The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat.
David C MontefioriMaria V Filsinger InterranteBenjamin N BellAdonis A RubioJoseph G JoyceJohn W ShiverCelia C LaBranchePeter S KimPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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 FcγRI 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 FcγRI-dependent manner. As FcγRI 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.
Keyphrases
- men who have sex with men
- hiv testing
- hiv positive
- hiv infected
- antiretroviral therapy
- dendritic cells
- human immunodeficiency virus
- drug administration
- hiv aids
- sars cov
- immune response
- emergency department
- induced apoptosis
- mental health
- hepatitis c virus
- signaling pathway
- risk assessment
- escherichia coli
- oxidative stress
- climate change
- biofilm formation
- electronic health record
- south africa