The immunosuppressive properties of the HIV Vpr protein are linked to a single highly conserved residue, R90

Irina Tcherepanova, Aijing Starr, Brad Lackford, Melissa D. Adams, Jean Pierre Routy, Mohamed Rachid Boulassel, David Calderhead, Don Healey, Charles Nicolette

Research output: Contribution to journalArticle

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Abstract

Background: A hallmark of AIDS progression is a switch of cytokines from Th1 to Th2 in the plasma of patients. IL-12, a critical Th1 cytokine secreted by antigen presenting cells (APCs) is suppressed by Vpr, implicating it as an important virulence factor. We hypothesize that Vpr protein packaged in the virion may be required for disabling APCs of the first infected mucosal tissues. Consistent with this idea are reports that defects in the C-terminus of Vpr are associated with long-term non-progression. Principal Findings: Vpr RNA amplified from various sources was electroporated into monocyte-derived DC and IL-12 levels in supernatants were analyzed. The analysis of previously reported C-terminal Vpr mutations demonstrate that they do not alleviate the block of IL-12 secretion. However, a novel single conservative amino acid substitution, R90K, reverses the IL-12 suppression. Analysis of 1226 Vpr protein sequences demonstrated arginine (R) present at position 90 in 98.8%, with other substitutions at low frequency. Furthermore, none of sequences report lysine (K) in position 90. Vpr clones harboring the reported substitutions in position 90 were studied for their ability to suppress IL-12. Our data demonstrates that none of tested substitutions other than K relieve IL-12 suppression. This suggests a natural selection for sequences which suppress IL-12 secretion by DC and against mutations which relieve such suppression. Further analyses demonstrated that the R90K, as well as deletion of the C-terminus, directs the Vpr protein for rapid degradation. Conclusion: This study supports Vpr as an HIV virulence factor during HIV infection and for the first time provides a link between evolutionary conservation of Vpr and its ability to suppress IL-12 secretion by DC. DC activated in the presence of Vpr would be defective in the production of IL-12, thus contributing to the prevailing Th2 cytokine profile associated with progressive HIV disease. These findings should be considered in the design of future immunotherapies that incorporate Vpr as an antigen.

Original languageEnglish
Article numbere5853
JournalPLoS One
Volume4
Issue number6
DOIs
Publication statusPublished - Jun 10 2009

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vpr Gene Products
Human Immunodeficiency Virus Proteins
immunosuppressive agents
interleukin-12
Interleukin-12
Immunosuppressive Agents
proteins
Substitution reactions
cytokines
antigen-presenting cells
secretion
Virulence Factors
Antigen-Presenting Cells
Cytokines
virulence
HIV
mutation
Mutation
Genetic Selection
immunotherapy

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

The immunosuppressive properties of the HIV Vpr protein are linked to a single highly conserved residue, R90. / Tcherepanova, Irina; Starr, Aijing; Lackford, Brad; Adams, Melissa D.; Routy, Jean Pierre; Boulassel, Mohamed Rachid; Calderhead, David; Healey, Don; Nicolette, Charles.

In: PLoS One, Vol. 4, No. 6, e5853, 10.06.2009.

Research output: Contribution to journalArticle

Tcherepanova, I, Starr, A, Lackford, B, Adams, MD, Routy, JP, Boulassel, MR, Calderhead, D, Healey, D & Nicolette, C 2009, 'The immunosuppressive properties of the HIV Vpr protein are linked to a single highly conserved residue, R90', PLoS One, vol. 4, no. 6, e5853. https://doi.org/10.1371/journal.pone.0005853
Tcherepanova, Irina ; Starr, Aijing ; Lackford, Brad ; Adams, Melissa D. ; Routy, Jean Pierre ; Boulassel, Mohamed Rachid ; Calderhead, David ; Healey, Don ; Nicolette, Charles. / The immunosuppressive properties of the HIV Vpr protein are linked to a single highly conserved residue, R90. In: PLoS One. 2009 ; Vol. 4, No. 6.
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abstract = "Background: A hallmark of AIDS progression is a switch of cytokines from Th1 to Th2 in the plasma of patients. IL-12, a critical Th1 cytokine secreted by antigen presenting cells (APCs) is suppressed by Vpr, implicating it as an important virulence factor. We hypothesize that Vpr protein packaged in the virion may be required for disabling APCs of the first infected mucosal tissues. Consistent with this idea are reports that defects in the C-terminus of Vpr are associated with long-term non-progression. Principal Findings: Vpr RNA amplified from various sources was electroporated into monocyte-derived DC and IL-12 levels in supernatants were analyzed. The analysis of previously reported C-terminal Vpr mutations demonstrate that they do not alleviate the block of IL-12 secretion. However, a novel single conservative amino acid substitution, R90K, reverses the IL-12 suppression. Analysis of 1226 Vpr protein sequences demonstrated arginine (R) present at position 90 in 98.8{\%}, with other substitutions at low frequency. Furthermore, none of sequences report lysine (K) in position 90. Vpr clones harboring the reported substitutions in position 90 were studied for their ability to suppress IL-12. Our data demonstrates that none of tested substitutions other than K relieve IL-12 suppression. This suggests a natural selection for sequences which suppress IL-12 secretion by DC and against mutations which relieve such suppression. Further analyses demonstrated that the R90K, as well as deletion of the C-terminus, directs the Vpr protein for rapid degradation. Conclusion: This study supports Vpr as an HIV virulence factor during HIV infection and for the first time provides a link between evolutionary conservation of Vpr and its ability to suppress IL-12 secretion by DC. DC activated in the presence of Vpr would be defective in the production of IL-12, thus contributing to the prevailing Th2 cytokine profile associated with progressive HIV disease. These findings should be considered in the design of future immunotherapies that incorporate Vpr as an antigen.",
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AU - Tcherepanova, Irina

AU - Starr, Aijing

AU - Lackford, Brad

AU - Adams, Melissa D.

AU - Routy, Jean Pierre

AU - Boulassel, Mohamed Rachid

AU - Calderhead, David

AU - Healey, Don

AU - Nicolette, Charles

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