期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2018027118
关键词
HIV-1; vaccine; prehairpin intermediate; gp41; Fc receptor
资金
- NIH [T32GM007276, T32GM007365, DP1DA043893]
- NIH/National Institute of Allergy and Infectious Diseases [HHSN272201800004C]
- Bill and Melinda Gates Foundation, Virginia [OPP1113682]
- D. K. Ludwig Fund for Cancer Research
- Chan Zuckerberg Biohub
- NSF Graduate Research Fellowship Program
Research has shown that the neutralization activity of the well-characterized NHR-targeting antibody D5 is significantly enhanced in TZM-bl cells expressing Fc gamma RI, resulting in potent neutralization of tier-2 viruses. Moreover, guinea pig antisera immunized with the NHR-based vaccine candidate (ccIZN36)(3) neutralized tier-2 viruses from multiple clades in an Fc gamma RI-dependent manner, suggesting the potential importance of targeting Fc gamma RI in the development of a prophylactic HIV-1 vaccine.
The HIV-1 gp41 N-heptad repeat (NHR) region of the prehairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the Food and Drug Administration (FDA)-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been largely restricted to tier-1 viruses, which are most sensitive to neutralization by sera from HIV-1-infected individuals. Here, we show that the neutralization activity of the well-characterized NHR-targeting antibody D5 is potentiated >5,000-fold in TZM-bl cells expressing Fc gamma RI compared with those without, resulting in neutralization of many tier-2 viruses (which are less susceptible to neutralization by sera from HIV-1-infected individuals and are the target of current antibody-based vaccine efforts). Further, antisera from guinea pigs immunized with the NHR-based vaccine candidate (ccIZN36)(3) neutralized tier-2 viruses from multiple clades in an Fc gamma RI-dependent manner. As Fc gamma RI is expressed on macrophages and dendritic cells, which are present at mucosal surfaces and are implicated in the early establishment of HIV-1 infection following sexual transmission, these results may be important in the development of a prophylactic HIV-1 vaccine.
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