Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice
Xilin Wu, … , Paul Zhou, Zhiwei Chen
Xilin Wu, … , Paul Zhou, Zhiwei Chen
Published February 20, 2018
Citation Information: J Clin Invest. 2018;128(6):2239-2251. https://doi.org/10.1172/JCI96764.
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Research Article AIDS/HIV Virology

Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice

Abstract

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 μg/ml (range < 0.001–1.03 μg/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.

Authors

Xilin Wu, Jia Guo, Mengyue Niu, Minghui An, Li Liu, Hui Wang, Xia Jin, Qi Zhang, Ka Shing Lam, Tongjin Wu, Hua Wang, Qian Wang, Yanhua Du, Jingjing Li, Lin Cheng, Hang Ying Tang, Hong Shang, Linqi Zhang, Paul Zhou, Zhiwei Chen

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Figure 6

Therapeutic efficacy of AAV-delivered BiIA-SG in infected NSG-HuPBL mice.

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Therapeutic efficacy of AAV-delivered BiIA-SG in infected NSG-HuPBL mice...
(A) Experimental schedule of AAV-delivered BiIA-SG for immunotherapy of HIV-1JR-FL–challenged humanized mice. A single intramuscular injection of each AAV was performed 2 weeks after HIV-1JR-FL challenge. (B) The top panel shows the peripheral viral loads tested over time among 4 groups of animals, including AAV-GFP (4 × 109 gc, n = 5), low-dose AAV-BiIA-SG/L (1 × 109 gc, n = 2), middle-dose AAV–BiIA-SG/M (4 × 109 gc, n = 5), and high-dose AAV–BiIA-SG/H (1 × 1011 gc, n = 8). The bottom panel shows peripheral concentration of BiIA-SG expressed over time among the same 4 groups of animals. Each line represents data from 1 mouse. (C) The correlation between plasma viral load and BiIA-SG concentration at 11 wpi among 3 AAV–BiIA-SG groups of animals. Correlation analyses were performed by linear regression using the GraphPad Prism 5.01 program. (D) Proviral loads of peripheral T cells at 11 wpi among uninfected (n = 4) and 4 groups of treated animals by digital PCR. The y axis represents the amount of DNA copies per cell, plotted as the ratio of HIV-1 DNA to CCR5 copies for each mouse. (E) Before cell adoptive transfer at 11 wpi, donor splenocytes from uninfected and 3 groups of AAV-treated mice were tested by VOA. The y axis indicates viral load copies per milliliter culture supernatants. (F–H) Four weeks after cell adoptive transfer, plasma viral load, the frequency of peripheral P24+ T cells, and the frequency of splenic P24+ T cells were determined in individual recipient mice. Uninfected, n = 4; AAV-GFP, n = 5; AAV–BiIA-SG/M, n = 5; AAV–BiIA-SG/H, n = 8. The color-coded symbols correspond to donor and recipient relationship. (D–H) Data represent mean ± SEM; 2-tailed, unpaired, Student’s t tests were performed. ***P < 0.001; **P < 0.01; *P < 0.05.