Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2

Tetherin, also known as BST2, CD317 or HM1.24, was recently identified as an interferon-inducible host-cell factor that interferes with the detachment of virus particles from infected cells. HIV-1 overcomes this restriction by expressing an accessory protein, Vpu, which counteracts tetherin. Since l...

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Bibliographic Details
Published in:PLoS pathogens 2009-05, Vol.5 (5), p.e1000429-e1000429
Main Authors: Jia, Bin, Serra-Moreno, Ruth, Neidermyer, William, Rahmberg, Andrew, Mackey, John, Fofana, Ismael Ben, Johnson, Welkin E, Westmoreland, Susan, Evans, David T
Format: Article
Language:English
Subjects:
Acquired immune deficiency syndrome
AIDS
Amino Acid Sequence
Amino acids
Animals
Antigens, CD - genetics
Antigens, CD - metabolism
Cell culture
Cell Line
Cercocebus atys
Down-Regulation
Experiments
Genetic aspects
GPI-Linked Proteins
Health aspects
HIV
HIV (Viruses)
HIV-1 - genetics
Human immunodeficiency virus
Human immunodeficiency virus 1
Human immunodeficiency virus 2
Human Immunodeficiency Virus Proteins - genetics
Human Immunodeficiency Virus Proteins - metabolism
Humans
Interferon
Interferons - metabolism
Lentivirus
Macaca mulatta
Medical research
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Molecular Sequence Data
Primates
Protein Structure, Tertiary
Proteins
Retroviridae Proteins - metabolism
Sequence Alignment
Simian immunodeficiency virus
Simian Immunodeficiency Virus - genetics
Species Specificity
Viral proteins
Viral Regulatory and Accessory Proteins - genetics
Viral Regulatory and Accessory Proteins - metabolism
Virology/Animal Models of Infection
Virology/Immune Evasion
Virology/Immunodeficiency Viruses
Virology/Mechanisms of Resistance and Susceptibility, including Host Genetics
Virology/Virus Evolution and Symbiosis
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Summary:Tetherin, also known as BST2, CD317 or HM1.24, was recently identified as an interferon-inducible host-cell factor that interferes with the detachment of virus particles from infected cells. HIV-1 overcomes this restriction by expressing an accessory protein, Vpu, which counteracts tetherin. Since lentiviruses of the SIV(smm/mac)/HIV-2 lineage do not have a vpu gene, this activity has likely been assumed by other viral gene products. We found that deletion of the SIV(mac)239 nef gene significantly impaired virus release in cells expressing rhesus macaque tetherin. Virus release could be restored by expressing Nef in trans. However, Nef was unable to facilitate virus release in the presence of human tetherin. Conversely, Vpu enhanced virus release in the presence of human tetherin, but not in the presence of rhesus tetherin. In accordance with the species-specificity of Nef in mediating virus release, SIV Nef downregulated cell-surface expression of rhesus tetherin, but did not downregulate human tetherin. The specificity of SIV Nef for rhesus tetherin mapped to four amino acids in the cytoplasmic domain of the molecule that are missing from human tetherin, whereas the specificity of Vpu for human tetherin mapped to amino acid differences in the transmembrane domain. Nef alleles of SIV(smm), HIV-2 and HIV-1 were also able to rescue virus release in the presence of both rhesus macaque and sooty mangabey tetherin, but were generally ineffective against human tetherin. Thus, the ability of Nef to antagonize tetherin from these Old World primates appears to be conserved among the primate lentiviruses. These results identify Nef as the viral gene product of SIV that opposes restriction by tetherin in rhesus macaques and sooty mangabeys, and reveal species-specificity in the activities of both Nef and Vpu in overcoming tetherin in their respective hosts.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1000429