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Article

In Vitro Selection and Characterization of HIV-1 Variants with Increased Resistance to LP-40, Enfuvirtide-Based Lipopeptide Inhibitor

by
Yue Hu
1,2,†,
Wenjiang Yu
1,2,†,
Xiuzhu Geng
1,2,
Yuanmei Zhu
1,2,
Huihui Chong
1,2,* and
Yuxian He
1,2,*
1
NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
2
Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2022, 23(12), 6638; https://doi.org/10.3390/ijms23126638
Submission received: 16 May 2022 / Revised: 10 June 2022 / Accepted: 13 June 2022 / Published: 14 June 2022
(This article belongs to the Special Issue Cell Fusion in the Living Matter)
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Abstract

In our previous work, we replaced the TRM (tryptophan-rich motif) of T20 (Enfuvirtide) with fatty acid (C16) to obtain the novel lipopeptide LP-40, and LP-40 displayed enhanced antiviral activity. In this study, we investigated whether the C16 modification could enhance the high-resistance barrier of the inhibitor LP-40. To address this question, we performed an in vitro simultaneous screening of HIV-1NL4-3 resistance to T20 and LP-40. The mechanism of drug resistance for HIV-1 Env was further studied using the expression and processing of the Env glycoprotein, the effect of the Env mutation on the entry and fusion ability of the virus, and an analysis of changes to the gp41 core structure. The results indicate that the LP-40 activity is enhanced and that it has a high resistance barrier. In a detailed analysis of the resistance sites, we found that mutations in L33S conferred a stronger resistance, except for the well-recognized mutations in amino acids 36–45 of gp41 NHR, which reduced the inhibitory activity of the CHR-derived peptides. The compensatory mutation of eight amino acids in the CHR region (NDQEEDYN) plays an important role in drug resistance. LP-40 and T20 have similar resistance mutation sites, and we speculate that the same resistance profile may arise if LP-40 is used in a clinical setting.
Keywords: HIV-1; gp41; fusion inhibitor; resistance; LP-40; T20 HIV-1; gp41; fusion inhibitor; resistance; LP-40; T20

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MDPI and ACS Style

Hu, Y.; Yu, W.; Geng, X.; Zhu, Y.; Chong, H.; He, Y. In Vitro Selection and Characterization of HIV-1 Variants with Increased Resistance to LP-40, Enfuvirtide-Based Lipopeptide Inhibitor. Int. J. Mol. Sci. 2022, 23, 6638. https://doi.org/10.3390/ijms23126638

AMA Style

Hu Y, Yu W, Geng X, Zhu Y, Chong H, He Y. In Vitro Selection and Characterization of HIV-1 Variants with Increased Resistance to LP-40, Enfuvirtide-Based Lipopeptide Inhibitor. International Journal of Molecular Sciences. 2022; 23(12):6638. https://doi.org/10.3390/ijms23126638

Chicago/Turabian Style

Hu, Yue, Wenjiang Yu, Xiuzhu Geng, Yuanmei Zhu, Huihui Chong, and Yuxian He. 2022. "In Vitro Selection and Characterization of HIV-1 Variants with Increased Resistance to LP-40, Enfuvirtide-Based Lipopeptide Inhibitor" International Journal of Molecular Sciences 23, no. 12: 6638. https://doi.org/10.3390/ijms23126638

APA Style

Hu, Y., Yu, W., Geng, X., Zhu, Y., Chong, H., & He, Y. (2022). In Vitro Selection and Characterization of HIV-1 Variants with Increased Resistance to LP-40, Enfuvirtide-Based Lipopeptide Inhibitor. International Journal of Molecular Sciences, 23(12), 6638. https://doi.org/10.3390/ijms23126638

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