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Posted On: 03/25/2025 7:55:45 PM
Post# of 151484
2025 Mar 25:e0201824.
doi: 10.1128/jvi.02018-24. Online ahead of print.
Authors
Hongxia Yan # 1 2 , Yue Gao # 1 3 , Yuanmei Zhu # 1 3 , Huihui Chong # 1 3 , Yani Gong 1 3 , Yue Chen 1 3 , Li Li 1 , Bin Su 2 , Yuxian He 1 3
Affiliations
1 NHC Key Laboratory of Systems Biology of Pathogens, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2 Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China.
3 Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
# Contributed equally.
PMID: 40130879
DOI: 10.1128/jvi.02018-24
Addition of a short HIV-1 fusion-inhibitory peptide to PRO 140 antibody dramatically increases its antiviral breadth and potency
Hongxia Yan et al. J Virol. 2025.
Show details
Cite
Abstract
PRO 140, a humanized anti-HIV monoclonal antibody targeting the cell coreceptor CCR5, is currently under clinical trials, but it only affects CCR5-tropic viruses. In this study, we have engineered two tandem fusion proteins (2P23-PRO140SC and 2P23-PRO140-Fc) with bifunctional activity by adding short fusion-inhibitory peptide 2P23 to the single-chain fragment variable (scFv) of PRO 140 (PRO140SC) with or without the Fc domain of human IgG4. We first demonstrated that 2P23-PRO140SC and 2P23-PRO140-Fc could efficiently bind to the cell membranes through CCR5 anchoring, which did not affect the expression level of CCR5 on the cell surface. We then verified that the addition of 2P23 peptide to PRO140SC enabled a very potent activity against CXCR4-tropic HIV-1 isolates. As expected, the bispecific fusion proteins exhibited highly potent activities in inhibiting divergent HIV-1 subtypes and viral mutants that were resistant to the fusion inhibitors 2P23 and T20, and they displayed relatively low in vitro cytotoxicity. Furthermore, both the fusion proteins had robust in vivo anti-HIV activities in rats, with 2P23-PRO140-Fc much better than 2P23-PRO140SC. In conclusion, our studies have provided bispecific HIV-1 inhibitors that overcome the drawbacks of PRO 140 antibody and offered novel tools for studying the mechanisms of HIV-1 infection.IMPORTANCEGiven that HIV-1 evolves with high variability and drug resistance, the development of novel antivirals is important. CCR5-directed antibody PRO 140 is currently under clinical trials, but it only inhibits CCR5-tropic HIV-1 isolates. The designed fusion proteins by adding a minimum fusion-inhibitory peptide to PRO 140 enable dramatically increased activities in inhibiting both CCR5-tropic and CXCR4-tropic viruses, thus offering novel antiviral agents with a bispecific functionality that can overcome the drawbacks of PRO 140 antibody.
Keywords: CCR5; HIV-1; PRO 140; fusion inhibitor.
https://pubmed.ncbi.nlm.nih.gov/40130879/
They added a small piece called a peptide (named 2P23) to PRO 140, creating two new versions:
• 2P23-PRO140SC: A basic combo of PRO
140 and 2P23.
• 2P23-PRO140-Fc: They tweaked it.
This peptide, 2P23, is great at stopping HIV-1 from fusing with cells a key step in infection.
By combining it with leronlimab, these new versions can now block both CCR5-using and CXCR4-using HIV-1 strains, making them way more powerful and versatile.
doi: 10.1128/jvi.02018-24. Online ahead of print.
Authors
Hongxia Yan # 1 2 , Yue Gao # 1 3 , Yuanmei Zhu # 1 3 , Huihui Chong # 1 3 , Yani Gong 1 3 , Yue Chen 1 3 , Li Li 1 , Bin Su 2 , Yuxian He 1 3
Affiliations
1 NHC Key Laboratory of Systems Biology of Pathogens, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2 Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China.
3 Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
# Contributed equally.
PMID: 40130879
DOI: 10.1128/jvi.02018-24
Addition of a short HIV-1 fusion-inhibitory peptide to PRO 140 antibody dramatically increases its antiviral breadth and potency
Hongxia Yan et al. J Virol. 2025.
Show details
Cite
Abstract
PRO 140, a humanized anti-HIV monoclonal antibody targeting the cell coreceptor CCR5, is currently under clinical trials, but it only affects CCR5-tropic viruses. In this study, we have engineered two tandem fusion proteins (2P23-PRO140SC and 2P23-PRO140-Fc) with bifunctional activity by adding short fusion-inhibitory peptide 2P23 to the single-chain fragment variable (scFv) of PRO 140 (PRO140SC) with or without the Fc domain of human IgG4. We first demonstrated that 2P23-PRO140SC and 2P23-PRO140-Fc could efficiently bind to the cell membranes through CCR5 anchoring, which did not affect the expression level of CCR5 on the cell surface. We then verified that the addition of 2P23 peptide to PRO140SC enabled a very potent activity against CXCR4-tropic HIV-1 isolates. As expected, the bispecific fusion proteins exhibited highly potent activities in inhibiting divergent HIV-1 subtypes and viral mutants that were resistant to the fusion inhibitors 2P23 and T20, and they displayed relatively low in vitro cytotoxicity. Furthermore, both the fusion proteins had robust in vivo anti-HIV activities in rats, with 2P23-PRO140-Fc much better than 2P23-PRO140SC. In conclusion, our studies have provided bispecific HIV-1 inhibitors that overcome the drawbacks of PRO 140 antibody and offered novel tools for studying the mechanisms of HIV-1 infection.IMPORTANCEGiven that HIV-1 evolves with high variability and drug resistance, the development of novel antivirals is important. CCR5-directed antibody PRO 140 is currently under clinical trials, but it only inhibits CCR5-tropic HIV-1 isolates. The designed fusion proteins by adding a minimum fusion-inhibitory peptide to PRO 140 enable dramatically increased activities in inhibiting both CCR5-tropic and CXCR4-tropic viruses, thus offering novel antiviral agents with a bispecific functionality that can overcome the drawbacks of PRO 140 antibody.
Keywords: CCR5; HIV-1; PRO 140; fusion inhibitor.
https://pubmed.ncbi.nlm.nih.gov/40130879/
They added a small piece called a peptide (named 2P23) to PRO 140, creating two new versions:
• 2P23-PRO140SC: A basic combo of PRO
140 and 2P23.
• 2P23-PRO140-Fc: They tweaked it.
This peptide, 2P23, is great at stopping HIV-1 from fusing with cells a key step in infection.
By combining it with leronlimab, these new versions can now block both CCR5-using and CXCR4-using HIV-1 strains, making them way more powerful and versatile.
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