WJA  Vol.4 No.2 , June 2014
Two Highly Variable Vpr84and Vpr85 Residues within the HIV-1-Vpr C-Terminal Protein Transduction Domain Control Transductionnal Activity and Define a Clade Specific Polymorphism
Abstract: The virally encoded HIV-1 viral protein R (VPR) is a multifunctional factor that is required for induced HIV-1 pathogenesis. VPR is also a cell-penetrating protein found in biological fluids from HIV-1 infected individuals. In this regard, we previously published that the C-terminal VPR77-92 sequence from HIV-1 89.6, but not from pNL4.3 strain, is a new pro-apoptotic and protein transduction domain (PTD). Here we report on a sequence analysis of VPR77-92 domain using the Los Alamos HIV-1 sequence database. The analysis showed that the two residues of the domain VPR84 and VPR85 are highly variable and differently biased in HIV-1 clade B and HIV-1 clade C. Furthermore, when Jurkat lymphoblastoid cells or PBMC were incubated with chemically synthesized peptides containing distinct VPR77-92 C-terminal sequences from clades B or C, we found that a clade-dependent polymorphism in VPR84 and VPR85 residues controlled the transducing activity of the C-terminal HIV-1 VPR77-92 domain. Together our data indicate that clade-dependent polymorphism in the VPR84 and VPR85 residues defines the transducing properties mediated by the C-terminal domain of HIV-1 VPR. Identification of this VPR polymorphism suggests new approaches to understand the HIV-1 biology and/or pathogenesis.
Cite this paper: Colle, J. , Rose, T. , Rouzioux, C. and Garcia, A. (2014) Two Highly Variable Vpr84and Vpr85 Residues within the HIV-1-Vpr C-Terminal Protein Transduction Domain Control Transductionnal Activity and Define a Clade Specific Polymorphism. World Journal of AIDS, 4, 148-155. doi: 10.4236/wja.2014.42019.

[1]   Romani, B. and Engelbrecht, S. (2009) Human Immunodeficiency virus Type 1 Vpr Functions and Molecular Interactions. Journal of General Virology, 90, 1795-1805.

[2]   Kamata, M., Nitahara-Kasahara, Y., Miyamoto, Y., Yoneda, Y. and Aida, Y. (2005) Importin-Alpha Promotes Passage through the Nuclear Pore Complex of Human Immunodeficiency Virus Type 1 Vpr. Journal of Virology, 79, 3557-3564.

[3]   Singh, S.P., Tomkowicz, B., Lai, D., Cartas, M., Mahalingam, S., Kalyanaraman, V.S., Murali, R. and Srinivasan, A. (2000) Functional Role of Residues Corresponding to Helical Domain II (Amino Acids 35 to 46) of Human Immuno-deficiency Virus Type 1 Vpr. Journal of Virology, 74, 10650-10657.

[4]   Schrofelbauer, B., Yu, Q., Zeitlin, S.G. and Landau, N.R. (2005) Human Immunodeficiency Virus Type 1 Vpr Induces the Degradation of the UNG and SMUG Uracil-DNA Glycosylases. Journal of Virology, 79, 10978-10987.

[5]   Mahalingam, S., Ayyavoo, V., Patel, M., Kieber-Emmons, T. and Weiner, D.B. (1997) Nuclear Import, Virion Incorporation and Cell Cycle Arrest/Differentiation Are Mediated by Distinct Functional Domains of Human Immunodeficiency virus Type 1 Vpr. Journal of Virology, 71, 6339-6347.

[6]   Forget, J., Yao, X.J., Mercier, J. and Cohen, E.A. (1998) Human Immunodeficiency Virus Type 1 Vpr Protein Transactivation Function: Mechanism and Identification of Domains Involved. Journal of Molecular Biology, 284, 915-923.

[7]   DeHart, J.L., Zimmerman, E.S., Ardon, O., Monteiro-Filho, C.M., Arganaraz, E.R. and Planelles, V. (2007) HIV-1 Vpr Activates the G2 Checkpoint through Manipulation of the Ubiquitin Proteasome System. Virology Journal, 4, 57.

[8]   Jacotot, E., Ravagnan, L., Loeffler, M., Ferri, K.F., Vieira, H.L., Zamzami, N., Costantini, P., Druillenec, S., Hoebeke, J., Briand, J.P., Irinopoulou, T., Daugas, E., Susin, S.A., Cointe, D., Xie, Z.H., Reed, J.C., Roques, B.P. and Kroemer, G. (2000) The HIV-1 Viral Protein R Induces Apoptosis via a Direct Effect on the Mitochondrial Permeability Transition Pore. Journal of Experimental Medicine, 191, 33-46.

[9]   Jacotot, E., Ferri, K.F., El Hamel, C., Brenner, C., Druillennec, S., Joebeke, J., Rustin, P., Métivier, D., Lenoir, C., Geuskens, M., Vieira, H.L., Loeffler, M., Belzacq, A.S., Briand, J.P., Zamzami, N., Edelman, L., Xie, Z.H., Reed, J.C., Roques, B.P. and Kroemer, G. (2001) Control of Mitochondrial Membrane Permeabilization by Adenine Nucleotide Translocator Interacting with HIV-1 Viral Protein R and Bcl-2. Journal of Experimental Medicine, 193, 509-519.

[10]   Rajan, D., Wildum, S., Rucker, E., Schindler, M. and Kirchhoff, F. (2006) Effect of R77Q, R77A and R80A Changes in Vpr on HIV-1 Replication and CD4 T Cell Depletion in Human Lymphoid Tissue Ex Vivo. AIDS, 20, 831-836.

[11]   Andersen, J.L., De Hart, J.L., Zimmerman, E.S., Ardon, O., Kim, B. and Jacquot, G. (2006) HIV-1 Vpr-Induced Apoptosis Is Cell Cycle Dependent and Requires Bax But Not ANT. PLoS Pathogens, 2, e127.

[12]   Godet, A.N., Guergnon, J., Croset, A., Cayla, X., Falanga, P.B., Colle, J-H. and Garcia, A. (2010) PP2A1 Binding, Cell Transducing and Apoptotic Properties of Vpr77-92 a New Functional Domain of HIV-1 Vpr Proteins. PloS ONE, 5 e13760.

[13]   Henklein, P., Bruns, K., Sherman, M.P., Tessmer, U., Licha, K., Kopp, J., de Noronha, C.M.C., Greene, W.C., Wray, V. and Schubert, U. (2000) Functional and Structural Characterization of Synthetic HIV-1 Vpr That Transduces Cells, Localizes to the Nucleus and Induces G2 cell Cycle Arrest. Journal of Biological Chemistry, 275, 32016-32026.

[14]   Huang, M.B., Weeks, O., Zhao, L.J., Saltarelli, M. and Bond, V.C. (2000) Effects of Extracellular Human Immunode-ficiency virus Type 1 Vpr Protein in Primary Rat Cortical Cell Cultures. Journal of Neurovirology, 6, 202-220.

[15]   Hoshino, S., Sun, B., Konishi, M., Shimura, M., Segawa, T., Hagiwara, Y., Koyanagi, Y., Iwamoto, A., Mimaya, J., Terunuma, H., Kano, S. and Ishizaka, Y. (2007) Vpr in Plasma of HIV Type 1-Positive Patients Is Correlated with the HIV Type 1 RNA Titers. AIDS Research and Human Retroviruses, 23, 391-397.

[16]   Levy, D.N., Refaeli, Y., MacGregor, R.R. and Weiner, D.B. (1994) Serum Vpr Regulates Productive Infection and Latency of Human Immunodeficiency Virus Type 1, 3. Proceedings of the National Academy of Sciences USA, 91, 10873-10877.

[17]   Levy, D.N., Refaeli, Y. and Weiner, D.B. (1995) Extracellular Vpr Protein Increases Cellular Permissiveness to Human Immunodeficiency Virus Replication and Reactivates Virus from Latency. Journal of Virology, 69, 1243-1252.

[18]   Thompson, J.D., Gibson, T.J., Plewniak, F., Jeanmougin, F. and Higgins, D.G. (1997) The CLUSTAL_X Windows Interface: Flexible Strategies for Multiple Sequence Alignment Aided by Quality Analysis Tools. Nucleic Acids Research, 25, 4876-4882.

[19]   Sherman, M.P., Schubert, U., Williams, S.A., de Noronha, C.M.C., Kreisberg, J.F., Henklein, P. and Greene, W.C. (2002) HIV-1 Vpr Displays Natural Protein-Transducing Properties: Implications for Viral Pathogenesis. Virology, 302, 95-105.

[20]   Piller, S.C., Ewart, G.D., Premkumar, A., Cox, G.B. and Gage, P.W. (1996) Vpr Protein of Human Immunodeficiency Virus Type 1 form Cation-Selective Channels in Planar Lipid Bilayers. Proceedings of the National Academy of Sciences USA, 93, 111-115.

[21]   Piller, S.C., Ewart, G.D., Jans, D.A., Gage, P.W. and Cox, G.B. (1999) The Amino-Terminal Region of Vpr from Human Immunodeficiency Virus Type 1 Forms Ion Channels and Kills Neurons. Journal of Virology, 73, 4230-4238.

[22]   Taguchi, T., Shimura, M., Osawa, Y., Suzuki, Y., Mizoguchi, I., Niino, K., Takabu, F. and Ishizaka, Y. (2004) Nuclear Trafficking of Macromolecules by an Oligopeptide Derived from Vpr of Human Immunodeficiency Virus Type-1. Biochemical and Biophysical Research Communications, 320, 18-26.

[23]   Schwarze, S.R., Ho, A., Vocero-Akbani, A. and Dowdy, S.F. (1999) In Vivo Protein Transduction: Delivery of a Biologically Active Protein into the Mouse. Science, 285 1569-1572.

[24]   Caron, N.J., Torrente, Y., Camirand, G., Bujold, M., Chapdelaine, P., Leriche, K., Bresolin, N. and Tremblay, J.P. (2001) Intracellular Delivery of a Tat-eGFP Fusion Protein into Muscle Cells. Molecular Therapy, 3, 310-318.

[25]   Xiao, Y., Chen, G., Richard, J., Rougeau, N., Li, H., Seidah, N.G. and Cohen, E.A. (2008) Cell-Surface Processing of Extracellular Human Immunodeficiency Virus Type 1 Vpr by Proprotein Convertases. Virology, 372, 384-397.