RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses

Todd Bradley; Dimitra Peppa; Isabela Pedroza-Pacheco; Dapeng Li; Derek W. Cain; Ricardo Henao; Vaishnavi Venkat; Bhavna Hora; Yue Chen; Nathan A. Vandergrift; R. Glenn Overman; R. Whitney Edwards; Chris W. Woods; Georgia D. Tomaras; Guido Ferrari; Geoffrey S. Ginsburg; Mark Connors; Myron S. Cohen; M. Anthony Moody; Persephone Borrow; Barton F. Haynes

doi:10.1016/j.cell.2018.08.064

RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses

Todd Bradley^*, Dimitra Peppa, Isabela Pedroza-Pacheco, Dapeng Li, Derek W. Cain, Ricardo Henao, Vaishnavi Venkat, Bhavna Hora, Yue Chen, Nathan A. Vandergrift, R. Glenn Overman, R. Whitney Edwards, Chris W. Woods, Georgia D. Tomaras, Guido Ferrari, Geoffrey S. Ginsburg, Mark Connors, Myron S. Cohen, M. Anthony Moody, Persephone BorrowBarton F. Haynes

^*Corresponding author for this work

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

63 Scopus citations

Abstract

HIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce with vaccines but are generated in ∼50% of HIV-1-infected individuals. Understanding the molecular mechanisms of host control of bnAb induction is critical to vaccine design. Here, we performed a transcriptome analysis of blood mononuclear cells from 47 HIV-1-infected individuals who made bnAbs and 46 HIV-1-infected individuals who did not and identified in bnAb individuals upregulation of RAB11FIP5, encoding a Rab effector protein associated with recycling endosomes. Natural killer (NK) cells had the highest differential expression of RAB11FIP5, which was associated with greater dysregulation of NK cell subsets in bnAb subjects. NK cells from bnAb individuals had a more adaptive/dysfunctional phenotype and exhibited impaired degranulation and cytokine production that correlated with RAB11FIP5 transcript levels. Moreover, RAB11FIP5 overexpression modulated the function of NK cells. These data suggest that NK cells and Rab11 recycling endosomal transport are involved in regulation of HIV-1 bnAb development. Generation of broadly neutralizing antibodies against HIV-1 in humans is linked to the expression of a specific recycling endosome-associated effector in natural killer cells.

Original language	English (US)
Pages (from-to)	387-399.e17
Journal	Cell
Volume	175
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2018.08.064
State	Published - Oct 4 2018

Bibliographical note

Funding Information:
We acknowledge Connor Hart for technical assistance, Kevin Wiehe for computational support, and Steve Waggoner and Andrew McMichael for discussions. This work was supported by the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID; UMI-AI100645 ) grant from NIH/NIAID/DAIDS and the Medical Research Council ( MR/K012037 and MR/M008614 ). P.B. is a Jenner Institute investigator.

Publisher Copyright:
© 2018 The Authors

Keywords

broadly neutralizing antibodies
HIV-1
natural killer cells
Rab11fip5
recycling endosomes
vaccine

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2018.08.064

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Bradley, T., Peppa, D., Pedroza-Pacheco, I., Li, D., Cain, D. W., Henao, R., Venkat, V., Hora, B., Chen, Y., Vandergrift, N. A., Overman, R. G., Edwards, R. W., Woods, C. W., Tomaras, G. D., Ferrari, G., Ginsburg, G. S., Connors, M., Cohen, M. S., Moody, M. A., ... Haynes, B. F. (2018). RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses. Cell, 175(2), 387-399.e17. https://doi.org/10.1016/j.cell.2018.08.064

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title = "RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses",

abstract = "HIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce with vaccines but are generated in ∼50% of HIV-1-infected individuals. Understanding the molecular mechanisms of host control of bnAb induction is critical to vaccine design. Here, we performed a transcriptome analysis of blood mononuclear cells from 47 HIV-1-infected individuals who made bnAbs and 46 HIV-1-infected individuals who did not and identified in bnAb individuals upregulation of RAB11FIP5, encoding a Rab effector protein associated with recycling endosomes. Natural killer (NK) cells had the highest differential expression of RAB11FIP5, which was associated with greater dysregulation of NK cell subsets in bnAb subjects. NK cells from bnAb individuals had a more adaptive/dysfunctional phenotype and exhibited impaired degranulation and cytokine production that correlated with RAB11FIP5 transcript levels. Moreover, RAB11FIP5 overexpression modulated the function of NK cells. These data suggest that NK cells and Rab11 recycling endosomal transport are involved in regulation of HIV-1 bnAb development. Generation of broadly neutralizing antibodies against HIV-1 in humans is linked to the expression of a specific recycling endosome-associated effector in natural killer cells.",

keywords = "broadly neutralizing antibodies, HIV-1, natural killer cells, Rab11fip5, recycling endosomes, vaccine",

author = "Todd Bradley and Dimitra Peppa and Isabela Pedroza-Pacheco and Dapeng Li and Cain, {Derek W.} and Ricardo Henao and Vaishnavi Venkat and Bhavna Hora and Yue Chen and Vandergrift, {Nathan A.} and Overman, {R. Glenn} and Edwards, {R. Whitney} and Woods, {Chris W.} and Tomaras, {Georgia D.} and Guido Ferrari and Ginsburg, {Geoffrey S.} and Mark Connors and Cohen, {Myron S.} and Moody, {M. Anthony} and Persephone Borrow and Haynes, {Barton F.}",

note = "Funding Information: We acknowledge Connor Hart for technical assistance, Kevin Wiehe for computational support, and Steve Waggoner and Andrew McMichael for discussions. This work was supported by the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID; UMI-AI100645 ) grant from NIH/NIAID/DAIDS and the Medical Research Council ( MR/K012037 and MR/M008614 ). P.B. is a Jenner Institute investigator. Publisher Copyright: {\textcopyright} 2018 The Authors",

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Bradley, T, Peppa, D, Pedroza-Pacheco, I, Li, D, Cain, DW, Henao, R, Venkat, V, Hora, B, Chen, Y, Vandergrift, NA, Overman, RG, Edwards, RW, Woods, CW, Tomaras, GD, Ferrari, G, Ginsburg, GS, Connors, M, Cohen, MS, Moody, MA, Borrow, P & Haynes, BF 2018, 'RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses', Cell, vol. 175, no. 2, pp. 387-399.e17. https://doi.org/10.1016/j.cell.2018.08.064

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T1 - RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses

AU - Bradley, Todd

AU - Peppa, Dimitra

AU - Pedroza-Pacheco, Isabela

AU - Li, Dapeng

AU - Cain, Derek W.

AU - Henao, Ricardo

AU - Venkat, Vaishnavi

AU - Hora, Bhavna

AU - Chen, Yue

AU - Vandergrift, Nathan A.

AU - Overman, R. Glenn

AU - Edwards, R. Whitney

AU - Woods, Chris W.

AU - Tomaras, Georgia D.

AU - Ferrari, Guido

AU - Ginsburg, Geoffrey S.

AU - Connors, Mark

AU - Cohen, Myron S.

AU - Moody, M. Anthony

AU - Borrow, Persephone

AU - Haynes, Barton F.

N1 - Funding Information: We acknowledge Connor Hart for technical assistance, Kevin Wiehe for computational support, and Steve Waggoner and Andrew McMichael for discussions. This work was supported by the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID; UMI-AI100645 ) grant from NIH/NIAID/DAIDS and the Medical Research Council ( MR/K012037 and MR/M008614 ). P.B. is a Jenner Institute investigator. Publisher Copyright: © 2018 The Authors

PY - 2018/10/4

Y1 - 2018/10/4

N2 - HIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce with vaccines but are generated in ∼50% of HIV-1-infected individuals. Understanding the molecular mechanisms of host control of bnAb induction is critical to vaccine design. Here, we performed a transcriptome analysis of blood mononuclear cells from 47 HIV-1-infected individuals who made bnAbs and 46 HIV-1-infected individuals who did not and identified in bnAb individuals upregulation of RAB11FIP5, encoding a Rab effector protein associated with recycling endosomes. Natural killer (NK) cells had the highest differential expression of RAB11FIP5, which was associated with greater dysregulation of NK cell subsets in bnAb subjects. NK cells from bnAb individuals had a more adaptive/dysfunctional phenotype and exhibited impaired degranulation and cytokine production that correlated with RAB11FIP5 transcript levels. Moreover, RAB11FIP5 overexpression modulated the function of NK cells. These data suggest that NK cells and Rab11 recycling endosomal transport are involved in regulation of HIV-1 bnAb development. Generation of broadly neutralizing antibodies against HIV-1 in humans is linked to the expression of a specific recycling endosome-associated effector in natural killer cells.

AB - HIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce with vaccines but are generated in ∼50% of HIV-1-infected individuals. Understanding the molecular mechanisms of host control of bnAb induction is critical to vaccine design. Here, we performed a transcriptome analysis of blood mononuclear cells from 47 HIV-1-infected individuals who made bnAbs and 46 HIV-1-infected individuals who did not and identified in bnAb individuals upregulation of RAB11FIP5, encoding a Rab effector protein associated with recycling endosomes. Natural killer (NK) cells had the highest differential expression of RAB11FIP5, which was associated with greater dysregulation of NK cell subsets in bnAb subjects. NK cells from bnAb individuals had a more adaptive/dysfunctional phenotype and exhibited impaired degranulation and cytokine production that correlated with RAB11FIP5 transcript levels. Moreover, RAB11FIP5 overexpression modulated the function of NK cells. These data suggest that NK cells and Rab11 recycling endosomal transport are involved in regulation of HIV-1 bnAb development. Generation of broadly neutralizing antibodies against HIV-1 in humans is linked to the expression of a specific recycling endosome-associated effector in natural killer cells.

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KW - natural killer cells

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RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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