Substitution of the transmembrane domain of Vpu in simian-human immunodeficiency virus (SHIV{sub KU1bMC33}) with that of M2 of influenza A results in a virus that is sensitive to inhibitors of the M2 ion channel and is pathogenic for pig-tailed macaques

Hout, David R; Gomez, Melissa L; Pacyniak, Erik; Gomez, Lisa M; Fegley, Barbara; Mulcahy, Ellyn R; Hill, M Sarah; Culley, Nathan; Pinson, David M; Nothnick, Warren; Powers, Michael F; Wong, Scott W; Stephens, Edward B

doi:10.1016/J.VIROL.2005.0

Title: Substitution of the transmembrane domain of Vpu in simian-human immunodeficiency virus (SHIV{sub KU1bMC33}) with that of M2 of influenza A results in a virus that is sensitive to inhibitors of the M2 ion channel and is pathogenic for pig-tailed macaques

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Abstract

The Vpu protein of human immunodeficiency virus type 1 has been shown to shunt the CD4 receptor molecule to the proteasome for degradation and to enhance virus release from infected cells. The exact mechanism by which the Vpu protein enhances virus release is currently unknown but some investigators have shown that this function is associated with the transmembrane domain and potential ion channel properties. In this study, we determined if the transmembrane domain of Vpu could be functionally substituted with that of the prototypical viroporin, the M2 protein of influenza A virus. We constructed chimeric vpu gene in which the transmembrane domain of Vpu was replaced with that of the M2 protein of influenza. This chimeric vpu gene was substituted for the vpu gene in the genome of a pathogenic simian human immunodeficiency virus, SHIV{sub KU-1bMC33}. The resulting virus, SHIV{sub M2}, synthesized a Vpu protein that had a slightly different M{sub r} compared to the parental SHIV{sub KU-1bMC33}, reflecting the different sizes of the two Vpu proteins. The SHIV{sub M2} was shown to replicate with slightly reduced kinetics when compared to the parental SHIV{sub KU-1bMC33} but electron microscopy revealed that the site of maturation was similar to the parental virusmore »« less

Authors:

Hout, David R ^[1]; Gomez, Melissa L ^[1]; Pacyniak, Erik ^[1]; Gomez, Lisa M ^[1]; Fegley, Barbara ^[1]; Mulcahy, Ellyn R ^[1]; Hill, M Sarah ^[1]; Culley, Nathan ^[2]; Pinson, David M ^[3]; Nothnick, Warren ^[4]; Powers, Michael F; Wong, Scott W ^[5]; Stephens, Edward B ^[1]

Department of Anatomy and Cell Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160 (United States)
Laboratory Animal Resources, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160 (United States)
Department of Laboratory Medicine and Pathology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160 (United States)
Department of Obstetrics and Gynecology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160 (United States)
Vaccine and Gene Therapy Institute, Oregon National Primate Research Center, Oregon University for the Health Sciences, Beaverton, OR 97003 (United States)

Publication Date:: Fri Jan 20 00:00:00 EST 2006

OSTI Identifier:: 20779451

Resource Type:: Journal Article

Journal Name:: Virology

Additional Journal Information:: Journal Volume: 344; Journal Issue: 2; Other Information: DOI: 10.1016/j.virol.2005.08.022; PII: S0042-6822(05)00469-1; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0042-6822

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; AIDS VIRUS; CULTURE MEDIA; DRUGS; ELECTRON MICROSCOPY; GENES; INFLUENZA; INOCULATION; PATHOGENESIS; RECEPTORS; SWINE

Citation Formats


                    Hout, David R, Gomez, Melissa L, Pacyniak, Erik, Gomez, Lisa M, Fegley, Barbara, Mulcahy, Ellyn R, Hill, M Sarah, Culley, Nathan, Pinson, David M, Nothnick, Warren, Powers, Michael F, Wong, Scott W, and Stephens, Edward B. Substitution of the transmembrane domain of Vpu in simian-human immunodeficiency virus (SHIV{sub KU1bMC33}) with that of M2 of influenza A results in a virus that is sensitive to inhibitors of the M2 ion channel and is pathogenic for pig-tailed macaques.  United States: N. p., 2006. 
        Web.  doi:10.1016/J.VIROL.2005.0.

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                    Hout, David R, Gomez, Melissa L, Pacyniak, Erik, Gomez, Lisa M, Fegley, Barbara, Mulcahy, Ellyn R, Hill, M Sarah, Culley, Nathan, Pinson, David M, Nothnick, Warren, Powers, Michael F, Wong, Scott W, & Stephens, Edward B. Substitution of the transmembrane domain of Vpu in simian-human immunodeficiency virus (SHIV{sub KU1bMC33}) with that of M2 of influenza A results in a virus that is sensitive to inhibitors of the M2 ion channel and is pathogenic for pig-tailed macaques.  United States.  https://doi.org/10.1016/J.VIROL.2005.0

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                    Hout, David R, Gomez, Melissa L, Pacyniak, Erik, Gomez, Lisa M, Fegley, Barbara, Mulcahy, Ellyn R, Hill, M Sarah, Culley, Nathan, Pinson, David M, Nothnick, Warren, Powers, Michael F, Wong, Scott W, and Stephens, Edward B. 2006.  
        "Substitution of the transmembrane domain of Vpu in simian-human immunodeficiency virus (SHIV{sub KU1bMC33}) with that of M2 of influenza A results in a virus that is sensitive to inhibitors of the M2 ion channel and is pathogenic for pig-tailed macaques".  United States.  https://doi.org/10.1016/J.VIROL.2005.0.

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@article{osti_20779451,

  title        = {Substitution of the transmembrane domain of Vpu in simian-human immunodeficiency virus (SHIV{sub KU1bMC33}) with that of M2 of influenza A results in a virus that is sensitive to inhibitors of the M2 ion channel and is pathogenic for pig-tailed macaques},

  author       = {Hout, David R and Gomez, Melissa L and Pacyniak, Erik and Gomez, Lisa M and Fegley, Barbara and Mulcahy, Ellyn R and Hill, M Sarah and Culley, Nathan and Pinson, David M and Nothnick, Warren and Powers, Michael F and Wong, Scott W and Stephens, Edward B},

  abstractNote = {The Vpu protein of human immunodeficiency virus type 1 has been shown to shunt the CD4 receptor molecule to the proteasome for degradation and to enhance virus release from infected cells. The exact mechanism by which the Vpu protein enhances virus release is currently unknown but some investigators have shown that this function is associated with the transmembrane domain and potential ion channel properties. In this study, we determined if the transmembrane domain of Vpu could be functionally substituted with that of the prototypical viroporin, the M2 protein of influenza A virus. We constructed chimeric vpu gene in which the transmembrane domain of Vpu was replaced with that of the M2 protein of influenza. This chimeric vpu gene was substituted for the vpu gene in the genome of a pathogenic simian human immunodeficiency virus, SHIV{sub KU-1bMC33}. The resulting virus, SHIV{sub M2}, synthesized a Vpu protein that had a slightly different M{sub r} compared to the parental SHIV{sub KU-1bMC33}, reflecting the different sizes of the two Vpu proteins. The SHIV{sub M2} was shown to replicate with slightly reduced kinetics when compared to the parental SHIV{sub KU-1bMC33} but electron microscopy revealed that the site of maturation was similar to the parental virus SHIV{sub KU1bMC33}. We show that the replication and spread of SHIV{sub M2} could be blocked with the antiviral drug rimantadine, which is known to target the M2 ion channel. Our results indicate a dose dependent inhibition of SHIV{sub M2} with 100 {mu}M rimantadine resulting in a >95% decrease in p27 released into the culture medium. Rimantadine did not affect the replication of the parental SHIV{sub KU-1bMC33}. Examination of SHIV{sub M2}-infected cells treated with 50 {mu}M rimantadine revealed numerous viral particles associated with the cell plasma membrane and within intracytoplasmic vesicles, which is similar to HIV-1 mutants lacking a functional vpu. To determine if SHIV{sub M2} was as pathogenic as the parental SHIV{sub KU-1bMC33} virus, two pig-tailed macaques were inoculated and followed for up to 8 months. Both pig-tailed macaques developed severe CD4{sup +} T cell loss within 1 month of inoculation, high viral loads, and histological lesions consistent with lymphoid depletion similar to the parental SHIV{sub KU-1bMC33}. Taken together, these results indicate for the first time that the TM domain of the Vpu protein can be functionally substituted with the TM of M2 of influenza A virus, and shows that compounds that target the TM domain of Vpu protein of HIV-1 could serve as novel anti-HIV-1 drugs.},

  doi          = {10.1016/J.VIROL.2005.0},

  url          = {https://www.osti.gov/biblio/20779451},
  journal      = {Virology},

  issn         = {0042-6822},

  number       = 2,

  volume       = 344,

  place        = {United States},

  year         = {Fri Jan 20 00:00:00 EST 2006},

  month        = {Fri Jan 20 00:00:00 EST 2006}

}

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https://doi.org/10.1016/J.VIROL.2005.0

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A single amino acid substitution within the transmembrane domain of the human immunodeficiency virus type 1 Vpu protein renders simian-human immunodeficiency virus (SHIV{sub KU-1bMC33}) susceptible to rimantadine

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