Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 128, Issue 6, Pages 2239-2251Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI96764
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Funding
- National Natural Science Foundation of China (NSFC) [N_HKU709/11]
- Hong Kong Research Grants Council (RGC) [N_HKU709/11]
- Health and Medical Research Fund [HMRF12110952]
- RGC [HKU5/CRF/13G]
- Innovation and Technology Fund [ITS/170/17]
- University of Hong Kong Seed Fund [201611160018]
- China's National Science and Technology Major Project [2013ZX10001005002001]
- NSFC [81530065]
- Grand Challenge China [81661128042]
- University of Hong Kong Development Fund
- Li Ka Shing Faculty of Medicine Matching Fund
- San-Ming Project of Medicine in Shenzhen
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The discovery of an HIV-1 cure remains a medical challenge because the virus rebounds quickly after the cessation of combination antiretroviral therapy (cART). Here, we investigate the potential of an engineered tandem bispecific broadly neutralizing antibody (bs-bnAb) as an innovative product for HIV-1 prophylactic and therapeutic interventions. We discovered that by preserving 2 single-chain variable fragment (scFv) binding domains of each parental bnAb, a single gene-encoded tandem bs-bnAb, BiIA-SG, displayed substantially improved breadth and potency. BiIA-SG neutralized all 124 HIV-1-pseudotyped viruses tested, including global subtypes/recombinant forms, transmitted/founder viruses, variants not susceptible to parental bnAbs and to many other bnAbs with an average IC50 value of 0.073 mu g/ml (range < 0.001-1.03 mu g/ml). In humanized mice, an injection of BiIA-SG conferred sterile protection when administered prior to challenges with diverse live HIV-1 stains. Moreover, whereas BiIA-SG delayed viral rebound in a short-term therapeutic setting when combined with cART, a single injection of adeno-associated virus-transferred (AAV-transferred) BiIA-SG gene resulted dose-dependently in prolonged in vivo expression of BiIA-SG, which was associated with complete viremia control and subsequent elimination of infected cells in humanized mice. These results warrant the clinical development of BiIA-SG as a promising bs-bnAb-based biomedical intervention for the prevention and treatment of HIV-1 infection.
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