Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells
Antiretroviral therapy can successfully suppress HIV-1 replication to undetectable levels but fails to eliminate latent and persistent HIV-1 reservoirs. Recent studies have focused on the immunomodulatory agents such as Toll-like receptor 7 and 8 (TLR7 and TLR8) capable of activating, thereby render...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2023.1033448/full |
| _version_ | 1811176963344171008 |
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| author | Yangyang Li Zhisong Wang Ying Hou Xiaoyu Liu Junxian Hong Xuanling Shi Xiaojie Huang Tong Zhang Xuebin Liao Linqi Zhang |
| author_facet | Yangyang Li Zhisong Wang Ying Hou Xiaoyu Liu Junxian Hong Xuanling Shi Xiaojie Huang Tong Zhang Xuebin Liao Linqi Zhang |
| author_sort | Yangyang Li |
| collection | DOAJ |
| description | Antiretroviral therapy can successfully suppress HIV-1 replication to undetectable levels but fails to eliminate latent and persistent HIV-1 reservoirs. Recent studies have focused on the immunomodulatory agents such as Toll-like receptor 7 and 8 (TLR7 and TLR8) capable of activating, thereby rendering the reservoir susceptible to antiretroviral inhibition and immune recognition and elimination. In this context, this study focused on generating a diverse repertoire of TLR7/8 agonists to identify more potent candidates for activating latent HIV-1 and immune cells’ response. Through combinational strategies of computer-aided design and biological characterization, 159 pyrido [3,2-d] pyrimidine and pyridine-2-amine-based derivatives were synthesized. Of which, two TLR7/8 dual and one TLR8-specific agonists with exceptionally high potency in activating HIV-1 latent reservoirs in cell lines and PBMCs of patients with persistent and durable virologic controls were identified. Particularly, these agonists appeared to enhance NK and T cells activity, which were correlated with the degree of surface activation markers. The outcome of this study highlights the remarkable potential of TLR7/8 agonists in simultaneously activating HIV-1 from the latently infected cells and augmenting immune effector cells. |
| first_indexed | 2024-04-10T20:01:34Z |
| format | Article |
| id | doaj.art-84763039d59843d6bfd5a3de5349592a |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-04-10T20:01:34Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-84763039d59843d6bfd5a3de5349592a2023-01-27T06:28:19ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2023-01-011410.3389/fmicb.2023.10334481033448Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cellsYangyang Li0Zhisong Wang1Ying Hou2Xiaoyu Liu3Junxian Hong4Xuanling Shi5Xiaojie Huang6Tong Zhang7Xuebin Liao8Linqi Zhang9Department of Basic Medical Sciences, School of Medicine, NexVac Research Center, Comprehensive AIDS Research Center, Tsinghua University, Beijing, ChinaKey Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Tsinghua University, Beijing, ChinaDepartment of Basic Medical Sciences, School of Medicine, NexVac Research Center, Comprehensive AIDS Research Center, Tsinghua University, Beijing, ChinaDepartment of Basic Medical Sciences, School of Medicine, NexVac Research Center, Comprehensive AIDS Research Center, Tsinghua University, Beijing, ChinaDepartment of Basic Medical Sciences, School of Medicine, NexVac Research Center, Comprehensive AIDS Research Center, Tsinghua University, Beijing, ChinaDepartment of Basic Medical Sciences, School of Medicine, NexVac Research Center, Comprehensive AIDS Research Center, Tsinghua University, Beijing, ChinaCenter for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, ChinaCenter for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, ChinaKey Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Tsinghua University, Beijing, ChinaDepartment of Basic Medical Sciences, School of Medicine, NexVac Research Center, Comprehensive AIDS Research Center, Tsinghua University, Beijing, ChinaAntiretroviral therapy can successfully suppress HIV-1 replication to undetectable levels but fails to eliminate latent and persistent HIV-1 reservoirs. Recent studies have focused on the immunomodulatory agents such as Toll-like receptor 7 and 8 (TLR7 and TLR8) capable of activating, thereby rendering the reservoir susceptible to antiretroviral inhibition and immune recognition and elimination. In this context, this study focused on generating a diverse repertoire of TLR7/8 agonists to identify more potent candidates for activating latent HIV-1 and immune cells’ response. Through combinational strategies of computer-aided design and biological characterization, 159 pyrido [3,2-d] pyrimidine and pyridine-2-amine-based derivatives were synthesized. Of which, two TLR7/8 dual and one TLR8-specific agonists with exceptionally high potency in activating HIV-1 latent reservoirs in cell lines and PBMCs of patients with persistent and durable virologic controls were identified. Particularly, these agonists appeared to enhance NK and T cells activity, which were correlated with the degree of surface activation markers. The outcome of this study highlights the remarkable potential of TLR7/8 agonists in simultaneously activating HIV-1 from the latently infected cells and augmenting immune effector cells.https://www.frontiersin.org/articles/10.3389/fmicb.2023.1033448/fullHIV-1latent reservoirTLR7 and TLR8 agonistsTNF-αT cellsNK cells |
| spellingShingle | Yangyang Li Zhisong Wang Ying Hou Xiaoyu Liu Junxian Hong Xuanling Shi Xiaojie Huang Tong Zhang Xuebin Liao Linqi Zhang Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells Frontiers in Microbiology HIV-1 latent reservoir TLR7 and TLR8 agonists TNF-α T cells NK cells |
| title | Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells |
| title_full | Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells |
| title_fullStr | Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells |
| title_full_unstemmed | Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells |
| title_short | Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells |
| title_sort | novel tlr7 8 agonists promote activation of hiv 1 latent reservoirs and human t and nk cells |
| topic | HIV-1 latent reservoir TLR7 and TLR8 agonists TNF-α T cells NK cells |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2023.1033448/full |
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