IgG Fc-binding motif-conjugated HIV-1 fusion inhibitor exhibits improved potency and in vivo half-life: Potential application in combination with broad neutralizing antibodies

English version

Autoři: Wenwen Bi ^aff001; Wei Xu ^aff001; Liang Cheng ^aff002; Jing Xue ^aff003; Qian Wang ^aff001; Fei Yu ^aff001; Shuai Xia ^aff001; Qi Wang ^aff002; Guangming Li ^aff002; Chuan Qin ^aff003; Lu Lu ^aff001; Lishan Su ^aff002; Shibo Jiang ^aff001
Působiště autorů: Key Laboratory of Medical Molecular Virology of MOE/NHC/CAMS, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, China ^aff001; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America ^aff002; Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Re-emerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Com ^aff003; Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America ^aff004
Vyšlo v časopise: IgG Fc-binding motif-conjugated HIV-1 fusion inhibitor exhibits improved potency and in vivo half-life: Potential application in combination with broad neutralizing antibodies. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008082
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008082

Souhrn

The clinical application of conventional peptide drugs, such as the HIV-1 fusion inhibitor enfuvirtide, is limited by their short half-life in vivo. To overcome this limitation, we developed a new strategy to extend the in vivo half-life of a short HIV-1 fusion inhibitory peptide, CP24, by fusing it with the human IgG Fc-binding peptide (IBP). The newly engineered peptide IBP-CP24 exhibited potent and broad anti-HIV-1 activity with IC₅₀ values ranging from 0.2 to 173.7 nM for inhibiting a broad spectrum of HIV-1 strains with different subtypes and tropisms, including those resistant to enfuvirtide. Most importantly, its half-life in the plasma of rhesus monkeys was 46.1 h, about 26- and 14-fold longer than that of CP24 (t_1/2 = 1.7 h) and enfuvirtide (t_1/2 = 3 h), respectively. IBP-CP24 intravenously administered in rhesus monkeys could not induce significant IBP-CP24-specific antibody response and it showed no obvious in vitro or in vivo toxicity. In the prophylactic study, humanized mice pretreated with IBP-CP24 were protected from HIV-1 infection. As a therapeutic treatment, coadministration of IBP-CP24 and normal human IgG to humanized mice with chronic HIV-1 infection resulted in a significant decrease of plasma viremia. Combining IBP-CP24 with a broad neutralizing antibody (bNAb) targeting CD4-binding site (CD4bs) in gp120 or a membrane proximal external region (MPER) in gp41 exhibited synergistic effect, resulting in significant dose-reduction of the bNAb and IBP-CP24. These results suggest that IBP-CP24 has the potential to be further developed as a new HIV-1 fusion inhibitor-based, long-acting anti-HIV drug that can be used alone or in combination with a bNAb for treatment and prevention of HIV-1 infection.

Klíčová slova:

Blood plasma – Cell fusion – Enzyme-linked immunoassays – HIV-1 – Mouse models – Rhesus monkeys – Elimination half-life calculation

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