The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat

Montefiori, D. C.; Filsinger Interrante, M. V.; Bell, B. N.; Rubio, A. A.; Joyce, J. G.; Shiver, J. W.; LaBranche, C. C.; Kim, P. S.

doi:10.1101/2020.08.27.271064

bioRxiv · 10.1101/2020.08.27.271064

The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat

Montefiori, D. C.·Filsinger Interrante, M. V.·Bell, B. N.·Rubio, A. A.·Joyce, J. G.·Shiver, J. W.·LaBranche, C. C.·Kim, P. S.

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Abstract

The HIV-1 gp41 N-heptad repeat (NHR) region of the pre-hairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the 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 to 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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Montefiori, D. C., Filsinger Interrante, M. V., Bell, B. N., Rubio, A. A., Joyce, J. G., Shiver, J. W., LaBranche, C. C., Kim, P. S.. 2020-08-28. The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat. https://doi.org/10.1101/2020.08.27.271064

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