CCL2: a Chemokine Potentially Promoting Early Seeding of the Latent HIV Reservoir

Thomas A. Packard; Roland Schwarzer; Eytan Herzig; Deepashri Rao; Xiaoyu Luo; Johanne H. Egedal; Feng Hsiao; Marek Widera; Judd F. Hultquist; Zachary W. Grimmett; Ronald J. Messer; Nevan J. Krogan; Steven G. Deeks; Nadia R. Roan; Ulf Dittmer; Kim J. Hasenkrug; Warner C. Greene

doi:10.1128/mbio.01891-22

CCL2: a Chemokine Potentially Promoting Early Seeding of the Latent HIV Reservoir

Thomas A. Packard, Roland Schwarzer, Eytan Herzig, Deepashri Rao, Xiaoyu Luo, Johanne H. Egedal, Feng Hsiao, Marek Widera, Judd F. Hultquist, Zachary W. Grimmett, Ronald J. Messer, Nevan J. Krogan, Steven G. Deeks, Nadia R. Roan, Ulf Dittmer, Kim J. Hasenkrug, Warner C. Greene^*

^*Corresponding author for this work

Medicine, Infectious Diseases Division

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

10 Scopus citations

Abstract

HIV infects long-lived CD4 memory T cells, establishing a latent viral reservoir that necessitates lifelong antiretroviral therapy (ART). How this reservoir is formed so quickly after infection remains unclear. We now show the innate inflammatory response to HIV infection results in CCL2 chemokine release, leading to recruitment of cells expressing the CCR2 receptor, including a subset of central memory CD4 T cells. Supporting a role for the CCL2/CCR2 axis in rapid reservoir formation, we find (i) treatment of humanized mice with anti-CCL2 antibodies during early HIV infection decreases reservoir seeding and preserves CCR2/5¹ cells and (ii) CCR2/5¹ cells from the blood of HIV-infected individuals on long-term ART contain significantly more integrated provirus than CCR2/5-negative memory or naive cells. Together, these studies support a model where the host’s innate inflammatory response to HIV infection, including CCL2 production, leads to the recruitment of CCR2/5¹ central memory CD4 T cells to zones of virus-associated inflammation, likely contributing to rapid formation of the latent HIV reservoir.

Original language	English (US)
Journal	mBio
Volume	13
Issue number	5
DOIs	https://doi.org/10.1128/mbio.01891-22
State	Published - Sep 2022

Funding

We thank Jane Srivastava and Nandhini Raman of the Gladstone Flow Cytometry Core, the UCSF Diabetes Research Center for use of their CyTOF instrument, the UCSF Parnassus Flow Cytometry Core for CyTOF assistance, John C. W. Carroll for graphic arts, Francoise Chanut for editorial assistance, and Robin Givens for administrative assistance. Research reported in this publication was supported by the NIAID Intramural Research Program, NIAID, NHLBI, NIDA, NINDS, NIMH, and NIDDK of the National Institutes of Health under award number UM1AI164559 to the HOPE Collaboratory and R01 AI147777, R01 AI127219, and P01 AI131374. The Gladstone Institutes acknowledges the generous support of the James B. Pendleton Charitable Trust. M.W. and U.D. were supported by the DFG priority program 556 SPP1923 (WI 5086/1-1 and DI 714/18-2). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. There are no competing interests. Research reported in this publication was supported by the NIAID Intramural Research Program, NIAID, NHLBI, NIDA, NINDS, NIMH, and NIDDK of the National Institutes of Health under award number UM1AI164559 to the HOPE Collaboratory and R01 AI147777, R01 AI127219, and P01 AI131374. The Gladstone Institutes acknowledges the generous support of the James B. Pendleton Charitable Trust. M.W. and U.D. were supported by the DFG priority program 556 SPP1923 (WI 5086/1-1 and DI 714/18-2).

Keywords

CCL2
CRISPR
CyTOF
human immunodeficiency virus
latency
reservoir

ASJC Scopus subject areas

Microbiology
Virology

UN SDGs

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

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10.1128/mbio.01891-22

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Packard, T. A., Schwarzer, R., Herzig, E., Rao, D., Luo, X., Egedal, J. H., Hsiao, F., Widera, M., Hultquist, J. F., Grimmett, Z. W., Messer, R. J., Krogan, N. J., Deeks, S. G., Roan, N. R., Dittmer, U., Hasenkrug, K. J., & Greene, W. C. (2022). CCL2: a Chemokine Potentially Promoting Early Seeding of the Latent HIV Reservoir. mBio, 13(5). https://doi.org/10.1128/mbio.01891-22

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title = "CCL2: a Chemokine Potentially Promoting Early Seeding of the Latent HIV Reservoir",

abstract = "HIV infects long-lived CD4 memory T cells, establishing a latent viral reservoir that necessitates lifelong antiretroviral therapy (ART). How this reservoir is formed so quickly after infection remains unclear. We now show the innate inflammatory response to HIV infection results in CCL2 chemokine release, leading to recruitment of cells expressing the CCR2 receptor, including a subset of central memory CD4 T cells. Supporting a role for the CCL2/CCR2 axis in rapid reservoir formation, we find (i) treatment of humanized mice with anti-CCL2 antibodies during early HIV infection decreases reservoir seeding and preserves CCR2/51 cells and (ii) CCR2/51 cells from the blood of HIV-infected individuals on long-term ART contain significantly more integrated provirus than CCR2/5-negative memory or naive cells. Together, these studies support a model where the host{\textquoteright}s innate inflammatory response to HIV infection, including CCL2 production, leads to the recruitment of CCR2/51 central memory CD4 T cells to zones of virus-associated inflammation, likely contributing to rapid formation of the latent HIV reservoir.",

keywords = "CCL2, CRISPR, CyTOF, human immunodeficiency virus, latency, reservoir",

author = "Packard, {Thomas A.} and Roland Schwarzer and Eytan Herzig and Deepashri Rao and Xiaoyu Luo and Egedal, {Johanne H.} and Feng Hsiao and Marek Widera and Hultquist, {Judd F.} and Grimmett, {Zachary W.} and Messer, {Ronald J.} and Krogan, {Nevan J.} and Deeks, {Steven G.} and Roan, {Nadia R.} and Ulf Dittmer and Hasenkrug, {Kim J.} and Greene, {Warner C.}",

note = "Funding Information: We thank Jane Srivastava and Nandhini Raman of the Gladstone Flow Cytometry Core, the UCSF Diabetes Research Center for use of their CyTOF instrument, the UCSF Parnassus Flow Cytometry Core for CyTOF assistance, John C. W. Carroll for graphic arts, Francoise Chanut for editorial assistance, and Robin Givens for administrative assistance. Research reported in this publication was supported by the NIAID Intramural Research Program, NIAID, NHLBI, NIDA, NINDS, NIMH, and NIDDK of the National Institutes of Health under award number UM1AI164559 to the HOPE Collaboratory and R01 AI147777, R01 AI127219, and P01 AI131374. The Gladstone Institutes acknowledges the generous support of the James B. Pendleton Charitable Trust. M.W. and U.D. were supported by the DFG priority program 556 SPP1923 (WI 5086/1-1 and DI 714/18-2). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. There are no competing interests. Funding Information: Research reported in this publication was supported by the NIAID Intramural Research Program, NIAID, NHLBI, NIDA, NINDS, NIMH, and NIDDK of the National Institutes of Health under award number UM1AI164559 to the HOPE Collaboratory and R01 AI147777, R01 AI127219, and P01 AI131374. The Gladstone Institutes acknowledges the generous support of the James B. Pendleton Charitable Trust. M.W. and U.D. were supported by the DFG priority program 556 SPP1923 (WI 5086/1-1 and DI 714/18-2). Publisher Copyright: {\textcopyright} 2022 American Society for Microbiology. All rights reserved.",

year = "2022",

month = sep,

doi = "10.1128/mbio.01891-22",

language = "English (US)",

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journal = "mBio",

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T2 - a Chemokine Potentially Promoting Early Seeding of the Latent HIV Reservoir

AU - Packard, Thomas A.

AU - Schwarzer, Roland

AU - Herzig, Eytan

AU - Rao, Deepashri

AU - Luo, Xiaoyu

AU - Egedal, Johanne H.

AU - Hsiao, Feng

AU - Widera, Marek

AU - Hultquist, Judd F.

AU - Grimmett, Zachary W.

AU - Messer, Ronald J.

AU - Krogan, Nevan J.

AU - Deeks, Steven G.

AU - Roan, Nadia R.

AU - Dittmer, Ulf

AU - Hasenkrug, Kim J.

AU - Greene, Warner C.

N1 - Funding Information: We thank Jane Srivastava and Nandhini Raman of the Gladstone Flow Cytometry Core, the UCSF Diabetes Research Center for use of their CyTOF instrument, the UCSF Parnassus Flow Cytometry Core for CyTOF assistance, John C. W. Carroll for graphic arts, Francoise Chanut for editorial assistance, and Robin Givens for administrative assistance. Research reported in this publication was supported by the NIAID Intramural Research Program, NIAID, NHLBI, NIDA, NINDS, NIMH, and NIDDK of the National Institutes of Health under award number UM1AI164559 to the HOPE Collaboratory and R01 AI147777, R01 AI127219, and P01 AI131374. The Gladstone Institutes acknowledges the generous support of the James B. Pendleton Charitable Trust. M.W. and U.D. were supported by the DFG priority program 556 SPP1923 (WI 5086/1-1 and DI 714/18-2). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. There are no competing interests. Funding Information: Research reported in this publication was supported by the NIAID Intramural Research Program, NIAID, NHLBI, NIDA, NINDS, NIMH, and NIDDK of the National Institutes of Health under award number UM1AI164559 to the HOPE Collaboratory and R01 AI147777, R01 AI127219, and P01 AI131374. The Gladstone Institutes acknowledges the generous support of the James B. Pendleton Charitable Trust. M.W. and U.D. were supported by the DFG priority program 556 SPP1923 (WI 5086/1-1 and DI 714/18-2). Publisher Copyright: © 2022 American Society for Microbiology. All rights reserved.

PY - 2022/9

Y1 - 2022/9

N2 - HIV infects long-lived CD4 memory T cells, establishing a latent viral reservoir that necessitates lifelong antiretroviral therapy (ART). How this reservoir is formed so quickly after infection remains unclear. We now show the innate inflammatory response to HIV infection results in CCL2 chemokine release, leading to recruitment of cells expressing the CCR2 receptor, including a subset of central memory CD4 T cells. Supporting a role for the CCL2/CCR2 axis in rapid reservoir formation, we find (i) treatment of humanized mice with anti-CCL2 antibodies during early HIV infection decreases reservoir seeding and preserves CCR2/51 cells and (ii) CCR2/51 cells from the blood of HIV-infected individuals on long-term ART contain significantly more integrated provirus than CCR2/5-negative memory or naive cells. Together, these studies support a model where the host’s innate inflammatory response to HIV infection, including CCL2 production, leads to the recruitment of CCR2/51 central memory CD4 T cells to zones of virus-associated inflammation, likely contributing to rapid formation of the latent HIV reservoir.

AB - HIV infects long-lived CD4 memory T cells, establishing a latent viral reservoir that necessitates lifelong antiretroviral therapy (ART). How this reservoir is formed so quickly after infection remains unclear. We now show the innate inflammatory response to HIV infection results in CCL2 chemokine release, leading to recruitment of cells expressing the CCR2 receptor, including a subset of central memory CD4 T cells. Supporting a role for the CCL2/CCR2 axis in rapid reservoir formation, we find (i) treatment of humanized mice with anti-CCL2 antibodies during early HIV infection decreases reservoir seeding and preserves CCR2/51 cells and (ii) CCR2/51 cells from the blood of HIV-infected individuals on long-term ART contain significantly more integrated provirus than CCR2/5-negative memory or naive cells. Together, these studies support a model where the host’s innate inflammatory response to HIV infection, including CCL2 production, leads to the recruitment of CCR2/51 central memory CD4 T cells to zones of virus-associated inflammation, likely contributing to rapid formation of the latent HIV reservoir.

KW - CCL2

KW - CRISPR

KW - CyTOF

KW - human immunodeficiency virus

KW - latency

KW - reservoir

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CCL2: a Chemokine Potentially Promoting Early Seeding of the Latent HIV Reservoir

Abstract

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Keywords

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UN SDGs

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