Opinion
Self-DNA Sensing Fuels HIV-1-Associated Inflammation

https://doi.org/10.1016/j.molmed.2019.06.004Get rights and content

Highlights

  • Stressed or dying cells release immunogenic self-DNA. Cytoplasmic self-DNA and its exchange among cells primes innate immunity and circulating DNA can trigger systemic inflammation and autoimmune diseases.

  • HIV-1 primes DNA-sensing, favours DNA damage, and triggers bystander cell pyroptosis and the subsequent release of cellular content, including self-DNA and other DAMPs.

  • Extracellular self-DNA gains immunogenic properties when bound to DAMPs.

  • Self-DNA might not only trigger inflammatory feedforward-loops in HIV-1-infected individuals but also open up avenues for optimizing shock and kill strategies for HIV elimination.

Inflammation, over-reacting innate immunity, and CD4+ T cell depletion are hallmarks of HIV-1 infection. Self-DNA is usually not considered in the context of HIV-1-associated inflammation, although self-DNA contributes to inflammation in diverse pathologies, including autoimmune diseases, cancer, multiorgan failure after trauma, and even virus infections. Cells undergoing HIV-1-associated pyroptotic bystander cell death release self-DNA and other damage-associated molecular patterns (DAMPs), including chaperones and histones. In complexes with such DAMPs or extracellular vesicles, self-DNA gains immunogenic potential and becomes accessible to intracellular DNA sensors. Therefore, we hypothesize that self-DNA can contribute to HIV-1-associated inflammation. Self-DNA might not only drive HIV-1-associated ‘inflamm-ageing’ but also provide new opportunities for ‘shock and kill’ strategies aimed at eliminating latent HIV-1.

Section snippets

Detecting Infection: Sensing the Non-Self and ‘Damaged Self’

Successful immunity requires the recognition of the ‘infectious non-self’ [1] and of the damaged self 2, 3. To detect infecting bacteria or fungi, pattern recognition receptors (PRRs, see Glossary) sense microbial molecules such as flagellin or chitin as pathogen-associated molecular patterns (PAMPs). By contrast, detecting viruses mainly depends on the sensing of viral nucleic acids and the subsequent type I interferon (IFN) response: the induction of hundreds of chemokines, cytokines, and

HIV-1, Pyroptosis, and Inflammation

Independent of the original site of entry, the infection of gut-associated lymphatic tissue (GALT) with HIV-1 is a crucial step (Figure 2). GALT harbours the largest population of activated memory CD4+ T cells and, therefore, serves as the first site of massive HIV-1 replication 27, 28, 29. In human tonsil- or spleen-derived lymphoid cell cultures that were exposed to HIV-1, over 95% of the dying cells were not productively infected, indicating that CD4+ T cell depletion is mainly due to

DNA Sensing Triggers Immunity to Virus Infection

Research into the sensing of dsDNA has been performed mainly within the general framework of virus infection, but experimental evidence is frequently generated using repetitive synthetic dsDNA sequences such as poly (dA:dT). Therefore, if not specified otherwise, in the following subchapter we do not distinguish between DNA from different sources.

Hypothesis: Self-DNA Contributes to HIV-1-Associated Inflammation

Here, we hypothesise that self-DNA can contribute to HIV-1-associated inflammation. This hypothesis is based on five main lines of evidence: (i) PRRs that sense self- and microbial DNA converge in shared signalling hubs and trigger the type I IFN response; (ii) immune cells from HIV-1-infected individuals exhibit primed DNA-sensing pathways; (iii) HIV-1 triggers DNA damage; (iv) in complexes with DAMPs or extracellular vesicles dsDNA gains immunogenic properties; and (v) HIV-1-infected

Immunogenic Self-DNA in HIV-1 Infection

The studies reviewed here differed in pathological contexts and experimental systems, but all identified self-DNA as an agonist of mammalian DNA sensors (Table 1). Nucleic acid binding polymers were suggested as scavengers that capture circulating mtDNA and nDNA, thereby, preventing their proinflammatory effects in the therapy of cancer, lupus erythematosus, or multiorgan failure following severe trauma 8, 53. For example, in male rats subjected to severe trauma and haemorrhagic shock, an

Concluding Remarks

Self-DNA triggers a dosage-dependent type I IFN response, HIV-1 infection primes the DNA sensing machinery – including inflammasomes – in a dose-dependent manner, and caspase-1 drives gasdermin D-dependent pyroptosis. We conclude that HIV-1 infection generates an environment in which all prerequisites for a proinflammatory role of self-DNA are fulfilled. Any proinflammatory factor that is released during pyroptosis can affect many surrounding cells, including those which have not been in

Acknowledgements

We gratefully acknowledge Hélène C F Côté for performing additional evaluations of published data (ref. [75]), Enrique Hurtado Bautista for help with the artwork, and Claudia Willmes for her tremendous patience and ongoing support during the revision process. We thank Mariana Esther Martínez-Sánchez, Claudia Willmes, Jacques Deguine, and eight anonymous referees for multiple constructive comments on earlier versions of the manuscript and Caroline Woods for revising the English. M.H. is funded

Glossary

Antigen-presenting cells (APCs)
most mammalian cells are capable of antigen presentation, but only professional APCs such as DCs, monocytes, and macrophages can activate T cells.
CD4+ T cells
CD4 cooperates with the MHC II receptor for antigen recognition but also serves as docking point for HIV-1.
Damage-associated molecular patterns (DAMPs)
molecules of host origin – or their fragments – that signal danger when they appear in aberrant compartments.
Dendritic cells (DCs)
innate immune cells that

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