Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection
Liang Cheng, Haisheng Yu, Guangming Li, Feng Li, Jianping Ma, Jingyun Li, Liqun Chi, Liguo Zhang, Lishan Su
Liang Cheng, Haisheng Yu, Guangming Li, Feng Li, Jianping Ma, Jingyun Li, Liqun Chi, Liguo Zhang, Lishan Su
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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

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 3

IFNAR1 blockade during persistent HIV-1 infection enhances viral replication in humanized mice.

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IFNAR1 blockade during persistent HIV-1 infection enhances viral replica...
Humanized mice infected with HIV-1 were treated from 6 to 10 weeks postinfection (wpi) with a mAb against IFN-α/β receptor 1 (IFNAR1) or isotype control (mouse IgG2a) twice per week. (A) Relative mRNA levels of human interferon-stimulated genes including Mx2, IFITM3, TRIM22, and IRF7 in peripheral blood mononuclear cells at 9 wpi. (B) Plasma HIV-1 RNA levels at indicated time points after HIV-1 infection. (C) Human IFN-α levels in the plasma after HIV-1 infection. Shown (A–C) are representative data (mock, n = 3; HIV-1 + mIgG2a, n = 5; HIV-1 + anti-IFNAR1, n = 5 ) of 3 independent experiments (mock, n = 7; HIV-1 + mIgG2a, n = 11; HIV-1 + anti-IFNAR1, n = 12 in total) with mean values ± SEM. (D) Relative mRNA levels of human Mx2, IFITM3, TRIM22, and IRF7 in splenocytes at 10 wpi. (E) Representative FACS plots and summarized data show the percentages of HIV-1 p24–positive CD4+ T cells (CD3+CD8–) in the spleen at 10 wpi. Shown (D and E) are combined data of 2 independent experiments (mock, n = 6; HIV-1 + mIgG2a, n = 9; HIV-1 + anti-IFNAR1, n = 9) with mean values ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. One-way ANOVA and Bonferroni’s post hoc test were performed to compare between groups at singular time points (B and C) or between groups (A, D, and E).