A research team led by scientists at AIDS Institute and Department of Microbiology, Li Ka Shing Faculty of Medicine of The University of Hong Kong (HKU) invents a universal antibody drug against HIV/AIDS. By engineering a tandem bi-specific broadly neutralizing antibody, the team found that this novel antibody drug is universally effective not only against all genetically divergent global HIV-1 strains tested but also promoting the elimination of latently infected cells in a humanized mouse model. The new findings are now published in the April issue of Journal of Clinical Investigation.
AIDS remains an incurable disease. In the world, HIV/AIDS has resulted in estimated 40 million deaths while 36.9 million people are still living with the virus. To end the HIV/AIDS pandemic, it is important to discover either an effective vaccine or a therapeutic cure. There are, however, two major scientific challenges: the tremendous HIV-1 diversity and the antiviral drug-unreachable latency. Since it is extremely difficult to develop an appropriate immunogen to elicit broadly neutralizing antibodies (bnAbs) against genetically divergent HIV-1 subtypes, developing existing bnAbs as passive immunization becomes a useful approach for HIV-1 prophylaxis and immunotherapy.
Previous studies have investigated the potency, breadth and crystal structure of many bnAbs including their combination both in vitro and in vivo. Naturally occurring HIV-1 resistant strains, however, are readily found against these so-called bnAbs and result in the failure of durable viral suppression in bnAb-based monotherapy. To improve HIV-1 neutralization breadth and potency, bispecific bnAb, which blocks two essential steps of HIV-1 entry into target cells, have been engineered and show promising efficacy in animal models. Before the publication, tandem bi-specific bnAb has not been previously investigated in vivo against HIV-1 infection.
Research method and findings
The HKU research team invented a single gene-encoded tandem broadly neutralizing antibody, titled “BiIA-SG”, which “kills two birds with one stone”. By attaching to host protein CD4, BiIA-SG strategically ambushes invading HIV-1 particles to protect CD4 positive T cells. BiIA-SG not only displays a potent activity against all three panels of 124 genetically divergent global HIV-1 strains tested, but also prevents diverse live viral challenges completely in humanized mice. Moreover, gene transfer of BiIA-SG achieves pro-longed drug availability in vivo, leading to a promising efficacy of eliminating HIV-1 infected cells in humanized mice. Therefore, the research team provides a proof-of-concept that BiIA-SG is a novel universal antibody drug for prevention and immunotherapy against HIV-1 infection.
Significance of the study
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