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

Publication ,  Journal Article
Montefiori, DC; Filsinger Interrante, MV; Bell, BN; Rubio, AA; Joyce, JG; Shiver, JW; LaBranche, CC; Kim, PS
Published in: Proc Natl Acad Sci U S A
January 19, 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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 19, 2021

Volume

118

Issue

3

Location

United States

Related Subject Headings

  • Virus Internalization
  • Repetitive Sequences, Amino Acid
  • Receptors, IgG
  • Immunoglobulin G
  • Immunization
  • Immune Sera
  • Humans
  • HIV-1
  • HIV Seropositivity
  • HIV Infections
 

Citation

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ICMJE
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Montefiori, D. C., Filsinger Interrante, M. V., Bell, B. N., Rubio, A. A., Joyce, J. G., Shiver, J. W., … Kim, P. S. (2021). The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat. Proc Natl Acad Sci U S A, 118(3). https://doi.org/10.1073/pnas.2018027118
Montefiori, David C., Maria V. Filsinger Interrante, Benjamin N. Bell, Adonis A. Rubio, Joseph G. Joyce, John W. Shiver, Celia C. LaBranche, and Peter S. Kim. “The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat.Proc Natl Acad Sci U S A 118, no. 3 (January 19, 2021). https://doi.org/10.1073/pnas.2018027118.
Montefiori DC, Filsinger Interrante MV, Bell BN, Rubio AA, Joyce JG, Shiver JW, et al. The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat. Proc Natl Acad Sci U S A. 2021 Jan 19;118(3).
Montefiori, David C., et al. “The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat.Proc Natl Acad Sci U S A, vol. 118, no. 3, Jan. 2021. Pubmed, doi:10.1073/pnas.2018027118.
Montefiori DC, Filsinger Interrante MV, Bell BN, Rubio AA, Joyce JG, Shiver JW, LaBranche CC, Kim PS. The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat. Proc Natl Acad Sci U S A. 2021 Jan 19;118(3).
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 19, 2021

Volume

118

Issue

3

Location

United States

Related Subject Headings

  • Virus Internalization
  • Repetitive Sequences, Amino Acid
  • Receptors, IgG
  • Immunoglobulin G
  • Immunization
  • Immune Sera
  • Humans
  • HIV-1
  • HIV Seropositivity
  • HIV Infections