gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity

doi:10.1038/s41423-024-01144-y

. 2024 May;21(5):479-494.

doi: 10.1038/s41423-024-01144-y. Epub 2024 Mar 5.

gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity

Suiyi Tan^#¹, Wenjuan Li^#², Chan Yang^#², Qingping Zhan², Kunyu Lu², Jun Liu³, Yong-Mei Jin³, Jin-Song Bai³, Lin Wang⁴, Jinqing Li², Zhaofeng Li², Fei Yu⁵, Yu-Ye Li⁶, Yue-Xun Duan⁷, Lu Lu⁸, Tong Zhang⁹, Jiaqi Wei⁹, Lin Li², Yong-Tang Zheng¹⁰, Shibo Jiang¹¹, Shuwen Liu¹²

Affiliations

¹ Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. suiyitan@smu.edu.cn.
² Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
³ Department of Infectious Disease, The Third People's Hospital of Kunming, Kunming, 650041, China.
⁴ Department of Pathology, The Third People's Hospital of Kunming, Kunming, 650041, China.
⁵ Hebei Key Laboratory of Analysis and Control of Zoonotic Pathogenic Microorganism, College of Life Sciences, Hebei Agricultural University, Baoding, 071001, China.
⁶ Department of Dermatology and Venereology, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
⁷ Yunnan Provincial Infectious Disease Hospital, Kunming, 650301, China.
⁸ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
⁹ Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
¹⁰ State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.
¹¹ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. shibojiang@fudan.edu.cn.
¹² Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. liusw@smu.edu.cn.

^# Contributed equally.

PMID: 38443447
PMCID: PMC11061181 (available on 2025-05-01)
DOI: 10.1038/s41423-024-01144-y

gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity

Suiyi Tan et al. Cell Mol Immunol. 2024 May.

. 2024 May;21(5):479-494.

doi: 10.1038/s41423-024-01144-y. Epub 2024 Mar 5.

Authors

Affiliations

¹ Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. suiyitan@smu.edu.cn.
² Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
³ Department of Infectious Disease, The Third People's Hospital of Kunming, Kunming, 650041, China.
⁴ Department of Pathology, The Third People's Hospital of Kunming, Kunming, 650041, China.
⁵ Hebei Key Laboratory of Analysis and Control of Zoonotic Pathogenic Microorganism, College of Life Sciences, Hebei Agricultural University, Baoding, 071001, China.
⁶ Department of Dermatology and Venereology, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
⁷ Yunnan Provincial Infectious Disease Hospital, Kunming, 650301, China.
⁸ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
⁹ Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
¹⁰ State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.
¹¹ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. shibojiang@fudan.edu.cn.
¹² Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. liusw@smu.edu.cn.

^# Contributed equally.

PMID: 38443447
PMCID: PMC11061181 (available on 2025-05-01)
DOI: 10.1038/s41423-024-01144-y

Abstract

Apart from mediating viral entry, the function of the free HIV-1 envelope protein (gp120) has yet to be elucidated. Our group previously showed that EP2 derived from one β-strand in gp120 can form amyloid fibrils that increase HIV-1 infectivity. Importantly, gp120 contains ~30 β-strands. We examined whether gp120 might serve as a precursor protein for the proteolytic release of amyloidogenic fragments that form amyloid fibrils, thereby promoting viral infection. Peptide array scanning, enzyme degradation assays, and viral infection experiments in vitro confirmed that many β-stranded peptides derived from gp120 can indeed form amyloid fibrils that increase HIV-1 infectivity. These gp120-derived amyloidogenic peptides, or GAPs, which were confirmed to form amyloid fibrils, were termed gp120-derived enhancers of viral infection (GEVIs). GEVIs specifically capture HIV-1 virions and promote their attachment to target cells, thereby increasing HIV-1 infectivity. Different GAPs can cross-interact to form heterogeneous fibrils that retain the ability to increase HIV-1 infectivity. GEVIs even suppressed the antiviral activity of a panel of antiretroviral agents. Notably, endogenous GAPs and GEVIs were found in the lymphatic fluid, lymph nodes, and cerebrospinal fluid (CSF) of AIDS patients in vivo. Overall, gp120-derived amyloid fibrils might play a crucial role in the process of HIV-1 infectivity and thus represent novel targets for anti-HIV therapeutics.

Keywords: Amyloid fibril; Enhancement of viral infectivity; HIV-1; gp120.

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Conflict of interest statement

The authors declare no competing interests.

References

1. Pu J, Wang Q, Xu W, Lu L, Jiang S. Development of protein- and peptide-based HIV entry inhibitors targeting gp120 or gp41. Viruses. 2019;11:705. - PMC - PubMed
1. Ronaldson PT, Bendayan R. HIV-1 viral envelope glycoprotein gp120 triggers an inflammatory response in cultured rat astrocytes and regulates the functional expression of P-glycoprotein. Mol Pharm. 2006;70:1087–98. - PubMed
1. Cossarizza A. Apoptosis and HIV infection: about molecules and genes. Curr Pharm Des. 2008;14:237–44. - PubMed
1. He X, Yang W, Zeng Z, Wei Y, Gao J, Zhang B, et al. NLRP3-dependent pyroptosis is required for HIV-1 gp120-induced neuropathology. Cell Mol Immunol. 2020;17:283–99. - PMC - PubMed
1. Smith LK, Kuhn TB, Chen J, Bamburg JR. HIV associated neurodegenerative disorders: a new perspective on the role of lipid rafts in Gp120-mediated neurotoxicity. Curr HIV Res. 2018;16:258–69. - PMC - PubMed

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[1] Pu J, Wang Q, Xu W, Lu L, Jiang S. Development of protein- and peptide-based HIV entry inhibitors targeting gp120 or gp41. Viruses. 2019;11:705. - PMC - PubMed

[2] Pu J, Wang Q, Xu W, Lu L, Jiang S. Development of protein- and peptide-based HIV entry inhibitors targeting gp120 or gp41. Viruses. 2019;11:705. - PMC - PubMed

[3] Ronaldson PT, Bendayan R. HIV-1 viral envelope glycoprotein gp120 triggers an inflammatory response in cultured rat astrocytes and regulates the functional expression of P-glycoprotein. Mol Pharm. 2006;70:1087–98. - PubMed

[4] Ronaldson PT, Bendayan R. HIV-1 viral envelope glycoprotein gp120 triggers an inflammatory response in cultured rat astrocytes and regulates the functional expression of P-glycoprotein. Mol Pharm. 2006;70:1087–98. - PubMed

[5] Cossarizza A. Apoptosis and HIV infection: about molecules and genes. Curr Pharm Des. 2008;14:237–44. - PubMed

[6] Cossarizza A. Apoptosis and HIV infection: about molecules and genes. Curr Pharm Des. 2008;14:237–44. - PubMed

[7] He X, Yang W, Zeng Z, Wei Y, Gao J, Zhang B, et al. NLRP3-dependent pyroptosis is required for HIV-1 gp120-induced neuropathology. Cell Mol Immunol. 2020;17:283–99. - PMC - PubMed

[8] He X, Yang W, Zeng Z, Wei Y, Gao J, Zhang B, et al. NLRP3-dependent pyroptosis is required for HIV-1 gp120-induced neuropathology. Cell Mol Immunol. 2020;17:283–99. - PMC - PubMed

[9] Smith LK, Kuhn TB, Chen J, Bamburg JR. HIV associated neurodegenerative disorders: a new perspective on the role of lipid rafts in Gp120-mediated neurotoxicity. Curr HIV Res. 2018;16:258–69. - PMC - PubMed

[10] Smith LK, Kuhn TB, Chen J, Bamburg JR. HIV associated neurodegenerative disorders: a new perspective on the role of lipid rafts in Gp120-mediated neurotoxicity. Curr HIV Res. 2018;16:258–69. - PMC - PubMed

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gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity

Affiliations

gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity

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