Journal Article

Arsenic Trioxide Impacts Viral Latency and Delays Viral Rebound after Termination of ART in Chronically SIV‐Infected Macaques

Wu, Chunxiu, Li, Pingchao, Lehner, Thomas, Hu, Fengyu, Feng, Fengling, Feng, Liqiang, Zhang, Fan, Sun, Caijun, Cai, Weiping, Li, Ruiting, Zhao, Jin, Zou, Huachun, He, Yizi, Yang, Qing, Pan, Enxiang, Chen, Ling, Li, Linghua

2019

Overview

The latent viral reservoir is the source of viral rebound after interruption of antiretroviral therapy (ART) and is the major obstacle in eradicating the latent human immunodeficiency virus‐1 (HIV‐1). In this study, arsenic class of mineral, arsenic trioxide, clinically approved for treating acute promyelocytic leukemia, is demonstrated to reactivate latent provirus in CD4+ T cells from HIV‐1 patients and Simian immunodeficiency virus (SIV)‐infected macaques, without significant systemic T cell activation and inflammatory responses. In a proof‐of‐concept study using chronically SIVmac239‐infected macaques, arsenic trioxide combined with ART delays viral rebound after ART termination, reduces the integrated SIV DNA copies in CD4+ T cells, and restores CD4+ T cells counts in vivo. Most importantly, half of arsenic trioxide‐treated macaques show no detectable viral rebound in the plasma for at least 80 days after ART discontinuation. Mechanistically, the study reveals that CD4 receptors and CCR5 co‐receptors of CD4+ T cells are significantly downregulated by arsenic trioxide treatment, which reduces susceptibility to infection after provirus reactivation. Furthermore, an increase in SIV‐specific immune responses after arsenic trioxide treatment may contribute to suppression of viral rebound. This work suggests that arsenic trioxide in combination with ART is a novel regimen in down‐sizing or even eradicating latent HIV‐1 reservoir. In combination with antiretroviral therapy (ART), treatment with arsenic trioxide delays viral rebound, and half of treated macaques show no detectable rebound for 80 days, after ART discontinuation in chronically simian immunodeficiency virus‐infected macaques, without devastating T cell activation and proinflammatory responses. The mechanism for this potentially functional cure of human immunodeficiency virus may involve multiple modes acting synergistically.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Acquired immune deficiency syndrome / AIDS / Antiretroviral drugs / antiretroviral therapy (ART) / Arsenic / arsenic trioxide / Communication / Communications / functional cures / HIV / Human immunodeficiency virus / human immunodeficiency virus‐1 (HIV‐1) / Kinases / latency / Simian immunodeficiency virus (SIV)