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 1

Chronic HIV infection results in elevated expression of activation and exhaustion markers and exhaustion of viral-specific CD8 cells.

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Chronic HIV infection results in elevated expression of activation and e...
NSG-BLT humanized mice were constructed by implantation of fetal liver and fetal thymus as well as hematopoietic stem cells into the NSG mice. After human immune reconstitution, mice were mock-infected or infected with HIVNL4-3. Thirteen weeks after infection, whole blood from each mouse was collected, and cells were stained with anti-human antibodies CD45, CD3, CD4, CD8, TIM-3, PD-1, and HLA-DR and analyzed by flow cytometry. (A–D) Expression of HLA-DR, CD38, PD-1, and TIM-3 on human CD4 (A and B) and CD8 cells (C and D) was accessed by gating and by measurement of the percentage positive (A and C) and relative MFI (B and D) of marker expression (n = 3–5 mice per group and more than 1,000 events were acquired for each flow analysis). For relative MFI, data displayed are the mean relative MFI ± SEM of these markers as compared with the mean MFI of uninfected controls, showing differences between these populations. (E) Splenocytes from HIV-infected NSG mice were stimulated with mitogen for 6 hours with GolgiPlug and were stained for expression of CD8, TIM-3, PD-1, and intracellular expression of IL-2 and IFN-γ. More than 1,000 events were acquired for each flow analysis, and the experiment was repeated more than 3 times. (F) Summary and statistical analysis of the intracellular cytokine expression assay in E (n = 4–6 mice per group). The Mann-Whitney test was used to compare 2 groups (*P < 0.05, **P < 0.005) (A–E), and the Kruskal-Wallis test was used for multiple comparisons (F, P < 0.05). Data represent mean ± SEM.