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Understand the Role of HIV-1 Envelope Glycoprotein in Counteracting Restriction Factor SERINC5.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Understand the Role of HIV-1 Envelope Glycoprotein in Counteracting Restriction Factor SERINC5./
Author:	Beitari, Saina.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	173 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-10, Section: B.
Contained By:	Dissertations Abstracts International82-10B.
Subject:	Monoclonal antibodies. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28383774
ISBN:	9798708717108

Understand the Role of HIV-1 Envelope Glycoprotein in Counteracting Restriction Factor SERINC5.
Beitari, Saina.

Understand the Role of HIV-1 Envelope Glycoprotein in Counteracting Restriction Factor SERINC5. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 173 p.

Source: Dissertations Abstracts International, Volume: 82-10, Section: B.

Thesis (Ph.D.)--McGill University (Canada), 2020.

This item must not be sold to any third party vendors.

Despite the success of the antiretroviral therapies in long-term suppression of HIV-1 viremia in the infected individuals, HIV-1 continues to infect two million people every year and causes close to one million deaths. Cure approaches and vaccines are the priorities of HIV research in an effort to end this decades-long pandemic. My research project is dedicated to understand the host restriction mechanisms that have posed a barrier for the cross-species transmission of HIV from non-human primates into humans. The goal is to elucidate the detailed molecular mechanisms and use the knowledge to develop HIV cure. A group of HIV-1 restriction factors inhibiting distinct steps of HIV-1 replication have been identified in the past two decades. In return, HIV-1 encodes accessory proteins to counter these host restriction factors and to warrant viral replication in vivo. One of the HIV-1 accessory proteins, Nef, plays a crucial role in HIV-1 pathogenesis. Recent findings reveal that Nef increases viral infectivity by countering a restriction factor called serine incorporator 5 (SERINC5), which belongs to a protein family with 10 transmembrane domains. Studies show that SERINC5 ablates HIV-1 infectivity through incorporating into progeny virions and blocking viral entry. I have discovered that in addition to Nef, HIV-1 envelope (Env) glycoprotein also overcomes SERINC5 inhibition. By testing a large panel of primary HIV-1 Env clones of different subtypes against ectopically expressed SERINC5, I found a high prevalence of SERINC5-resistant HIV-1 strains. These SERINC5-resistant HIV-1 Env proteins do not prevent SERINC5 incorporation into the virus particles. But the virus-bearing SERINC5 protein sensitizes HIV-1 to broadly neutralizing antibodies that target the membrane proximal external region (MPER) of Env. This finding explains the necessity of Nef-mediated removal of SERINC5 from HIV-1 particles so that HIV-1 can protect itself from the MPER-targeting antibodies. I further tested the sensitivity of HIV-1 Env clones to the interferon-inducible transmembrane protein 3 (IFITM3) which also inhibits HIV-1 entry. In contrast to the resistance of primary HIV-1 Env clones to SERINC5, the Env clones from the chronic stage are sensitive to IFITM3 whereas the Env clones from the transmitted/founder HIV-1 are resistant. This suggests that IFITM3 and SERINC5 exert different levels of pressures on HIV-1 during the course of HIV-1 infection. Interestingly, I observed that SERINC5 incorporation into HIV-1 virions render particles more sensitive to entry inhibitors such as CD4 mimetic peptide M48U1.Together, I have discovered the role of HIV-1 Env protein in countering SERINC5 restriction, observed that SERINC5 and IFITM3 exert differential inhibitory pressures on HIV-1 Env over different stages of HIV-1 progression, and HIV-1 Env uses varied strategies to resist these two restriction factors.

ISBN: 9798708717108Subjects--Topical Terms:

603890
Monoclonal antibodies.
Subjects--Index Terms:

HIV-1 envelope glycoprotein

Understand the Role of HIV-1 Envelope Glycoprotein in Counteracting Restriction Factor SERINC5.
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245 1 0 $a Understand the Role of HIV-1 Envelope Glycoprotein in Counteracting Restriction Factor SERINC5.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2020
300 $a 173 p.
500 $a Source: Dissertations Abstracts International, Volume: 82-10, Section: B.
500 $a Advisor: Liang, Chen.
502 $a Thesis (Ph.D.)--McGill University (Canada), 2020.
506 $a This item must not be sold to any third party vendors.
520 $a Despite the success of the antiretroviral therapies in long-term suppression of HIV-1 viremia in the infected individuals, HIV-1 continues to infect two million people every year and causes close to one million deaths. Cure approaches and vaccines are the priorities of HIV research in an effort to end this decades-long pandemic. My research project is dedicated to understand the host restriction mechanisms that have posed a barrier for the cross-species transmission of HIV from non-human primates into humans. The goal is to elucidate the detailed molecular mechanisms and use the knowledge to develop HIV cure. A group of HIV-1 restriction factors inhibiting distinct steps of HIV-1 replication have been identified in the past two decades. In return, HIV-1 encodes accessory proteins to counter these host restriction factors and to warrant viral replication in vivo. One of the HIV-1 accessory proteins, Nef, plays a crucial role in HIV-1 pathogenesis. Recent findings reveal that Nef increases viral infectivity by countering a restriction factor called serine incorporator 5 (SERINC5), which belongs to a protein family with 10 transmembrane domains. Studies show that SERINC5 ablates HIV-1 infectivity through incorporating into progeny virions and blocking viral entry. I have discovered that in addition to Nef, HIV-1 envelope (Env) glycoprotein also overcomes SERINC5 inhibition. By testing a large panel of primary HIV-1 Env clones of different subtypes against ectopically expressed SERINC5, I found a high prevalence of SERINC5-resistant HIV-1 strains. These SERINC5-resistant HIV-1 Env proteins do not prevent SERINC5 incorporation into the virus particles. But the virus-bearing SERINC5 protein sensitizes HIV-1 to broadly neutralizing antibodies that target the membrane proximal external region (MPER) of Env. This finding explains the necessity of Nef-mediated removal of SERINC5 from HIV-1 particles so that HIV-1 can protect itself from the MPER-targeting antibodies. I further tested the sensitivity of HIV-1 Env clones to the interferon-inducible transmembrane protein 3 (IFITM3) which also inhibits HIV-1 entry. In contrast to the resistance of primary HIV-1 Env clones to SERINC5, the Env clones from the chronic stage are sensitive to IFITM3 whereas the Env clones from the transmitted/founder HIV-1 are resistant. This suggests that IFITM3 and SERINC5 exert different levels of pressures on HIV-1 during the course of HIV-1 infection. Interestingly, I observed that SERINC5 incorporation into HIV-1 virions render particles more sensitive to entry inhibitors such as CD4 mimetic peptide M48U1.Together, I have discovered the role of HIV-1 Env protein in countering SERINC5 restriction, observed that SERINC5 and IFITM3 exert differential inhibitory pressures on HIV-1 Env over different stages of HIV-1 progression, and HIV-1 Env uses varied strategies to resist these two restriction factors.
520 $a Malgre le succes des therapies antiretrovirales dans la suppression a long terme de la viremie du VIH-1 chez les personnes infectees, le VIH-1 continue d'infecter deux millions de personnes chaque annee et provoque pres d'un million de deces. Les approches de guerison et les vaccins sont les priorites de la recherche sur le VIH afin de mettre fin a cette pandemie de plusieurs decennies. Mon projet de recherche vise a comprendre les mecanismes de restriction de l'hote qui ont pose une barriere a la transmission inter-especes du VIH, des primates non-humains aux humains. Le but est d'elucider les mecanismes moleculaires detailles et d'utiliser ces connaissances pour developper un traitement contre le VIH. Des facteurs cellulaires de restriction du VIH inhibant des etapes specifiques de la replication du virus ont ete identifies au cours des deux dernieres decennies. Le VIH-1 code pour des proteines accessoires qui contrent ces facteurs de restriction et garantissent sa replication virale in vivo. L'une de ces proteines accessoires, Nef, joue un role crucial dans la pathogenese du VIH-1. De recentes decouvertes ont revele que Nef augmente l'infectiosite virale en bloquant un nouveau facteur de restriction appele serine incorporator 5 (SERINC5) qui fait partie d'une famille de proteines contenant 10 domaines transmembranaires. Des etudes montrent que SERINC5 elimine l'infectiosite du VIH-1 en s'incorporant dans la descendance des virions et en bloquant l'entree virale. J'ai decouvert qu'en plus de Nef, la glycoproteine d'enveloppe (Env) du VIH-1, surmonte l'inhibition de SERINC5. En testant un large panel de clones primaires de Env de differents sous-types contre SERINC5 exprimee ectopiquement, j'ai decouvert une forte prevalence de souches de VIH-1 resistantes a SERINC5. Ces proteines Env resistantes a SERINC5 n'empechent pas l'incorporation de SERINC5 dans les particules virales. Cependant, elles le sensibilisent aux anticorps neutralisants a grande echelle qui ciblent la region externe proximale de la membrane (membrane proximal external region; MPER) de Env. Cette decouverte explique la necessite d'eliminer SERINC5 des particules du VIH-1 par l'intermediaire du Nef afin que le virus puisse se proteger contre les anticorps ciblant le MPER. De plus, j'ai teste la sensibilite des clones Env du VIH-1 a la proteine transmembranaire inductible par l'interferon 3 (IFITM3) qui inhibe egalement l'entree du virus. Contrairement a la resistance des clones Env primaires du VIH-1 a SERINC5, les clones Env du stade chronique sont sensibles a IFITM3 tandis que les clones Env du VIH-1 transmetteur/fondateur sont resistants. Cela suggere que IFITM3 et SERINC5 exercent differents niveaux de pression sur le VIH-1 au cours de l'infection virale. De facon interessante, j'ai observe que l'incorporation de SERINC5 dans les virions du VIH-1 rend les particules plus sensibles aux inhibiteurs d'entree tels que le peptide M48U1, mime du recepteur CD4.Ainsi, j'ai decouvert et caracterise le role de la proteine Env du VIH-1 contre la restriction de SERINC5. J'ai egalement observe que SERINC5 et IFITM3 exercent des pressions inhibitrices differentielles sur Env a des stades distincts de la progression du VIH-1, et enfin qu'Env utilise des strategies variees pour resister a ces deux facteurs de restriction.
590 $a School code: 0781.
650 4 $a Monoclonal antibodies. $3 603890
650 4 $a Glycoproteins. $3 667972
650 4 $a Vaccines. $3 684854
650 4 $a Viruses. $3 571474
650 4 $a Human immunodeficiency virus--HIV. $3 3564909
650 4 $a Acquired immune deficiency syndrome--AIDS. $3 3564911
650 4 $a Cytotoxicity. $3 3682273
650 4 $a Cloning. $3 571606
650 4 $a Binding sites. $3 3560349
650 4 $a Virology. $3 642304
650 4 $a Proteins. $3 558769
650 4 $a Microbiology. $3 536250
650 4 $a Immunology. $3 611031
653 $a HIV-1 envelope glycoprotein
653 $a Counteracting restriction factor SERINC5
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