Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques
ABSTRACT Latent viral reservoir is recognized as the major obstacle to achieving a functional cure for HIV infection. We previously reported that arsenic trioxide (As2O3) combined with antiretroviral therapy (ART) can reactivate the viral reservoir and delay viral rebound after ART interruption in c...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2023-10-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.00525-23 |
| _version_ | 1827792065189117952 |
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| author | Yizi He Chunxiu Wu Zijian Liu Yudi Zhang Fengling Feng Zihan Lin Congcong Wang Qing Yang Ziyu Wen Yichu Liu Fan Zhang Yanqin Lin Hao Zhang Linbing Qu Linghua Li Weiping Cai Caijun Sun Ling Chen Pingchao Li |
| author_facet | Yizi He Chunxiu Wu Zijian Liu Yudi Zhang Fengling Feng Zihan Lin Congcong Wang Qing Yang Ziyu Wen Yichu Liu Fan Zhang Yanqin Lin Hao Zhang Linbing Qu Linghua Li Weiping Cai Caijun Sun Ling Chen Pingchao Li |
| author_sort | Yizi He |
| collection | DOAJ |
| description | ABSTRACT Latent viral reservoir is recognized as the major obstacle to achieving a functional cure for HIV infection. We previously reported that arsenic trioxide (As2O3) 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 As2O3 independent of ART in chronically SIV-infected macaques. We found that As2O3-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 As2O3 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 As2O3 treatment specifically induced apoptosis of SIV-infected CD4+ T cells. These findings revealed that As2O3 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 As2O3 + 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 As2O3 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 As2O3 independent of ART in chronically SIV-infected macaques and explored the underlying mechanisms of the potential of As2O3 in the treatment of HIV/SIV infection. Meanwhile, we investigated the therapeutic effects of ART+As2O3 in acutely SIVmac239-infected macaques. This study showed that As2O3 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. |
| first_indexed | 2024-03-11T17:56:35Z |
| format | Article |
| id | doaj.art-e330467c62154c6688206307fa4e6aa4 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-03-11T17:56:35Z |
| publishDate | 2023-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-e330467c62154c6688206307fa4e6aa42023-10-17T13:04:35ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-10-0111510.1128/spectrum.00525-23Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaquesYizi He0Chunxiu Wu1Zijian Liu2Yudi Zhang3Fengling Feng4Zihan Lin5Congcong Wang6Qing Yang7Ziyu Wen8Yichu Liu9Fan Zhang10Yanqin Lin11Hao Zhang12Linbing Qu13Linghua Li14Weiping Cai15Caijun Sun16Ling Chen17Pingchao Li18Guangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaGuangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaGuangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaGuangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaSchool of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University , Shenzhen, ChinaGuangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaSchool of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University , Shenzhen, ChinaGuangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaSchool of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University , Shenzhen, ChinaGuangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaGuangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaGuangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaGuangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaGuangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaGuangzhou Eighth People’s Hospital, Guangzhou Medical University , Guangzhou, ChinaGuangzhou Eighth People’s Hospital, Guangzhou Medical University , Guangzhou, ChinaSchool of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University , Shenzhen, ChinaGuangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaGuangdong Laboratory of Computational Biomedicine, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, ChinaABSTRACT Latent viral reservoir is recognized as the major obstacle to achieving a functional cure for HIV infection. We previously reported that arsenic trioxide (As2O3) 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 As2O3 independent of ART in chronically SIV-infected macaques. We found that As2O3-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 As2O3 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 As2O3 treatment specifically induced apoptosis of SIV-infected CD4+ T cells. These findings revealed that As2O3 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 As2O3 + 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 As2O3 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 As2O3 independent of ART in chronically SIV-infected macaques and explored the underlying mechanisms of the potential of As2O3 in the treatment of HIV/SIV infection. Meanwhile, we investigated the therapeutic effects of ART+As2O3 in acutely SIVmac239-infected macaques. This study showed that As2O3 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.https://journals.asm.org/doi/10.1128/spectrum.00525-23arsenic trioxideHIV/SIVlatent viral reservoirrhesus macaquesapoptosis |
| spellingShingle | Yizi He Chunxiu Wu Zijian Liu Yudi Zhang Fengling Feng Zihan Lin Congcong Wang Qing Yang Ziyu Wen Yichu Liu Fan Zhang Yanqin Lin Hao Zhang Linbing Qu Linghua Li Weiping Cai Caijun Sun Ling Chen Pingchao Li Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques Microbiology Spectrum arsenic trioxide HIV/SIV latent viral reservoir rhesus macaques apoptosis |
| title | Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques |
| title_full | Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques |
| title_fullStr | Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques |
| title_full_unstemmed | Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques |
| title_short | Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques |
| title_sort | arsenic trioxide induced apoptosis contributes to suppression of viral reservoir in siv infected rhesus macaques |
| topic | arsenic trioxide HIV/SIV latent viral reservoir rhesus macaques apoptosis |
| url | https://journals.asm.org/doi/10.1128/spectrum.00525-23 |
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