Targeting type I interferon–mediated activation restores immune function in chronic HIV infection
Anjie Zhen, … , David G. Brooks, Scott G. Kitchen
Anjie Zhen, … , David G. Brooks, Scott G. Kitchen
Published December 12, 2016
Citation Information: J Clin Invest. 2017;127(1):260-268. https://doi.org/10.1172/JCI89488.
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Research Article AIDS/HIV Immunology

Targeting type I interferon–mediated activation restores immune function in chronic HIV infection

Abstract

Chronic immune activation, immunosuppression, and T cell exhaustion are hallmarks of HIV infection, yet the mechanisms driving these processes are unclear. Chronic activation can be a driving force in immune exhaustion, and type I interferons (IFN-I) are emerging as critical components underlying ongoing activation in HIV infection. Here, we have tested the effect of blocking IFN-I signaling on T cell responses and virus replication in a murine model of chronic HIV infection. Using HIV-infected humanized mice, we demonstrated that in vivo blockade of IFN-I signaling during chronic HIV infection diminished HIV-driven immune activation, decreased T cell exhaustion marker expression, restored HIV-specific CD8 T cell function, and led to decreased viral replication. Antiretroviral therapy (ART) in combination with IFN-I blockade accelerated viral suppression, further decreased viral loads, and reduced the persistently infected HIV reservoir compared with ART treatment alone. Our data suggest that blocking IFN-I signaling in conjunction with ART treatment can restore immune function and may reduce viral reservoirs during chronic HIV infection, providing validation for IFN-I blockade as a potential therapy for HIV infection.

Authors

Anjie Zhen, Valerie Rezek, Cindy Youn, Brianna Lam, Nelson Chang, Jonathan Rick, Mayra Carrillo, Heather Martin, Saro Kasparian, Philip Syed, Nicholas Rice, David G. Brooks, Scott G. Kitchen

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Figure 4

IFNR blockade treatment reduces viral load, and combination of ART and IFNR blockade promotes faster viral suppression and reduces viral reservoir.

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IFNR blockade treatment reduces viral load, and combination of ART and I...
(A) Changes of plasma viral load before and after isotype treatment or IFNR blockade. (B) MX1 and OAS1 expression levels from PBMCs in infected mice in different treatment groups as measured by real-time RT-PCR (n = 5–11 per group). (C) Relative TIM-3 expression level of CD8+ T cells in PBMCs from infected mice in different treatment groups as compared with uninfected mice (n = 5–11 per group). (D) Relative IFN-γ MFI of PMA/ionomycin–stimulated CD8+ T cells from infected mice in different treatment groups as compared with uninfected mice (n = 5–11 per group). (E) Changes of viral loads in HIV-1–infected NSG-BLT mice that were treated with ART or ART plus IFNR blockade (n = 7–10 per group). (F) Fold viral suppression after ART treatment, ART with IFNR blockade, or IFNR blockade alone (n = 7–10 per group). (G) HIV p24 production in the supernatant (as measured by ELISA collected from stimulated, sorted HSA– cells following the indicated treatments; n = 4–9 per group). The Mann-Whitney U test was used to compare 2 groups (*P < 0.05, **P < 0.005), and the Kruskal-Wallis test was used for multiple comparisons (B–D, F, and G; all have P < 0.05). Data represent mean ± SEM.