Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5

ABSTRACT It has recently emerged that HIV-1 Nef counteracts the antiviral host proteins SERINC3 and SERINC5. In particular, SERINC5 inhibits the infectivity of progeny virions when incorporated. SERINC3 and SERINC5 are also counteracted by the unrelated murine leukemia virus glycosylated Gag (glycoG...

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Autores principales:	Yuanfei Wu, Balaji Olety, Eric R. Weiss, Elena Popova, Hikaru Yamanaka, Heinrich Göttlinger
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Nef SERINC5 human immunodeficiency virus infectivity virus replication Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4570759b8a0d412fab429d4bc1dbaa0d
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spelling	oai:doaj.org-article:4570759b8a0d412fab429d4bc1dbaa0d2021-11-15T15:55:23ZPotent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC510.1128/mBio.01071-192150-7511https://doaj.org/article/4570759b8a0d412fab429d4bc1dbaa0d2019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01071-19https://doaj.org/toc/2150-7511ABSTRACT It has recently emerged that HIV-1 Nef counteracts the antiviral host proteins SERINC3 and SERINC5. In particular, SERINC5 inhibits the infectivity of progeny virions when incorporated. SERINC3 and SERINC5 are also counteracted by the unrelated murine leukemia virus glycosylated Gag (glycoGag) protein, which possesses a potent Nef-like activity on HIV-1 infectivity. We now report that a minimal glycoGag termed glycoMA can fully substitute for Nef in promoting HIV-1 replication in Jurkat T lymphoid cells, indicating that Nef enhances replication in these cells mainly by counteracting SERINCs. In contrast, the SERINC antagonist glycoMA was unable to substitute for Nef in MOLT-3 T lymphoid cells, in which HIV-1 replication was highly dependent on Nef, and remained so even in the absence of SERINC3 and SERINC5. As in MOLT-3 cells, glycoMA was unable to substitute for Nef in stimulating HIV-1 replication in primary human cells. Although the ability of Nef mutants to promote HIV-1 replication in MOLT-3 cells correlated with the ability to engage endocytic machinery and to downregulate CD4, Nef nevertheless rescued virus replication under conditions where CD4 downregulation did not occur. Taken together, our observations raise the possibility that Nef triggers the endocytosis of a novel antiviral factor that is active against both laboratory-adapted and primary HIV-1 strains. IMPORTANCE The Nef protein of HIV-1 and the unrelated glycoGag protein of a murine leukemia virus similarly prevent the uptake of antiviral host proteins called SERINC3 and SERINC5 into HIV-1 particles, which enhances their infectiousness. We now show that although both SERINC antagonists can in principle similarly enhance HIV-1 replication, glycoGag is unable to substitute for Nef in primary human cells and in a T cell line called MOLT-3. In MOLT-3 cells, Nef remained crucial for HIV-1 replication even in the absence of SERINC3 and SERINC5. The pronounced effect of Nef on HIV-1 spreading in MOLT-3 cells correlated with the ability of Nef to engage cellular endocytic machinery and to downregulate the HIV-1 receptor CD4 but nevertheless persisted in the absence of CD4 downregulation. Collectively, our results provide evidence for a potent novel restriction activity that affects even relatively SERINC-resistant HIV-1 isolates and is counteracted by Nef.Yuanfei WuBalaji OletyEric R. WeissElena PopovaHikaru YamanakaHeinrich GöttlingerAmerican Society for MicrobiologyarticleNefSERINC5human immunodeficiency virusinfectivityvirus replicationMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Nef SERINC5 human immunodeficiency virus infectivity virus replication Microbiology QR1-502
spellingShingle	Nef SERINC5 human immunodeficiency virus infectivity virus replication Microbiology QR1-502 Yuanfei Wu Balaji Olety Eric R. Weiss Elena Popova Hikaru Yamanaka Heinrich Göttlinger Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5
description	ABSTRACT It has recently emerged that HIV-1 Nef counteracts the antiviral host proteins SERINC3 and SERINC5. In particular, SERINC5 inhibits the infectivity of progeny virions when incorporated. SERINC3 and SERINC5 are also counteracted by the unrelated murine leukemia virus glycosylated Gag (glycoGag) protein, which possesses a potent Nef-like activity on HIV-1 infectivity. We now report that a minimal glycoGag termed glycoMA can fully substitute for Nef in promoting HIV-1 replication in Jurkat T lymphoid cells, indicating that Nef enhances replication in these cells mainly by counteracting SERINCs. In contrast, the SERINC antagonist glycoMA was unable to substitute for Nef in MOLT-3 T lymphoid cells, in which HIV-1 replication was highly dependent on Nef, and remained so even in the absence of SERINC3 and SERINC5. As in MOLT-3 cells, glycoMA was unable to substitute for Nef in stimulating HIV-1 replication in primary human cells. Although the ability of Nef mutants to promote HIV-1 replication in MOLT-3 cells correlated with the ability to engage endocytic machinery and to downregulate CD4, Nef nevertheless rescued virus replication under conditions where CD4 downregulation did not occur. Taken together, our observations raise the possibility that Nef triggers the endocytosis of a novel antiviral factor that is active against both laboratory-adapted and primary HIV-1 strains. IMPORTANCE The Nef protein of HIV-1 and the unrelated glycoGag protein of a murine leukemia virus similarly prevent the uptake of antiviral host proteins called SERINC3 and SERINC5 into HIV-1 particles, which enhances their infectiousness. We now show that although both SERINC antagonists can in principle similarly enhance HIV-1 replication, glycoGag is unable to substitute for Nef in primary human cells and in a T cell line called MOLT-3. In MOLT-3 cells, Nef remained crucial for HIV-1 replication even in the absence of SERINC3 and SERINC5. The pronounced effect of Nef on HIV-1 spreading in MOLT-3 cells correlated with the ability of Nef to engage cellular endocytic machinery and to downregulate the HIV-1 receptor CD4 but nevertheless persisted in the absence of CD4 downregulation. Collectively, our results provide evidence for a potent novel restriction activity that affects even relatively SERINC-resistant HIV-1 isolates and is counteracted by Nef.
format	article
author	Yuanfei Wu Balaji Olety Eric R. Weiss Elena Popova Hikaru Yamanaka Heinrich Göttlinger
author_facet	Yuanfei Wu Balaji Olety Eric R. Weiss Elena Popova Hikaru Yamanaka Heinrich Göttlinger
author_sort	Yuanfei Wu
title	Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5
title_short	Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5
title_full	Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5
title_fullStr	Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5
title_full_unstemmed	Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5
title_sort	potent enhancement of hiv-1 replication by nef in the absence of serinc3 and serinc5
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/4570759b8a0d412fab429d4bc1dbaa0d
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Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5

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