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

Nature Medicine volume 22, pages 807–811 (2016)Cite this article

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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.

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Figure 1: Acitretin induces HIV expression and reduces cellular HIV DNA in CD4+ T cells.
Figure 2: Acitretin preferentially induces apoptosis in HIV-infected cells.
Figure 3: Acitretin increases the expression of RIG-I-signaling-pathway proteins, including MAVS, IRF3, phosphorylated IRF3 (p-IRF3), and BAX, and increases the production of IFN-β and CXCL10 in cells infected with HIV.
Figure 4: shRNA knockdown of RIG-I expression markedly inhibits acitretin enhancement of apoptosis, induction of IFN-β and CXCL10 production and preferential depletion of HIV-DNA+ cells.

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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.).

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Authors and 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

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  1. Peilin Li
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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.

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Correspondence to Peilin Li.

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Li, P., Kaiser, P., Lampiris, H. et al. Stimulating the RIG-I pathway to kill cells in the latent HIV reservoir following viral reactivation. Nat Med 22, 807–811 (2016). https://doi.org/10.1038/nm.4124

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