HIV-1 Vpu Promotes Phagocytosis of Infected CD4<sup>+</sup> T Cells by Macrophages through Downregulation of CD47

ABSTRACT Human immunodeficiency virus (HIV) remodels the cell surface of infected cells to facilitate viral dissemination and promote immune evasion. The membrane-associated viral protein U (Vpu) accessory protein encoded by HIV-1 plays a key role in this process by altering cell surface levels of m...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Lijun Cong, Scott M. Sugden, Pascal Leclair, Chinten James Lim, Tram N. Q. Pham, Éric A. Cohen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	CD47 HIV HIV dissemination HIV infection Vpu macrophage reservoir Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d6fdd7d783664074913626708b92d350
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:d6fdd7d783664074913626708b92d350
record_format	dspace
spelling	oai:doaj.org-article:d6fdd7d783664074913626708b92d3502021-11-10T18:37:52ZHIV-1 Vpu Promotes Phagocytosis of Infected CD4<sup>+</sup> T Cells by Macrophages through Downregulation of CD4710.1128/mBio.01920-212150-7511https://doaj.org/article/d6fdd7d783664074913626708b92d3502021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01920-21https://doaj.org/toc/2150-7511ABSTRACT Human immunodeficiency virus (HIV) remodels the cell surface of infected cells to facilitate viral dissemination and promote immune evasion. The membrane-associated viral protein U (Vpu) accessory protein encoded by HIV-1 plays a key role in this process by altering cell surface levels of multiple host proteins. Using an unbiased quantitative plasma membrane profiling approach, we previously identified CD47 as a putative host target downregulated by Vpu. CD47 is a ubiquitously expressed cell surface protein that interacts with the myeloid cell inhibitory receptor signal regulatory protein-alpha (SIRPα) to deliver a “don’t-eat-me” signal, thus protecting cells from phagocytosis. In this study, we investigate whether CD47 modulation by HIV-1 Vpu might promote the susceptibility of macrophages to viral infection via phagocytosis of infected CD4+ T cells. Indeed, we find that Vpu downregulates CD47 expression on infected CD4+ T cells, leading to enhanced capture and phagocytosis by macrophages. We further provide evidence that this Vpu-dependent process allows a C-C chemokine receptor type 5 (CCR5)-tropic transmitted/founder (T/F) virus, which otherwise poorly infects macrophages in its cell-free form, to efficiently infect macrophages. Importantly, we show that HIV-1-infected cells expressing a Vpu-resistant CD47 mutant are less prone to infecting macrophages through phagocytosis. Mechanistically, Vpu forms a physical complex with CD47 through its transmembrane domain and targets the latter for lysosomal degradation. These results reveal a novel role of Vpu in modulating macrophage infection, which has important implications for HIV-1 transmission in early stages of infection and the establishment of viral reservoir. IMPORTANCE Macrophages play critical roles in human immunodeficiency virus (HIV) transmission, viral spread early in infection, and as a reservoir of virus. Selective capture and engulfment of HIV-1-infected T cells was shown to drive efficient macrophage infection, suggesting that this mechanism represents an important mode of infection notably for weakly macrophage-tropic T/F viruses. In this study, we provide insight into the signals that regulate this process. We show that the HIV-1 accessory protein viral protein U (Vpu) downregulates cell surface levels of CD47, a host protein that interacts with the inhibitory receptor signal regulatory protein-alpha (SIRPα), to deliver a “don’t-eat-me” signal to macrophages. This allows for enhanced capture and phagocytosis of infected T cells by macrophages, ultimately leading to their productive infection even with transmitted/founder (T/F) virus. These findings provide new insights into the mechanisms governing the intercellular transmission of HIV-1 to macrophages with implications for the establishment of the macrophage reservoir and early HIV-1 dissemination in vivo.Lijun CongScott M. SugdenPascal LeclairChinten James LimTram N. Q. PhamÉric A. CohenAmerican Society for MicrobiologyarticleCD47HIVHIV disseminationHIV infectionVpumacrophage reservoirMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CD47 HIV HIV dissemination HIV infection Vpu macrophage reservoir Microbiology QR1-502
spellingShingle	CD47 HIV HIV dissemination HIV infection Vpu macrophage reservoir Microbiology QR1-502 Lijun Cong Scott M. Sugden Pascal Leclair Chinten James Lim Tram N. Q. Pham Éric A. Cohen HIV-1 Vpu Promotes Phagocytosis of Infected CD4<sup>+</sup> T Cells by Macrophages through Downregulation of CD47
description	ABSTRACT Human immunodeficiency virus (HIV) remodels the cell surface of infected cells to facilitate viral dissemination and promote immune evasion. The membrane-associated viral protein U (Vpu) accessory protein encoded by HIV-1 plays a key role in this process by altering cell surface levels of multiple host proteins. Using an unbiased quantitative plasma membrane profiling approach, we previously identified CD47 as a putative host target downregulated by Vpu. CD47 is a ubiquitously expressed cell surface protein that interacts with the myeloid cell inhibitory receptor signal regulatory protein-alpha (SIRPα) to deliver a “don’t-eat-me” signal, thus protecting cells from phagocytosis. In this study, we investigate whether CD47 modulation by HIV-1 Vpu might promote the susceptibility of macrophages to viral infection via phagocytosis of infected CD4+ T cells. Indeed, we find that Vpu downregulates CD47 expression on infected CD4+ T cells, leading to enhanced capture and phagocytosis by macrophages. We further provide evidence that this Vpu-dependent process allows a C-C chemokine receptor type 5 (CCR5)-tropic transmitted/founder (T/F) virus, which otherwise poorly infects macrophages in its cell-free form, to efficiently infect macrophages. Importantly, we show that HIV-1-infected cells expressing a Vpu-resistant CD47 mutant are less prone to infecting macrophages through phagocytosis. Mechanistically, Vpu forms a physical complex with CD47 through its transmembrane domain and targets the latter for lysosomal degradation. These results reveal a novel role of Vpu in modulating macrophage infection, which has important implications for HIV-1 transmission in early stages of infection and the establishment of viral reservoir. IMPORTANCE Macrophages play critical roles in human immunodeficiency virus (HIV) transmission, viral spread early in infection, and as a reservoir of virus. Selective capture and engulfment of HIV-1-infected T cells was shown to drive efficient macrophage infection, suggesting that this mechanism represents an important mode of infection notably for weakly macrophage-tropic T/F viruses. In this study, we provide insight into the signals that regulate this process. We show that the HIV-1 accessory protein viral protein U (Vpu) downregulates cell surface levels of CD47, a host protein that interacts with the inhibitory receptor signal regulatory protein-alpha (SIRPα), to deliver a “don’t-eat-me” signal to macrophages. This allows for enhanced capture and phagocytosis of infected T cells by macrophages, ultimately leading to their productive infection even with transmitted/founder (T/F) virus. These findings provide new insights into the mechanisms governing the intercellular transmission of HIV-1 to macrophages with implications for the establishment of the macrophage reservoir and early HIV-1 dissemination in vivo.
format	article
author	Lijun Cong Scott M. Sugden Pascal Leclair Chinten James Lim Tram N. Q. Pham Éric A. Cohen
author_facet	Lijun Cong Scott M. Sugden Pascal Leclair Chinten James Lim Tram N. Q. Pham Éric A. Cohen
author_sort	Lijun Cong
title	HIV-1 Vpu Promotes Phagocytosis of Infected CD4<sup>+</sup> T Cells by Macrophages through Downregulation of CD47
title_short	HIV-1 Vpu Promotes Phagocytosis of Infected CD4<sup>+</sup> T Cells by Macrophages through Downregulation of CD47
title_full	HIV-1 Vpu Promotes Phagocytosis of Infected CD4<sup>+</sup> T Cells by Macrophages through Downregulation of CD47
title_fullStr	HIV-1 Vpu Promotes Phagocytosis of Infected CD4<sup>+</sup> T Cells by Macrophages through Downregulation of CD47
title_full_unstemmed	HIV-1 Vpu Promotes Phagocytosis of Infected CD4<sup>+</sup> T Cells by Macrophages through Downregulation of CD47
title_sort	hiv-1 vpu promotes phagocytosis of infected cd4<sup>+</sup> t cells by macrophages through downregulation of cd47
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/d6fdd7d783664074913626708b92d350
work_keys_str_mv	AT lijuncong hiv1vpupromotesphagocytosisofinfectedcd4supsuptcellsbymacrophagesthroughdownregulationofcd47 AT scottmsugden hiv1vpupromotesphagocytosisofinfectedcd4supsuptcellsbymacrophagesthroughdownregulationofcd47 AT pascalleclair hiv1vpupromotesphagocytosisofinfectedcd4supsuptcellsbymacrophagesthroughdownregulationofcd47 AT chintenjameslim hiv1vpupromotesphagocytosisofinfectedcd4supsuptcellsbymacrophagesthroughdownregulationofcd47 AT tramnqpham hiv1vpupromotesphagocytosisofinfectedcd4supsuptcellsbymacrophagesthroughdownregulationofcd47 AT ericacohen hiv1vpupromotesphagocytosisofinfectedcd4supsuptcellsbymacrophagesthroughdownregulationofcd47
_version_	1718439821482917888

HIV-1 Vpu Promotes Phagocytosis of Infected CD4<sup>+</sup> T Cells by Macrophages through Downregulation of CD47

Ejemplares similares