Increased BST2 expression during simian immunodeficiency virus infection is not a determinant of disease progression in rhesus monkeys

Retrovirology

Sieghart Sopper²  Ulrike Sauermann³  Katharina Töpfer³  Aneela Javed¹  Bianka Mussil³ 

[1] Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Science and Technology (NUST), H12, Islamabad, Pakistan;Tyrolean Cancer Research Institute, Innsbruck, Austria;Unit of Infection Models, German Primate Centre, Goettingen, Germany

关键词: PBMC;    Real-time PCR;    LTNPs;    MX1;    SIV;    Rhesus macaque;    BST2;   

Others  :  1232030
DOI  :  10.1186/s12977-015-0219-8

 received in 2015-05-12, accepted in 2015-10-23,  发布年份 2015

【 摘 要 】

Background

Bone marrow stromal cell antigen 2 (BST2), also known as tetherin, HM1.24 or CD317 represents a type 2 integral membrane protein, which has been described to restrict the production of some enveloped viruses by inhibiting the virus release from the cell surface. This innate antiviral mechanism is counteracted by the HIV-1 viral factor Vpu, targeting BST2 for cellular degradation. Since antiviral BST2 activity has been mainly confirmed by in vitro data, we investigated its role in vivo on the disease progression using the SIV/macaque model for AIDS. We determined BST2 expression in PBMC and leukocyte subsets of uninfected and SIV-infected rhesus macaques by real-time PCR and flow cytometry and correlated it with disease progression and viral load.

Results

Compared to pre-infection levels, we found increased BST2 expression in PBMC, purified CD4 ⁺lymphocytes and CD14 ⁺monocytes of SIV-infected animals, which correlated with viral load. Highest BST2 levels were found in progressors and lowest levels comparable to uninfected macaques were observed in long-term non-progressors (LTNPs). During acute viremia, BST2 mRNA increased in parallel with MX1, a prototype interferon-stimulated gene. This association was maintained during the whole disease course.

Conclusion

The detected relationship between BST2 expression and viral load as well as with MX1 indicate a common regulation by the interferon response and suggest rather limited influence of BST2 in vivo on the disease outcome.

【 授权许可】

   
2015 Mussil et al.

【 图 表 】

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【 参考文献 】

• [1]Kestler H, Kodama T, Ringler D, Marthas M, Pedersen N, Lackner A et al.. Induction of AIDS in rhesus monkeys by molecularly cloned simian immunodeficiency virus. Science. 1990; 248(4959):1109-1112.
• [2]Stahl-Hennig C, Voss G, Dittmer U, Coulibaly C, Petry H, Makoschey B et al.. Protection of monkeys by a split vaccine against SIVmac depends upon biological properties of the challenge virus. AIDS. 1993; 7(6):787-795.
• [3]Abel K, Alegria-Hartman MJ, Zanotto K, McChesney MB, Marthas ML, Miller CJ. Anatomic site and immune function correlate with relative cytokine mRNA expression levels in lymphoid tissues of normal rhesus macaques. Cytokine. 2001; 16(5):191-204.
• [4]Rodriguez-Jimenez FJ, Krause A, Schulz S, Forssmann WG, Conejo-Garcia JR, Schreeb R et al.. Distribution of new human beta-defensin genes clustered on chromosome 20 in functionally different segments of epididymis. Genomics. 2003; 81(2):175-183.
• [5]Negri DR, Baroncelli S, Catone S, Comini A, Michelini Z, Maggiorella MT et al.. Protective efficacy of a multicomponent vector vaccine in cynomolgus monkeys after intrarectal simian immunodeficiency virus challenge. J Gen Virol. 2004; 85(Pt 5):1191-1201.
• [6]Zheng YH, Jeang KT, Tokunaga K. Host restriction factors in retroviral infection: promises in virus-host interaction. Retrovirology. 2012; 9:112. BioMed Central Full Text
• [7]Neil SJ, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature. 2008; 451(7177):425-430.
• [8]Van Damme N, Goff D, Katsura C, Jorgenson RL, Mitchell R, Johnson MC et al.. The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe. 2008; 3(4):245-252.
• [9]Perez-Caballero D, Zang T, Ebrahimi A, McNatt MW, Gregory DA, Johnson MC et al.. Tetherin inhibits HIV-1 release by directly tethering virions to cells. Cell. 2009; 139(3):499-511.
• [10]Douglas JL, Viswanathan K, McCarroll MN, Gustin JK, Fruh K, Moses AV. Vpu directs the degradation of the human immunodeficiency virus restriction factor BST-2/Tetherin via a {beta}TrCP-dependent mechanism. J Virol. 2009; 83(16):7931-7947.
• [11]Mitchell RS, Katsura C, Skasko MA, Fitzpatrick K, Lau D, Ruiz A et al.. Vpu antagonizes BST-2-mediated restriction of HIV-1 release via beta-TrCP and endo-lysosomal trafficking. PLoS Pathog. 2009; 5(5):e1000450.
• [12]Goffinet C, Allespach I, Homann S, Tervo HM, Habermann A, Rupp D et al.. HIV-1 antagonism of CD317 is species specific and involves Vpu-mediated proteasomal degradation of the restriction factor. Cell Host Microbe. 2009; 5(3):285-297.
• [13]Hammonds J, Wang JJ, Yi H, Spearman P. Immunoelectron microscopic evidence for Tetherin/BST2 as the physical bridge between HIV-1 virions and the plasma membrane. PLoS Pathog. 2010; 6(2):e1000749.
• [14]Andrew AJ, Miyagi E, Kao S, Strebel K. The formation of cysteine-linked dimers of BST-2/tetherin is important for inhibition of HIV-1 virus release but not for sensitivity to Vpu. Retrovirology. 2009; 6:80. BioMed Central Full Text
• [15]Kupzig S, Korolchuk V, Rollason R, Sugden A, Wilde A, Banting G. Bst-2/HM1.24 is a raft-associated apical membrane protein with an unusual topology. Traffic. 2003; 4(10):694-709.
• [16]Swiecki M, Scheaffer SM, Allaire M, Fremont DH, Colonna M, Brett TJ. Structural and biophysical analysis of BST-2/tetherin ectodomains reveals an evolutionary conserved design to inhibit virus release. J Biol Chem. 2011; 286(4):2987-2997.
• [17]Goto T, Kennel SJ, Abe M, Takishita M, Kosaka M, Solomon A et al.. A novel membrane antigen selectively expressed on terminally differentiated human B cells. Blood. 1994; 84(6):1922-1930.
• [18]Ohtomo T, Sugamata Y, Ozaki Y, Ono K, Yoshimura Y, Kawai S et al.. Molecular cloning and characterization of a surface antigen preferentially overexpressed on multiple myeloma cells. Biochem Biophys Res Commun. 1999; 258(3):583-591.
• [19]Evans DT, Serra-Moreno R, Singh RK, Guatelli JC. BST-2/tetherin: a new component of the innate immune response to enveloped viruses. Trends Microbiol. 2010; 18(9):388-396.
• [20]Masuyama N, Kuronita T, Tanaka R, Muto T, Hirota Y, Takigawa A et al.. HM1.24 is internalized from lipid rafts by clathrin-mediated endocytosis through interaction with alpha-adaptin. J Biol Chem. 2009; 284(23):15927-15941.
• [21]Erikson E, Adam T, Schmidt S, Lehmann-Koch J, Over B, Goffinet C et al.. In vivo expression profile of the antiviral restriction factor and tumor-targeting antigen CD317/BST-2/HM1.24/tetherin in humans. Proc Natl Acad Sci USA. 2011; 108(33):13688-13693.
• [22]Le Tortorec A, Willey S, Neil SJ. Antiviral inhibition of enveloped virus release by tetherin/BST-2: action and counteraction. Viruses. 2011; 3(5):520-540.
• [23]Jouvenet N, Neil SJ, Zhadina M, Zang T, Kratovac Z, Lee Y et al.. Broad-spectrum inhibition of retroviral and filoviral particle release by tetherin. J Virol. 2009; 83(4):1837-1844.
• [24]Kaletsky RL, Francica JR, Agrawal-Gamse C, Bates P. Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein. Proc Natl Acad Sci USA. 2009; 106(8):2886-2891.
• [25]Mangeat B, Cavagliotti L, Lehmann M, Gers-Huber G, Kaur I, Thomas Y et al.. Influenza virus partially counteracts restriction imposed by tetherin/BST-2. J Biol Chem. 2012; 287(26):22015-22029.
• [26]Sakuma T, Noda T, Urata S, Kawaoka Y, Yasuda J. Inhibition of Lassa and Marburg virus production by tetherin. J Virol. 2009; 83(5):2382-2385.
• [27]Jia B, Serra-Moreno R, Neidermyer W, Rahmberg A, Mackey J, Fofana IB et al.. Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2. PLoS Pathog. 2009; 5(5):e1000429.
• [28]Zhang F, Wilson SJ, Landford WC, Virgen B, Gregory D, Johnson MC et al.. Nef proteins from simian immunodeficiency viruses are tetherin antagonists. Cell Host Microbe. 2009; 6(1):54-67.
• [29]Hauser H, Lopez LA, Yang SJ, Oldenburg JE, Exline CM, Guatelli JC et al.. HIV-1 Vpu and HIV-2 Env counteract BST-2/tetherin by sequestration in a perinuclear compartment. Retrovirology. 2010; 7:51. BioMed Central Full Text
• [30]Le Tortorec A, Neil SJ. Antagonism to and intracellular sequestration of human tetherin by the human immunodeficiency virus type 2 envelope glycoprotein. J Virol. 2009; 83(22):11966-11978.
• [31]Kobayashi T, Ode H, Yoshida T, Sato K, Gee P, Yamamoto SP et al.. Identification of amino acids in the human tetherin transmembrane domain responsible for HIV-1 Vpu interaction and susceptibility. J Virol. 2011; 85(2):932-945.
• [32]Vigan R, Neil SJ. Determinants of tetherin antagonism in the transmembrane domain of the human immunodeficiency virus type 1 Vpu protein. J Virol. 2010; 84(24):12958-12970.
• [33]Sauter D, Schindler M, Specht A, Landford WN, Munch J, Kim KA et al.. Tetherin-driven adaptation of Vpu and Nef function and the evolution of pandemic and nonpandemic HIV-1 strains. Cell Host Microbe. 2009; 6(5):409-421.
• [34]Liberatore RA, Bieniasz PD. Tetherin is a key effector of the antiretroviral activity of type I interferon in vitro and in vivo. Proc Natl Acad Sci USA. 2011; 108(44):18097-18101.
• [35]Homann S, Smith D, Little S, Richman D, Guatelli J. Upregulation of BST-2/Tetherin by HIV infection in vivo. J Virol. 2011; 85(20):10659-10668.
• [36]Pillai SK, Abdel-Mohsen M, Guatelli J, Skasko M, Monto A, Fujimoto K et al.. Role of retroviral restriction factors in the interferon-alpha-mediated suppression of HIV-1 in vivo. Proc Natl Acad Sci USA. 2012; 109(8):3035-3040.
• [37]Neil SJ, Sandrin V, Sundquist WI, Bieniasz PD. An interferon-alpha-induced tethering mechanism inhibits HIV-1 and Ebola virus particle release but is counteracted by the HIV-1 Vpu protein. Cell Host Microbe. 2007; 2(3):193-203.
• [38]Galao RP, Le Tortorec A, Pickering S, Kueck T, Neil SJ. Innate sensing of HIV-1 assembly by Tetherin induces NFkappaB-dependent proinflammatory responses. Cell Host Microbe. 2012; 12(5):633-644.
• [39]Tokarev A, Suarez M, Kwan W, Fitzpatrick K, Singh R, Guatelli J. Stimulation of NF-kappaB activity by the HIV restriction factor BST2. J Virol. 2013; 87(4):2046-2057.
• [40]Cocka LJ, Bates P. Identification of alternatively translated Tetherin isoforms with differing antiviral and signaling activities. PLoS Pathog. 2012; 8(9):e1002931.
• [41]Cao W, Bover L, Cho M, Wen X, Hanabuchi S, Bao M et al.. Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction. J Exp Med. 2009; 206(7):1603-1614.
• [42]Cao W, Rosen DB, Ito T, Bover L, Bao M, Watanabe G et al.. Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilonRI gamma inhibits Toll-like receptor-induced interferon production. J Exp Med. 2006; 203(6):1399-1405.
• [43]Tavano B, Galao RP, Graham DR, Neil SJ, Aquino VN, Fuchs D et al.. Ig-like transcript 7, but not bone marrow stromal cell antigen 2 (also known as HM1.24, tetherin, or CD317), modulates plasmacytoid dendritic cell function in primary human blood leukocytes. J Immunol. 2013; 190(6):2622-2630.
• [44]Desrosiers RC. Non-human primate models for AIDS vaccines. AIDS. 1995; 9 Suppl A:S137-S141.
• [45]Joag SV. Primate models of AIDS. Microbes Infect. 2000; 2(2):223-229.
• [46]Abel K, Alegria-Hartman MJ, Rothaeusler K, Marthas M, Miller CJ. The relationship between simian immunodeficiency virus RNA levels and the mRNA levels of alpha/beta interferons (IFN-alpha/beta) and IFN-alpha/beta-inducible Mx in lymphoid tissues of rhesus macaques during acute and chronic infection. J Virol. 2002; 76(16):8433-8445.
• [47]Mussil B, Sauermann U, Motzkus D, Stahl-Hennig C, Sopper S. Increased APOBEC3G and APOBEC3F expression is associated with low viral load and prolonged survival in simian immunodeficiency virus infected rhesus monkeys. Retrovirology. 2011; 8:77. BioMed Central Full Text
• [48]Bego MG, Mercier J, Cohen EA. Virus-activated interferon regulatory factor 7 upregulates expression of the interferon-regulated BST2 gene independently of interferon signaling. J Virol. 2012; 86(7):3513-3527.
• [49]Guzzo C, Jung M, Graveline A, Banfield BW, Gee K. IL-27 increases BST-2 expression in human monocytes and T cells independently of type I IFN. Sci Rep. 2012; 2:974.
• [50]Rahmberg AR, Neidermyer WJ, Breed MW, Alvarez X, Midkiff CC, Piatak M et al.. Tetherin upregulation in simian immunodeficiency virus-infected macaques. J Virol. 2013; 87(24):13917-13921.
• [51]Hatziioannou T, Del Prete GQ, Keele BF, Estes JD, McNatt MW, Bitzegeio J et al.. HIV-1-induced AIDS in monkeys. Science. 2014; 344(6190):1401-1405.
• [52]Shingai M, Yoshida T, Martin MA, Strebel K. Some human immunodeficiency virus type 1 Vpu proteins are able to antagonize macaque BST-2 in vitro and in vivo: Vpu-negative simian-human immunodeficiency viruses are attenuated in vivo. J Virol. 2011; 85(19):9708-9715.
• [53]Pickering S, Hue S, Kim EY, Reddy S, Wolinsky SM, Neil SJ. Preservation of tetherin and CD4 counter-activities in circulating Vpu alleles despite extensive sequence variation within HIV-1 infected individuals. PLoS Pathog. 2014; 10(1):e1003895.
• [54]Serra-Moreno R, Zimmermann K, Stern LJ, Evans DT. Tetherin/BST-2 antagonism by Nef depends on a direct physical interaction between Nef and tetherin, and on clathrin-mediated endocytosis. PLoS Pathog. 2013; 9(7):e1003487.
• [55]Swiecki M, Wang Y, Gilfillan S, Lenschow DJ, Colonna M. Cutting edge: paradoxical roles of BST2/tetherin in promoting type I IFN response and viral infection. J Immunol. 2012; 188(6):2488-2492.
• [56]Dietrich I, McMonagle EL, Petit SJ, Vijayakrishnan S, Logan N, Chan CN et al.. Feline tetherin efficiently restricts release of feline immunodeficiency virus but not spreading of infection. J Virol. 2011; 85(12):5840-5852.
• [57]Gummuluru S, Kinsey CM, Emerman M. An in vitro rapid-turnover assay for human immunodeficiency virus type 1 replication selects for cell-to-cell spread of virus. J Virol. 2000; 74(23):10882-10891.
• [58]Jolly C, Booth NJ, Neil SJ. Cell-cell spread of human immunodeficiency virus type 1 overcomes tetherin/BST-2-mediated restriction in T cells. J Virol. 2010; 84(23):12185-12199.
• [59]Pais-Correia AM, Sachse M, Guadagnini S, Robbiati V, Lasserre R, Gessain A et al.. Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses. Nat Med. 2010; 16(1):83-89.
• [60]Martin N, Welsch S, Jolly C, Briggs JA, Vaux D, Sattentau QJ. Virological synapse-mediated spread of human immunodeficiency virus type 1 between T cells is sensitive to entry inhibition. J Virol. 2010; 84(7):3516-3527.
• [61]Sato H, Orenstein J, Dimitrov D, Martin M. Cell-to-cell spread of HIV-1 occurs within minutes and may not involve the participation of virus particles. Virology. 1992; 186(2):712-724.
• [62]Vendrame D, Sourisseau M, Perrin V, Schwartz O, Mammano F. Partial inhibition of human immunodeficiency virus replication by type I interferons: impact of cell-to-cell viral transfer. J Virol. 2009; 83(20):10527-10537.
• [63]Andrew A, Strebel K. The interferon-inducible host factor bone marrow stromal antigen 2/tetherin restricts virion release, but is it actually a viral restriction factor? J Interferon Cytokine Res. 2011; 31(1):137-144.
• [64]Hotter D, Sauter D, Kirchhoff F. Emerging role of the host restriction factor tetherin in viral immune sensing. J Mol Biol. 2013; 425(24):4956-4964.
• [65]von Wussow P, Jakschies D, Block B, Tschechne B, Schedel I, Horisberger MA et al.. The interferon-induced Mx-homologous protein in people with symptomatic HIV-1 infection. AIDS. 1990; 4(2):119-124.
• [66]Aamer HA, Rajakumar P, Nyaundi J, Murphey-Corb M. Resistance to simian immunodeficiency virus low dose rectal challenge is associated with higher constitutive TRIM5alpha expression in PBMC. Retrovirology. 2014; 11:39. BioMed Central Full Text
• [67]Imamichi T, Yang J, Huang DW, Brann TW, Fullmer BA, Adelsberger JW et al.. IL-27, a novel anti-HIV cytokine, activates multiple interferon-inducible genes in macrophages. AIDS. 2008; 22(1):39-45.
• [68]Zhang F, Landford WN, Ng M, McNatt MW, Bieniasz PD, Hatziioannou T. SIV Nef proteins recruit the AP-2 complex to antagonize Tetherin and facilitate virion release. PLoS Pathog. 2011; 7(5):e1002039.
• [69]Sopper S, Matz-Rensing K, Muhl T, Heeney J, Stahl-Hennig C, Sauermann U. Host factors determine differential disease progression after infection with nef-deleted simian immunodeficiency virus. J Gen Virol. 2014; 95(Pt 10):2273-2284.