Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs
Liang Cheng, … , Lishan Su, Liguo Zhang
Liang Cheng, … , Lishan Su, Liguo Zhang
Published January 3, 2017; First published December 12, 2016
Citation Information: J Clin Invest. 2017;127(1):269-279. https://doi.org/10.1172/JCI90745.
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Categories: Research Article AIDS/HIV

Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs

Abstract

Despite the efficient suppression of HIV-1 replication that can be achieved with combined antiretroviral therapy (cART), low levels of type I interferon (IFN-I) signaling persist in some individuals. This sustained signaling may impede immune recovery and foster viral persistence. Here we report studies using a monoclonal antibody to block IFN-α/β receptor (IFNAR) signaling in humanized mice (hu-mice) that were persistently infected with HIV-1. We discovered that effective cART restored the number of human immune cells in HIV-1–infected hu-mice but did not rescue their immune hyperactivation and dysfunction. IFNAR blockade fully reversed HIV-1–induced immune hyperactivation and rescued anti–HIV-1 immune responses in T cells from HIV-1–infected hu-mice. Finally, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1 reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1–infected hu-mice. We conclude that low levels of IFN-I signaling contribute to HIV-1–associated immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a potential strategy to enhance immune recovery and reduce HIV-1 reservoirs in individuals with sustained elevations in IFN-I signaling during suppressive cART.

Authors

Liang Cheng, Jianping Ma, Jingyun Li, Dan Li, Guangming Li, Feng Li, Qing Zhang, Haisheng Yu, Fumihiko Yasui, Chaobaihui Ye, Li-Chung Tsao, Zhiyuan Hu, Lishan Su, Liguo Zhang

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Figure 1

cART efficiently inhibits HIV-1 replication but fails to reverse inflammation and clear HIV-1 reservoirs in hu-mice.

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cART efficiently inhibits HIV-1 replication but fails to reverse inflamm...
(A and B) Hu-mice infected with HIV-1 were treated with cART from 4.5 to 11.5 weeks postinfection (wpi). (A) HIV-1 RNA levels in the plasma of HIV-1–infected (n = 3) and HIV-1–infected, cART-treated mice (n = 7) at indicated time points. (B) Percentage of p24+ CD4 T cells was determined by FACS. Shown are representative data of 3 independent experiments (mock, n = 9; HIV-1, n = 9; HIV-1+cART, n = 15 in total) from n = 4 (mock), n = 3 (HIV-1), or n = 7 (HIV-1+cART) hu-mice per group. (C) Hu-mice infected with HIV-1 were treated with cART from 4 to 10 wpi. Relative mRNA levels of OAS1 and IRF7 in PBMCs are shown at indicated time points. Unpaired, 2-tailed Student’s t test was performed to compare between mock and HIV-1+cART group at each single time point. *P < 0.05, **P < 0.01. Shown are combined data from 2 independent experiments with mean values ± SEM (mock, n = 7; HIV-1, n = 7; HIV-1+cART, n = 8). (D) Cell-associated HIV-1 DNA and relative level of cell-associated HIV-1 RNA to human CD4 mRNA in human cells from spleen were quantified by PCR. (E) Replication-competent HIV-1 viruses from spleen were detected by the quantitative virus outgrowth assay. Shown are representative data (D and E) from n = 4 (mock), n = 4 (HIV-1), and n = 4 (HIV-1+cART) hu-mice per group of 2 independent experiments. ***P < 0.001. One-way ANOVA and Bonferroni’s post hoc test was performed. (F) Hu-mice infected with HIV-1 were treated with cART from 4 to 10 wpi. cART was discontinued at week 10. HIV-1 RNA levels in the plasma of each mouse are shown. The broken horizontal line in F indicates the limit of detection of the assay.