

    et al. Genomic HIV RNA induces innate immune responses through RIG-I-dependent sensing of secondary-structured RNA. PLoS One 7, e29291 (2012).

  17. 17.

    , , , & RIG-I activation inhibits HIV replication in macrophages. J. Leukoc. Biol. 94, 337–341 (2013).

  18. 18.

    et al. RIG-I-mediated antiviral signaling is inhibited in HIV-1 infection by a protease-mediated sequestration of RIG-I. J. Virol. 85, 1224–1236 (2011).

  19. 19.

    , , , & Human immunodeficiency virus type 1 mediates global disruption of innate antiviral signaling and immune defenses within infected cells. J. Virol. 83, 10395–10405 (2009).

  20. 20.

    et al. Expression levels of the innate response gene RIG-I and its regulators RNF125 and TRIM25 in HIV-1-infected adult and pediatric individuals. AIDS 27, 1879–1885 (2013).

  21. 21.

    , , , & Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Mol. Aspects Med. 33, 63–76 (2012).

  22. 22.

    & Modulation of T cell and innate immune responses by retinoic acid. J. Immunol. 192, 2953–2958 (2014).

  23. 23.

    et al. CBP–p300 induction is required for retinoic acid sensitivity in human mammary cells. Biochem. Biophys. Res. Commun. 302, 841–848 (2003).

  24. 24.

    et al. Distinct roles of the co-activators p300 and CBP in retinoic-acid-induced F9 cell differentiation. Nature 393, 284–289 (1998).

  25. 25.

    , & Acitretin. Dermatol. Ther. 26, 390–399 (2013).

  26. 26.

    , , & Acitretin therapy is effective for psoriasis associated with human immunodeficiency virus infection. Arch. Dermatol. 133, 711–715 (1997).

  27. 27.

    et al. Monokine regulation of human immunodeficiency virus–1 expression in a chronically infected human T cell clone. J. Immunol. 142, 431–438 (1989).

  28. 28.

    et al. Curcumin is an inhibitor of p300 histone acetyltransferase. Med. Chem. 2, 169–174 (2006).

  29. 29.

    , , , & A flexible model of HIV-1 latency permitting evaluation of many primary CD4 T cell reservoirs. PLoS One 7, e30176 (2012).

  30. 30.

    et al. Directly infected resting CD4+ T cells can produce HIV Gag without spreading infection in a model of HIV latency. PLoS Pathog. 8, e1002818 (2012).

  31. 31.

    , , , & New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat. Med. 20, 425–429 (2014).

  32. 32.

    , , , & Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I. Nature 509, 110–114 (2014).

  33. 33.

    et al. IPS-1, an adaptor triggering RIG-I- and MDA5-mediated type I interferon induction. Nat. Immunol. 6, 981–988 (2005).

  34. 34.

    et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730–737 (2004).

  35. 35.

    et al. Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J. Virol. 79, 2689–2699 (2005).

  36. 36.

    , , , & EB virus–encoded RNAs are recognized by RIG-I and activate signaling to induce type I IFN. EMBO J. 25, 4207–4214 (2006).

  37. 37.

    Exposing viruses: RNA patterns sensed by RIG-I-like receptors. J. Clin. Immunol. 30, 491–495 (2010).

  38. 38.

    et al. Molecular imprinting as a signal-activation mechanism of the viral RNA sensor RIG-I. Mol. Cell 55, 511–523 (2014).

  39. 39.

    et al. Bax-inhibiting peptide derived from mouse and rat Ku70. Biochem. Biophys. Res. Commun. 321, 961–966 (2004).

  40. 40.

    & Pharmacokinetics of acitretin and etretinate. J. Am. Acad. Dermatol. 39, S25–S33 (1998).

Download references

Acknowledgements

We thank the study participants, without whom this research could not have been performed. We thank S. Deeks, H. Gunthard, C. Lopez, and H. Hatano for their helpful comments and support, and M. Vu for assistance with participant recruitment. We thank J.C.W. Carroll for graphics arts, S. Ordway for editorial assistance, and S. Wilcox for administrative assistance. We thank the US National Institutes of Health (NIH) AIDS Reagent Program, Division of AIDS, NIAID, NIH for cell lines, plasmid, and reagents. This work was supported by the NIH (grants 1R21AI104445-01A1 (P.L.), R56 AI116342 and R21 AI116218 (J.K.W.)), the Department of Veterans Affairs Merit Review Award 5101 BX001048 (J.K.W.), the UCSF–Gladstone Center for AIDS Research Virology Core P30AI027763 (W.C.G. and J.K.W.), U19 AI096113 (W.C.G.) and research supported as part of the amfAR Institute for HIV Cure Research with grant number 109301(W.G., J.K.W., and P.L.).

Author information

Affiliations

  1. Infectious Diseases Section, Medical Service, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA.

    • Peilin Li
    • , Philipp Kaiser
    • , Harry W Lampiris
    • , Peggy Kim
    • , Steven A Yukl
    •  & Joseph K Wong
  2. Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Peilin Li
    • , Harry W Lampiris
    • , Steven A Yukl
    • , Diane V Havlir
    • , Warner C Greene
    •  & Joseph K Wong
  3. HIV/AIDS Division, San Francisco General Hospital, San Francisco, California, USA.

    • Diane V Havlir
  4. Department of Microbiology and Biology, University of California, San Francisco, San Francisco, California, USA.

    • Warner C Greene
  5. Gladstone Institute of Virology and Immunology, San Francisco, California, USA.

    • Warner C Greene

Authors

  1. Search for Peilin Li in:

  2. Search for Philipp Kaiser in:

  3. Search for Harry W Lampiris in:

  4. Search for Peggy Kim in:

  5. Search for Steven A Yukl in:

  6. Search for Diane V Havlir in:

  7. Search for Warner C Greene in:

  8. Search for Joseph K Wong in:

Contributions

P.L. contributed to designing the research, performing the experiments, interpreting the data, and writing the paper. P. Kaiser assisted with experiments and contributed to interpreting the data and writing the paper. H.W.L. contributed to recruiting subjects with HIV for the study. P. Kim and S.A.Y. assisted with experiments. D.V.H. and W.C.G. provided key suggestions and contributed to interpreting the data. W.C.G. also contributed to writing the paper. J.K.W. contributed to recruiting subjects with HIV for the study, interpreting the data, and writing the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Peilin Li.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4 and Supplementary Table 1

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm.4124

Further reading