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 6

IFNAR1 blockade or inhibition of caspase-3 activity rescues CD4+ T cells from HIV-1–induced depletion.

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IFNAR1 blockade or inhibition of caspase-3 activity rescues CD4+ T cells...
(A) Humanized mice infected with HIV-1 were treated with a mAb against IFN-α/β receptor 1 (IFNAR1) or isotype control (mouse IgG2a) twice per week from 6 to 10 weeks postinfection (wpi). Mice were sacrificed at 10 wpi. Representative dot plots and summarized data (mock, n = 6; HIV-1 + mIgG2a, n = 9; HIV-1 + anti-IFNAR1, n = 9, combined data from 2 independent experiments with mean values ± SEM) show the percentage splenic CD4+ T cells expressing active caspase-3. (B–E) Splenocytes from mock (n = 2) or HIV-1–infected (n = 4) humanized mice were cultured with IL-2 (20 U/ml) in vitro in the presence of control mIgG2a (10 μg/ml), anti-IFNAR1 (10 μg/ml) or IFN-α (200 U/ml) for 10 days. At day 10, the cells were counted and used for analysis. (B) HIV-1 RNA levels in culture supernatant. (C and D) Representative dot plots (C) and summarized data (D) show the percentages of CD4+ T cells with active caspase-3. (E) Number of live CD4+ T cells in each group. (F–I) Splenocytes from mock (n = 2) or HIV-1–infected (n = 4) humanized mice were cultured with IL-2 in vitro in the presence of DMSO or caspase-3 inhibitor Z-DEVD-FMK or caspase-1 inhibitor Ac-YVAD-CMK for 10 days. At day 10, the cells were counted and used for staining. (F and G) Representative dot plots (F) and summarized data (G) show the percentages of active-caspase-3+ CD4+ T cells. (H and I) Number of live CD4+ T cells in each group. Data are representative of 2 independent experiments with mean values ± SEM). *P < 0.05, **P < 0.01 by unpaired, 2-tailed Student’s t test to compare differences between 2 groups. ns, not significant.