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Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection
Liang Cheng, … , Liguo Zhang, Lishan Su
Liang Cheng, … , Liguo Zhang, Lishan Su
Published June 15, 2017
Citation Information: JCI Insight. 2017;2(12):e94366. https://doi.org/10.1172/jci.insight.94366.
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Research Article AIDS/HIV

Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection

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Abstract

The direct link between sustained type I interferon (IFN-I) signaling and HIV-1–induced immunopathogenesis during chronic infection remains unclear. Here we report studies using a monoclonal antibody to block IFN-α/β receptor 1 (IFNAR1) signaling during persistent HIV-1 infection in humanized mice (hu-mice). We discovered that, during chronic HIV-1 infection, IFNAR blockade increased viral replication, which was correlated with elevated T cell activation. Thus, IFN-Is suppress HIV-1 replication during the chronic phase but are not essential for HIV-1–induced aberrant immune activation. Surprisingly, IFNAR blockade rescued both total human T cell and HIV-specific T cell numbers despite elevated HIV-1 replication and immune activation. We showed that IFNAR blockade reduced HIV-1–induced apoptosis of CD4+ T cells. Importantly, IFNAR blockade also rescued the function of human T cells, including HIV-1–specific CD8+ and CD4+ T cells. We conclude that during persistent HIV-1 infection, IFN-Is suppress HIV-1 replication, but contribute to depletion and dysfunction of T cells.

Authors

Liang Cheng, Haisheng Yu, Guangming Li, Feng Li, Jianping Ma, Jingyun Li, Liqun Chi, Liguo Zhang, Lishan Su

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Figure 1

Persistent HIV-1 infection in humanized mice leads to sustained and systemic type I IFN expression and IFN-stimulated gene induction.

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Persistent HIV-1 infection in humanized mice leads to sustained and syst...
Humanized mice were infected with HIV-1. (A) Plasma HIV-1 genomic RNA levels at indicated time points. (B) Human IFN-α (pan IFN-α) levels in plasma at indicated time points and IFN-β levels in plasma at 10.5 weeks post infection (wpi). (C) Relative mRNA levels of Mx2, IFITM3, Trim22, ISG15, OAS1, MxA, and IRF7 in peripheral blood mononuclear cells at indicated time points. (D) The relative mRNA levels of Mx2, IFITM3, Trim22, ISG15, OAS1, MxA, and IRF7 in spleens at termination (10.5 wpi). Shown are representative data (mock, n = 4; HIV-1, n = 5) of 4 independent experiments (mock, n = 12; HIV-1, n = 18 in total) with mean values ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. Unpaired, 2-tailed Student’s t test was performed to compare between groups at singular time points (B and C) or between 2 groups (D).

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