Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques

Latent viral reservoir is recognized as the major obstacle to achieving a functional cure for HIV infection. We previously reported that arsenic trioxide (As(2)O(3)) combined with antiretroviral therapy (ART) can reactivate the viral reservoir and delay viral rebound after ART interruption in chronically simian immunodeficiency virus (SIV)-infected macaques. In this study, we further investigated the effect of As(2)O(3) independent of ART in chronically SIV-infected macaques. We found that As(2)O(3)-only treatment significantly increased the CD4/CD8 ratio, improved SIV-specific T cell responses, and reactivated viral latency in chronically SIVmac239-infected macaques. RNA-sequencing analysis revealed that As(2)O(3) treatment downregulated the expression levels of genes related to HIV entry and infection, while the expression levels of genes related to transcription initiation, cell apoptosis, and host restriction factors were significantly upregulated. Importantly, we found that As(2)O(3) treatment specifically induced apoptosis of SIV-infected CD4(+) T cells. These findings revealed that As(2)O(3) might not only impact viral latency, but also induce the apoptosis of HIV-infected cells and thus block the secondary infection of bystanders. Moreover, we investigated the therapeutic potential of this regimen in acutely SIVmac239-infected macaques and found that As(2)O(3) + ART treatment effectively restored the CD4(+) T cell count, delayed disease progression, and improved survival in acutely SIV-infected macaques. In sum, this work provides new insights to develop As(2)O(3) as a component of the “shock-and-kill” strategy toward HIV functional cure. IMPORTANCE: Although antiretroviral therapy (ART) can effectively suppress the viral load of AIDS patients, it cannot functionally cure HIV infection due to the existence of HIV reservoir. Strategies toward HIV functional cure are still highly anticipated to ultimately end the pandemic of AIDS. Herein, we investigated the direct role of As(2)O(3) independent of ART in chronically SIV-infected macaques and explored the underlying mechanisms of the potential of As(2)O(3) in the treatment of HIV/SIV infection. Meanwhile, we investigated the therapeutic effects of ART+As(2)O(3) in acutely SIVmac239-infected macaques. This study showed that As(2)O(3) has the potential to be launched into the “shock-and-kill” strategy to suppress HIV/SIV reservoir due to its latency-reversing and apoptosis-inducing properties.