The mixed blessing of interferon

A study in monkeys finds that treatment with the protein interferon protects against simian immunodeficiency virus, but that prolonged interferon administration exacerbates the chronic stage of the infection. See Letter p.601

Soon after the identification of the AIDS epidemic in the early 1980s, many research groups reported on using interferon, a protein that triggers an antiviral response, to treat HIV-infected patients. However, an early review of the literature1 concluded that there was no evidence that interferon therapy exerted “any beneficial effect on the underlying immune defects” and that, in any case, many patients with advanced HIV-induced immunosuppression already exhibited elevated levels of interferon before its administration. But on page 601 of this issue, Sandler et al.2 report intriguing findings on interferons in HIV infection. They show that administering the interferon IFNα2a to rhesus macaques before exposure to simian immunodeficiency virus (SIV) prevented systemic viral infection, whereas treatment with an antagonist of the interferon receptor led to catastrophic infection. But they also find that prolonged exposure to interferon has a detrimental effect.

So what are the exact mediators of interferon that contribute to its beneficial effects in Sandler and colleagues' study? Triggering the interferon response induces the expression of several hundred genes3. The roles of many, if not most, interferon-stimulated proteins are unclear and little is known about their specificity. Some selectively target HIV and/or SIV, and these are generally referred to as restriction factors4. Such factors have protected humans from transmission of retroviruses from other species, but they failed to guard us against SIV from chimpanzees, and HIV is the result of this transmission. Unfortunately, HIV in humans and SIV strains in their natural hosts have developed mechanisms to evade these restriction factors. Thus, Sandler and colleagues' observed success with interferon administration probably results from other aspects of the interferon response, or from the actions of undescribed interferon-stimulated proteins that retain sufficient general or specific antiviral activity. These are not very satisfactory explanations when one considers that the goal is to understand human responses to a therapeutic strategy.

The finding that interferon treatment during SIV challenge increases host resistance to systemic infection reinforces previous data from studies in non-human primates, and places in perspective some existing data on interferon administration in humans (Fig. 1). In HIV-infected individuals5 and in individuals co-infected with hepatitis C virus6, use of interferon results in a modest decrease in HIV viral load in the blood. It was therefore a logical step for Sandler et al. to assess the effects of prolonged interferon administration during SIV infection. They observed that, despite the early beneficial effects, continued administration resulted in increased susceptibility to infection and greater depletion of CD4+ T cells (immune cells that are killed by SIV and HIV), and decreased expression of interferon-stimulated genes, compared to placebo.

Figure 1: Interferon in acute and chronic infection.

Sandler and colleagues' findings2 contribute to other evidence4,5,7,8,9,12 that there are strong parallels between the observed effects of experimentally administered interferon (IFN) on simian immunodeficiency virus (SIV) or HIV infections and the effects of endogenous IFN responses during natural SIV or HIV infections, at both the acute and chronic phases.

They describe this paradox as an interferon-desensitized state, and demonstrate that this is not the result of the animals developing neutralizing antibodies against the interferon. Interestingly, earlier studies had described a refractory state of cells to repeat interferon induction7. Furthermore, there is evidence8,9 that a persistent abnormal interferon response — elevated expression of interferon-stimulated genes — is linked to increased viral load and disease severity during the chronic phase of HIV infection. Thus, both continuous administration of interferon and persistent elevation of interferon-stimulated genes are associated with unfavourable outcomes in chronic HIV and SIV infection.

HIV is not thought to become resistant to interferon in chronic infection — in fact, recent data suggest the contrary10. Instead, there is increasing concern that when the host cannot clear an infection, continued interferon signalling leads to the induction of immunosuppressive pathways with the aim of limiting damage associated with chronic infection (reviewed in ref. 11). This concept resonates with the idea of 'tolerance', in which the host attempts to reduce the negative impact of an infection without directly affecting pathogen burden12. Tolerance is frequently observed in non-pathogenic SIV infections in natural hosts — animals may have a high viral load but there is minimal pathogenesis, and the interferon response normalizes after the initial stage of infection9. Unfortunately, in HIV infections the host rarely finds the sweet spot between viral load, disease and interferon: tolerance is rarely observed in humans13 and progressive immunosuppression almost always ensues.

Overall, there are strong parallels between the effects of deliberate interferon administration in experimental SIV infections and the outcome of endogenous interferon responses in natural HIV and SIV infection (Fig. 1). Sandler and colleagues' research highlights the importance of the timing and duration of interferon administration, but also underscores the difficulty of understanding the exact potential of intervening in the interferon signalling pathways during infection.

The interferon response, and more broadly, the innate immune response, remains a field of unknowns14. Challenges include identifying the exact set of effector molecules, their roles at portals of entry of pathogens and their individual actions in acute and chronic disease. Thus, deconvoluting the interferon response is needed if the aim is to better use this pathway for therapeutic purposes. The complex antiviral response to this protein can be summarized by the Cantonese expression 'equipped with knives all over, yet none is sharp' — a fitting metaphor for the failure of interferon to cut cleanly through HIV infections.


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Telenti, A. The mixed blessing of interferon. Nature 511, 537–538 (2014).

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