Editors' ChoiceHIV/AIDS

Interfering with HIV therapy

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Science Translational Medicine  04 Jan 2017:
Vol. 9, Issue 371, eaal4987
DOI: 10.1126/scitranslmed.aal4987


Type 1 interferon signaling promotes HIV persistence even during combined antiretroviral therapy.

Type 1 interferons (IFN-1) are rapidly produced in response to viral infection and act as a first line of defense. When IFN-1 is chronically expressed, however, it can conversely cause immune dysfunction, leading to enhanced viral replication and persistence. Chronic expression of IFN-I and the genes they stimulate is observed in HIV patients, even following reduction of infectious virus by combined antiretroviral therapy (cART). Those patients with highest levels of IFN-1 and IFN-stimulated genes experience higher viral loads, more immune dysfunction, and accelerated disease progression. In back to back publications, Cheng et al. and Zhen et al. interrogate the link between IFN-1, antiviral immunity, and viral clearance. The authors demonstrate that smoldering IFN-1 signaling during chronic HIV infection interferes with antiviral immunity and prevents complete viral clearance, even during cART.

In order to study the role of IFN-1 during chronic HIV infection both studies used humanized mouse models, in which human immune cells are engrafted into immunodeficient mice, allowing for infection with human-specific viruses. In chronically infected mice, persistent expression of IFN-1 and IFN-1–stimulated genes was observed, even in the presence of cART. Both groups described immune dysfunction in their models, characterized by reduced numbers of immune cells, lymphocyte hyperactivation, and expression of exhaustion markers. Treatment with cART reduced viral load and rescued immune cell number but failed to reduce the hyperactivated and exhausted immune phenotype. Conversely, blockade of the IFN-1 receptor, IFNAR1, both on its own and in combination with cART, reduced IFN-1 stimulated genes, reversed lymphocyte exhaustion, increased cytokine production, and resulted in decreased viral load. Interestingly, as a result of the altered immunity induced by IFN-1 blockade, rebounding virus after cessation of cART was delayed, indicating reduction of persistent viral reservoirs. Taken together, these studies elucidate the negative impact of sustained IFN-1 during HIV infection and indicate that combined use of IFN-1 blocking strategies with cART may present a novel strategy for treatment chronic HIV infection.

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