Scrambling of the amino acids within the transmembrane domain of Vpu results in a simian-human immunodeficiency virus (SHIVTM) that is less pathogenic for pig-tailed macaques

David R. Hout, Melissa L. Gomez, Erik Pacyniak, Lisa M. Gomez, Sarah H. Inbody, Ellyn R. Mulcahy, Nathan Culley, David M. Pinson, Michael F. Powers, Scott Wong, Edward B. Stephens

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Previous studies have shown that the transmembrane (TM) domain of the subtype B Vpu enhances virion release from cells and some studies have shown that this domain may form an oligomeric structure with properties of an ion channel. To date, no studies have been performed to assess the role of this domain in virus pathogenesis in a macaque model of disease. Using a pathogenic molecular clone of simian human immunodeficiency virus (SHIV KU-1bMC33), we have generated a novel virus in which the transmembrane domain of the Vpu protein was scrambled but maintained hydrophobic in nature (SHIVTM), which presumably would disrupt any ion channel TM properties of this protein. Vectors expressing the Vpu as a fusion protein with the enhanced green fluorescent protein (VpuTMEGFP) indicate that it was transported to the same intracellular compartment as the unmodified Vpu protein but did not down-regulate cell surface expression of CD4. To assess the pathogenicity of SHIVTM, three pig-tailed macaques were inoculated with the SHIVTM and monitored for 6-8 months for CD4+ T cell levels, viral loads and the stability of the sequence of the vpu gene. Our results indicated that unlike the parental SHIVKU-1bMC33, inoculation of macaques with SHIVTM did not cause a severe CD4+ T cell loss over the course of their infections. Sequence analysis of the vpu gene analyzed from sequential PBMC samples derived from macaques revealed that the scrambled TM was stable during the course of infection. At necropsy, examination of tissues revealed low viral loads and none of the pathology commonly observed in lymphoid and non-lymphoid tissues following inoculation with the pathogenic parental SHIVKU-1bMC33 virus. Thus, these results show for the first time that the TM domain of Vpu contributes to the pathogenicity of SHIV KU-1bMC33 in pig-tailed macaques.

Original languageEnglish (US)
Pages (from-to)56-69
Number of pages14
JournalVirology
Volume339
Issue number1
DOIs
StatePublished - Aug 15 2005

Fingerprint

Simian Immunodeficiency Virus
Macaca
Swine
HIV
vpu Genes
Amino Acids
Viruses
Viral Load
Ion Channels
Virulence
T-Lymphocytes
Proteins
Infection
Virion
Sequence Analysis
Down-Regulation
Clone Cells
Pathology

Keywords

  • HIV-1
  • Pathogenesis
  • SHIV
  • Transmembrane domain
  • Vpu

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

Cite this

Scrambling of the amino acids within the transmembrane domain of Vpu results in a simian-human immunodeficiency virus (SHIVTM) that is less pathogenic for pig-tailed macaques. / Hout, David R.; Gomez, Melissa L.; Pacyniak, Erik; Gomez, Lisa M.; Inbody, Sarah H.; Mulcahy, Ellyn R.; Culley, Nathan; Pinson, David M.; Powers, Michael F.; Wong, Scott; Stephens, Edward B.

In: Virology, Vol. 339, No. 1, 15.08.2005, p. 56-69.

Research output: Contribution to journalArticle

Hout, DR, Gomez, ML, Pacyniak, E, Gomez, LM, Inbody, SH, Mulcahy, ER, Culley, N, Pinson, DM, Powers, MF, Wong, S & Stephens, EB 2005, 'Scrambling of the amino acids within the transmembrane domain of Vpu results in a simian-human immunodeficiency virus (SHIVTM) that is less pathogenic for pig-tailed macaques', Virology, vol. 339, no. 1, pp. 56-69. https://doi.org/10.1016/j.virol.2005.04.038
Hout, David R. ; Gomez, Melissa L. ; Pacyniak, Erik ; Gomez, Lisa M. ; Inbody, Sarah H. ; Mulcahy, Ellyn R. ; Culley, Nathan ; Pinson, David M. ; Powers, Michael F. ; Wong, Scott ; Stephens, Edward B. / Scrambling of the amino acids within the transmembrane domain of Vpu results in a simian-human immunodeficiency virus (SHIVTM) that is less pathogenic for pig-tailed macaques. In: Virology. 2005 ; Vol. 339, No. 1. pp. 56-69.
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AU - Pacyniak, Erik

AU - Gomez, Lisa M.

AU - Inbody, Sarah H.

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