A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge

Navid Madani; Amy M. Princiotto; Linh Mach; Shilei Ding; Jérémie Prevost; Jonathan Richard; Bhavna Hora; Laura Sutherland; Connie A. Zhao; Brandon P. Conn; Todd Bradley; M. Anthony Moody; Bruno Melillo; Andrés Finzi; Barton F. Haynes; Amos B. Smith; Sampa Santra; Joseph Sodroski

doi:10.1038/s41467-018-04758-9

A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge

Navid Madani, Amy M. Princiotto, Linh Mach, Shilei Ding, Jérémie Prevost, Jonathan Richard, Bhavna Hora, Laura Sutherland, Connie A. Zhao, Brandon P. Conn, Todd Bradley, M. Anthony Moody, Bruno Melillo, Andrés Finzi, Barton F. Haynes, Amos B. Smith, Sampa Santra, Joseph Sodroski

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

Abstract

The envelope glycoprotein (Env) trimer ((gp120/gp41)₃) mediates human immunodeficiency virus (HIV-1) entry into cells. The "closed," antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies. Here, we show that a CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV). The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.

Original language	English
Article number	2363
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04758-9
State	Published - 1 Dec 2018
Externally published	Yes

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Madani, N., Princiotto, A. M., Mach, L., Ding, S., Prevost, J., Richard, J., Hora, B., Sutherland, L., Zhao, C. A., Conn, B. P., Bradley, T., Moody, M. A., Melillo, B., Finzi, A., Haynes, B. F., Smith, A. B., Santra, S., & Sodroski, J. (2018). A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge. Nature Communications, 9(1), Article 2363. https://doi.org/10.1038/s41467-018-04758-9

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title = "A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge",

abstract = "The envelope glycoprotein (Env) trimer ((gp120/gp41)3) mediates human immunodeficiency virus (HIV-1) entry into cells. The {"}closed,{"} antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies. Here, we show that a CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV). The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.",

author = "Navid Madani and Princiotto, \{Amy M.\} and Linh Mach and Shilei Ding and J{\'e}r{\'e}mie Prevost and Jonathan Richard and Bhavna Hora and Laura Sutherland and Zhao, \{Connie A.\} and Conn, \{Brandon P.\} and Todd Bradley and Moody, \{M. Anthony\} and Bruno Melillo and Andr{\'e}s Finzi and Haynes, \{Barton F.\} and Smith, \{Amos B.\} and Sampa Santra and Joseph Sodroski",

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year = "2018",

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doi = "10.1038/s41467-018-04758-9",

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Madani, N, Princiotto, AM, Mach, L, Ding, S, Prevost, J, Richard, J, Hora, B, Sutherland, L, Zhao, CA, Conn, BP, Bradley, T, Moody, MA, Melillo, B, Finzi, A, Haynes, BF, Smith, AB, Santra, S & Sodroski, J 2018, 'A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge', Nature Communications, vol. 9, no. 1, 2363. https://doi.org/10.1038/s41467-018-04758-9

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AU - Madani, Navid

AU - Princiotto, Amy M.

AU - Mach, Linh

AU - Ding, Shilei

AU - Prevost, Jérémie

AU - Richard, Jonathan

AU - Hora, Bhavna

AU - Sutherland, Laura

AU - Zhao, Connie A.

AU - Conn, Brandon P.

AU - Bradley, Todd

AU - Moody, M. Anthony

AU - Melillo, Bruno

AU - Finzi, Andrés

AU - Haynes, Barton F.

AU - Smith, Amos B.

AU - Santra, Sampa

AU - Sodroski, Joseph

PY - 2018/12/1

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N2 - The envelope glycoprotein (Env) trimer ((gp120/gp41)3) mediates human immunodeficiency virus (HIV-1) entry into cells. The "closed," antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies. Here, we show that a CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV). The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.

AB - The envelope glycoprotein (Env) trimer ((gp120/gp41)3) mediates human immunodeficiency virus (HIV-1) entry into cells. The "closed," antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies. Here, we show that a CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV). The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.

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VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

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ER -

A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge

Abstract

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