Substitution of gp120 C4 region compensates for V3 loss-of-fitness mutations in HIV-1 CRF01_AE co-receptor switching
ABSTRACTHIV-1 infection is mediated by a viral envelope subsequently binding to CD4 receptor and two main coreceptors, CCR5 (R5) for primary infection and CXCR4 (X4) in chronic infection. Switching from R5 to X4 tropism in HIV-1 infection is associated with increased viral pathogenesis and disease p...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Emerging Microbes and Infections |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2023.2169196 |
| _version_ | 1797652799715016704 |
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| author | Yueyang Yu Yi Feng Zehua Zhou Kang Li Xiaoyan Hu Lingjie Liao Hui Xing Yimig Shao |
| author_facet | Yueyang Yu Yi Feng Zehua Zhou Kang Li Xiaoyan Hu Lingjie Liao Hui Xing Yimig Shao |
| author_sort | Yueyang Yu |
| collection | DOAJ |
| description | ABSTRACTHIV-1 infection is mediated by a viral envelope subsequently binding to CD4 receptor and two main coreceptors, CCR5 (R5) for primary infection and CXCR4 (X4) in chronic infection. Switching from R5 to X4 tropism in HIV-1 infection is associated with increased viral pathogenesis and disease progression. The coreceptor switching is mainly due to variations in the V3 loop, while the mechanism needs to be further elucidated. We systematically studied the determinant for HIV-1 coreceptor switching by substitution of the genes from one R5 and one X4 pseudoviruses. The study results in successfully constructing two panels of chimeric viruses of R5 to X4 forward and X4 to R5 reverse switching. The determinants for tropism switching are the combined substitution of the V3 loop and C4 region of the HIV-1 envelope. The possible mechanism of the tropism switching includes two components, the V3 loop to enable the viral envelope binding to the newly switched coreceptor and the C4 region, to compensate for the loss of fitness caused by deleterious V3 loop mutations to maintain the overall viral viability. The combined C4 and V3 substitution showed at least an eightfold increase in replication activity compared with the pseudovirus with only V3 loop substitution. The site-directed mutations of N425R and S440-I442 with charged amino acids could especially increase viral activity. This study could facilitate HIV-1 phenotype surveillance and select right entry inhibitor, CCR5 or CXCR4 antagonists, for antiviral therapy. |
| first_indexed | 2024-03-11T16:35:12Z |
| format | Article |
| id | doaj.art-68197ebe6b70414897a058e4ebb7624b |
| institution | Directory Open Access Journal |
| issn | 2222-1751 |
| language | English |
| last_indexed | 2024-03-11T16:35:12Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj.art-68197ebe6b70414897a058e4ebb7624b2023-10-23T17:36:56ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512023-12-0112110.1080/22221751.2023.2169196Substitution of gp120 C4 region compensates for V3 loss-of-fitness mutations in HIV-1 CRF01_AE co-receptor switchingYueyang Yu0Yi Feng1Zehua Zhou2Kang Li3Xiaoyan Hu4Lingjie Liao5Hui Xing6Yimig Shao7School of Medicine, Nankai University, Tianjin, People’s Republic of ChinaState Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of ChinaSchool of Medicine, Nankai University, Tianjin, People’s Republic of ChinaSchool of Medicine, Nankai University, Tianjin, People’s Republic of ChinaSchool of Medicine, Nankai University, Tianjin, People’s Republic of ChinaState Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of ChinaState Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of ChinaSchool of Medicine, Nankai University, Tianjin, People’s Republic of ChinaABSTRACTHIV-1 infection is mediated by a viral envelope subsequently binding to CD4 receptor and two main coreceptors, CCR5 (R5) for primary infection and CXCR4 (X4) in chronic infection. Switching from R5 to X4 tropism in HIV-1 infection is associated with increased viral pathogenesis and disease progression. The coreceptor switching is mainly due to variations in the V3 loop, while the mechanism needs to be further elucidated. We systematically studied the determinant for HIV-1 coreceptor switching by substitution of the genes from one R5 and one X4 pseudoviruses. The study results in successfully constructing two panels of chimeric viruses of R5 to X4 forward and X4 to R5 reverse switching. The determinants for tropism switching are the combined substitution of the V3 loop and C4 region of the HIV-1 envelope. The possible mechanism of the tropism switching includes two components, the V3 loop to enable the viral envelope binding to the newly switched coreceptor and the C4 region, to compensate for the loss of fitness caused by deleterious V3 loop mutations to maintain the overall viral viability. The combined C4 and V3 substitution showed at least an eightfold increase in replication activity compared with the pseudovirus with only V3 loop substitution. The site-directed mutations of N425R and S440-I442 with charged amino acids could especially increase viral activity. This study could facilitate HIV-1 phenotype surveillance and select right entry inhibitor, CCR5 or CXCR4 antagonists, for antiviral therapy.https://www.tandfonline.com/doi/10.1080/22221751.2023.2169196HIV-1tropismcoreceptor-switchingC4 regionV3 loop |
| spellingShingle | Yueyang Yu Yi Feng Zehua Zhou Kang Li Xiaoyan Hu Lingjie Liao Hui Xing Yimig Shao Substitution of gp120 C4 region compensates for V3 loss-of-fitness mutations in HIV-1 CRF01_AE co-receptor switching Emerging Microbes and Infections HIV-1 tropism coreceptor-switching C4 region V3 loop |
| title | Substitution of gp120 C4 region compensates for V3 loss-of-fitness mutations in HIV-1 CRF01_AE co-receptor switching |
| title_full | Substitution of gp120 C4 region compensates for V3 loss-of-fitness mutations in HIV-1 CRF01_AE co-receptor switching |
| title_fullStr | Substitution of gp120 C4 region compensates for V3 loss-of-fitness mutations in HIV-1 CRF01_AE co-receptor switching |
| title_full_unstemmed | Substitution of gp120 C4 region compensates for V3 loss-of-fitness mutations in HIV-1 CRF01_AE co-receptor switching |
| title_short | Substitution of gp120 C4 region compensates for V3 loss-of-fitness mutations in HIV-1 CRF01_AE co-receptor switching |
| title_sort | substitution of gp120 c4 region compensates for v3 loss of fitness mutations in hiv 1 crf01 ae co receptor switching |
| topic | HIV-1 tropism coreceptor-switching C4 region V3 loop |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2023.2169196 |
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