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Binding of HIV-1 virions to α4β7 expressing cells and impact of antagonizing α4β7 on HIV-1 infection of primary CD4+ T cells

  • Research Article
  • Published:
Virologica Sinica

An Erratum to this article was published on 10 March 2015

Abstract

HIV-1 envelope glycoprotein is reported to interact with α4β7, an integrin mediating the homing of lymphocytes to gut-associated lymphoid tissue, but the significance of α4β7 in HIV-1 infection remains controversial. Here, using HIV-1 strain BaL, the gp120 of which was previously shown to be capable of interacting with α4β7, we demonstrated that α4β7 can mediate the binding of whole HIV-1 virions to α4β7-expressing transfectants. We further constructed a cell line stably expressing α4β7 and confirmed the α4β7-mediated HIV-1 binding. In primary lymphocytes with activated α4β7 expression, we also observed significant virus binding which can be inhibited by an anti-α4β7 antibody. Moreover, we investigated the impact of antagonizing α4β7 on HIV-1 infection of primary CD4+ T cells. In α4β7-activated CD4+ T cells, both anti-α4β7 antibodies and introduction of short-hairpin RNAs specifically targeting α4β7 resulted in a decreased HIV-1 infection. Our findings indicate that α4β7 may serve as an attachment factor at least for some HIV-1 strains. The established approach provides a promising means for the investigation of other viral strains to understand the potential roles of α4β7 in HIV-1 infection.

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References

  • Abram C L, Lowell C A. 2009. The ins and outs of leukocyte integrin signaling. Annu Rev Immunol, 27: 339–362.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Alvarez R A, Thorborn G, Reading J L, Reddy S K, Vyakarnam A. 2011. WFDC1 expression identifies memory CD4 T-lymphocytes rendered vulnerable to cell-cell HIV-1 transfer by promoting intercellular adhesive junctions. Retrovirology, 8: 29.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Andrew D P, Berlin C, Honda S, Yoshino T, Hamann A, Holzmann B, Kilshaw P J, Butcher E C. 1994. Distinct but overlapping epitopes are involved in α4β7-mediated adhesion to vascular cell adhesion molecule-1, mucosal addressin-1, fibronectin, and lymphocyte aggregation. J Immunol, 153: 3847–3861.

    CAS  PubMed  Google Scholar 

  • Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D, Xiao Z, Veenstra T D, Conrad T P, Lempicki R A, McLaughlin S, Pascuccio M, Gopaul R, McNally J, Cruz C C, Censoplano N, Chung E, Reitano K N, Kottilil S, Goode D J, Fauci A S. 2008. HIV-1 envelope protein binds to and signals through integrin α4β7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol, 9: 301–309.

    Article  CAS  PubMed  Google Scholar 

  • Berlin C, Berg E L, Briskin M J, Andrew D P, Kilshaw P J, Holzmann B, Weissman I L, Hamann A, Butcher E C. 1993. α4β7 integrin mediates lymphocyte binding to the muco sal vascular addressin MAdCAM-1. Cell, 74: 185–195.

    Article  CAS  PubMed  Google Scholar 

  • Birmingham A, Anderson E, Sullivan K, Reynolds A, Boese Q, Leake D, Karpilow J, Khvorova A. 2007. A protocol for designing siRNAs with high functionality and specificity. Nat Protoc, 2: 2068–2078.

    Article  CAS  PubMed  Google Scholar 

  • Boily M C, Baggaley R F, Wang L, Masse B, White R G, Hayes R J, Alary M. 2009. Heterosexual risk of HIV-1 infection per sexual act: systematic review and meta-analysis of observational studies. Lancet Infect Dis, 9: 118–129.

    Article  PubMed  Google Scholar 

  • Borrow P, Shattock R J, Vyakarnam A. 2010. Innate immunity against HIV: a priority target for HIV prevention research. Retrovirology, 7: 84.

    Article  PubMed Central  PubMed  Google Scholar 

  • Chohan B, Lang D, Sagar M, Korber B, Lavreys L, Richardson B, Overbaugh J. 2005. Selection for human immunodeficiency virus type 1 envelope glycosylation variants with shorter V1–V2 loop sequences occurs during transmission of certain genetic subtypes and may impact viral RNA levels. J Virol, 79: 6528–6531.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cicala C, Arthos J, Fauci A S. 2010. HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV. J Transl Med, 9Suppl 1: S2.

    Article  Google Scholar 

  • Cicala C, Martinelli E, McNally J P, Goode D J, Gopaul R, Hiatt J, Jelicic K, Kottilil S, Macleod K, O’Shea A, Patel N, Van Ryk D, Wei D, Pascuccio M, Yi L, McKinnon L, Izulla P, Kimani J, Kaul R, Fauci A S, Arthos J. 2009. The integrin α4β7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1. Proc Natl Acad Sci USA, 106: 20877–20882.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dale B M, Alvarez R A, Chen B K. 2013. Mechanisms of enhanced HIV spread through T-cell virological synapses. Immunol Rev, 251: 113–124.

    Article  PubMed  Google Scholar 

  • Darc M, Hait S H, Soares E A, Cicala C, Seuanez H N, Machado E S, Arthos J A, Soares M A. 2011. Polymorphisms in the α4 integrin of neotropical primates: insights for binding of natural ligands and HIV-1 gp120 to the human α4β7. PLoS One, 6: e24461.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Derdeyn C A, Decker J M, Bibollet-Ruche F, Mokili J L, Muldoon M, Denham S A, Heil M L, Kasolo F, Musonda R, Hahn B H, Shaw G M, Korber B T, Allen S, Hunter E. 2004. Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission. Science, 303: 2019–2022.

    Article  CAS  PubMed  Google Scholar 

  • Etemad B, Redd A, Serwadda D, Lutalo T, Reynolds S, Gray R, Quinn T, Sagar M. 2012. Envelopes found early after acquisition compared to those in the chronically infected partner do not have enhanced alpha4 beta7 binding or utilization. Retrovirology, 9: P149.

    Article  PubMed Central  Google Scholar 

  • Haase A T. 2010. Targeting early infection to prevent HIV-1 mucosal transmission. Nature, 464: 217–223.

    Article  CAS  PubMed  Google Scholar 

  • Harris A, Borgnia M J, Shi D, Bartesaghi A, He H, Pejchal R, Kang Y K, Depetris R, Marozsan A J, Sanders R W, Klasse P J, Milne J L, Wilson I A, Olson W C, Moore J P, Subramaniam S. 2011. Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures. Proc Natl Acad Sci U S A, 108: 11440–11445.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hu Q, Napier K B, Trent J O, Wang Z, Taylor S, Griffin G E, Peiper S C, Shattock R J. 2005. Restricted variable residues in the C-terminal segment of HIV-1 V3 loop regulate the molecular anatomy of CCR5 utilization. J Mol Biol, 350: 699–712.

    Article  CAS  PubMed  Google Scholar 

  • Jelicic K, Cimbro R, Nawaz F, Huang da W, Zheng X, Yang J, Lempicki R A, Pascuccio M, Van Ryk D, Schwing C, Hiatt J, Okwara N, Wei D, Roby G, David A, Hwang I Y, Kehrl J H, Arthos J, Cicala C, Fauci A S. 2013. The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-beta1 production and FcRL4 expression. Nat Immunol, 14: 1256–1265.

    Article  CAS  PubMed  Google Scholar 

  • Keele B F, Giorgi E E, Salazar-Gonzalez J F, Decker J M, Pham K T, Salazar M G, Sun C, Grayson T, Wang S, Li H, Wei X, Jiang C, Kirchherr J L, Gao F, Anderson J A, Ping L H, Swanstrom R, Tomaras G D, Blattner W A, Goepfert P A, Kilby J M, Saag M S, Delwart E L, Busch M P, Cohen M S, Montefiori D C, Haynes B F, Gaschen B, Athreya G S, Lee H Y, Wood N, Seoighe C, Perelson A S, Bhattacharya T, Korber B T, Hahn B H, Shaw G M. 2008. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci USA, 105: 7552–7557.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kishko M, Somasundaran M, Brewster F, Sullivan J L, Clapham P R, Luzuriaga K. 2011. Genotypic and functional properties of early infant HIV-1 envelopes. Retrovirology, 8: 67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Li H, Pauza C D. 2011. HIV envelope-mediated, CCR5/α4β7-dependent killing of CD4-negative γδ T cells which are lost during progression to AIDS. Blood, 118: 5824–5831.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liao Z, Roos J W, Hildreth J E. 2000. Increased infectivity of HIV type 1 particles bound to cell surface and solid-phase ICAM-1 and VCAM-1 through acquired adhesion molecules LFA-1 and VLA-4. AIDS Res Hum Retroviruses, 16: 355–366.

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Bartesaghi A, Borgnia M J, Sapiro G, Subramaniam S. 2008. Molecular architecture of native HIV-1 gp120 trimers. Nature, 455: 109–113.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Luo B H, Carman C V, Springer T A. 2007. Structural basis of integrin regulation and signaling. Annu Rev Immunol, 25: 619–647.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Martinelli E, Veglia F, Goode D, Guerra-Perez N, Aravantinou M, Arthos J, Piatak M, Jr., Lifson J D, Blanchard J, Gettie A, Robbiani M. 2013. The frequency of α4β7 high memory CD4+ T cells correlates with susceptibility to rectal SIV infection. J Acquir Immune Defic Syndr, 64: 325–331.

    Article  CAS  PubMed  Google Scholar 

  • Mavigner M, Cazabat M, Dubois M, L’Faqihi F E, Requena M, Pasquier C, Klopp P, Amar J, Alric L, Barange K, Vinel J P, Marchou B, Massip P, Izopet J, Delobel P. 2011. Altered CD4+ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals. J Clin Invest, 122: 62–69.

    Article  PubMed Central  PubMed  Google Scholar 

  • McKinnon L R, Nyanga B, Chege D, Izulla P, Kimani M, Huibner S, Gelmon L, Block K E, Cicala C, Anzala A O, Arthos J, Kimani J, Kaul R. 2011. Characterization of a human cervical CD4+ T cell subset coexpressing multiple markers of HIV susceptibility. J Immunol, 187: 6032–6042.

    Article  CAS  PubMed  Google Scholar 

  • McLellan J S, Pancera M, Carrico C, Gorman J, Julien J P, Khayat R, Louder R, Pejchal R, Sastry M, Dai K, O’Dell S, Patel N, Shahzad-ul-Hussan S, Yang Y, Zhang B, Zhou T, Zhu J, Boyington J C, Chuang G Y, Diwanji D, Georgiev I, Kwon Y D, Lee D, Louder M K, Moquin S, Schmidt S D, Yang Z Y, Bonsignori M, Crump J A, Kapiga S H, Sam N E, Haynes B F, Burton D R, Koff W C, Walker L M, Phogat S, Wyatt R, Orwenyo J, Wang L X, Arthos J, Bewley C A, Mascola J R, Nabel G J, Schief W R, Ward A B, Wilson I A, Kwong P D. 2011. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature, 480: 336–343.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mehandru S, Poles M A, Tenner-Racz K, Horowitz A, Hurley A, Hogan C, Boden D, Racz P, Markowitz M. 2004. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med, 200: 761–770.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Miller C J, Li Q, Abel K, Kim E Y, Ma Z M, Wietgrefe S, La Franco-Scheuch L, Compton L, Duan L, Shore M D, Zupancic M, Busch M, Carlis J, Wolinsky S, Haase A T. 2005. Propagation and dissemination of infection after vaginal transmission of simian immunodeficiency virus. J Virol, 79: 9217–9227.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mora J R, Bono M R, Manjunath N, Weninger W, Cavanagh L L, Rosemblatt M, Von Andrian U H. 2003. Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature, 424: 88–93.

    Article  CAS  PubMed  Google Scholar 

  • Nawaz F, Cicala C, Van Ryk D, Block K E, Jelicic K, McNally J P, Ogundare O, Pascuccio M, Patel N, Wei D, Fauci A S, Arthos J. 2011. The genotype of early-transmitting HIV gp120s promotes α4β7-reactivity, revealing α4β7 +/CD4+ T cells as key targets in mucosal transmission. PLoS Pathog, 7: e1001301.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Parrish N F, Wilen C B, Banks L B, Iyer S S, Pfaff J M, Salazar-Gonzalez J F, Salazar M G, Decker J M, Parrish E H, Berg A, Hopper J, Hora B, Kumar A, Mahlokozera T, Yuan S, Coleman C, Vermeulen M, Ding H, Ochsenbauer C, Tilton J C, Permar S R, Kappes J C, Betts M R, Busch M P, Gao F, Montefiori D, Haynes B F, Shaw G M, Hahn B H, Doms R W. 2012. Transmitted/founder and chronic subtype C HIV-1 use CD4 and CCR5 receptors with equal efficiency and are not inhibited by blocking the integrin α4β7. PLoS Pathog, 8: e1002686.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Perez L G, Chen H, Liao H X, Montefiori D C. 2014. Envelope glycoprotein binding to the integrin α4β7 is not a general property of most HIV-1 strains. J Virol, 88: 10767–10777.

    Article  PubMed Central  PubMed  Google Scholar 

  • Qi J, Zhang K, Zhang Q, Sun Y, Fu T, Li G, Chen J. 2012. Identification, characterization, and epitope mapping of human monoclonal antibody J19 that specifically recognizes activated integrin α4β7. J Biol Chem, 287: 15749–15759.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Qin X F, An D S, Chen I S, Baltimore D. 2003. Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proc Natl Acad Sci USA, 100: 183–188.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Richardson S I, Mkhize N, Abdool Karim S, Gray E, Morris L. 2013. Role of integrin α4β7 in HIV transmission and pathogenesis. Barcelona, Spain, pp. 73.

  • Ruegg C, Postigo A A, Sikorski E E, Butcher E C, Pytela R, Erle D J. 1992. Role of integrin α4β7/α4βP in lymphocyte adherence to fibronectin and VCAM-1 and in homotypic cell clustering. J Cell Biol, 117: 179–189.

    Article  CAS  PubMed  Google Scholar 

  • Sagar M, Wu X, Lee S, Overbaugh J. 2006. Human immu nodeficiency virus type 1 V1–V2 envelope loop sequences expand and add glycosylation sites over the course of infection, and these modifications affect antibody neutralization sensitivity. J Virol, 80: 9586–9598.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sattentau Q. 2008. HIV’s gut feeling. Nat Immunol, 9: 225–227.

    Article  CAS  PubMed  Google Scholar 

  • Spurrier B, Sampson J, Gorny M K, Zolla-Pazner S, Kong X P. 2014. Functional Implications of the Binding Mode of a Human Conformation-dependent V2 Monoclonal Antibody against HIV. J Virol.

    Google Scholar 

  • Temchura V, Tenbusch M. 2014. The two faces of vaccin e-induced immune response: protection or increased risk of HIV infection?! Virol Sin, 29: 7–9.

    Article  PubMed  Google Scholar 

  • Tidswell M, Pachynski R, Wu S W, Qiu S Q, Dunham E, Cochran N, Briskin M J, Kilshaw P J, Lazarovits A I, Andrew D P, Butcher E C, Yednock T A, Erle D J. 1997. Structure-function analysis of the integrin β7 subunit: identification of domains involved in adhesion to MAdCAM-1. J Immunol, 159: 1497–1505.

    CAS  PubMed  Google Scholar 

  • Tiscornia G, Singer O, Ikawa M, Verma I M. 2003. A gener al method for gene knockdown in mice by using lentiviral vectors expressing small interfering RNA. Proc Natl Acad Sci USA, 100: 1844–1848.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tjomsland V, Ellegard R, Kjolhede P, Wodlin N B, Hinkula J, Lifson J D, Larsson M. 2013. Blocking of integrins inhibits HIV-1 infection of human cervical mucosa immune cells with free and complement-opsonized virions. Eur J Immunol, 43: 2361–2372.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tsai L, Tasovski I, Leda A R, Chin M P, Cheng-Mayer C. 2014. The number and genetic relatedness of transmitted/founder virus impact clinical outcome in vaginal R5 SHIVSF162P3N infection. Retrovirology, 11: 22.

    Article  PubMed Central  PubMed  Google Scholar 

  • Veazey R S, DeMaria M, Chalifoux L V, Shvetz D E, Pauley D R, Knight H L, Rosenzweig M, Johnson R P, Desrosiers R C, Lackner A A. 1998. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science, 280: 427–431.

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Xu H, Gill A F, Pahar B, Kempf D, Rasmussen T, Lackner A A, Veazey R S. 2009. Monitoring α4β7 integrin expression on circulating CD4+ T cells as a surrogate marker for tracking intestinal CD4+ T-cell loss in SIV infection. Mucosal Immunol, 2: 518–526.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wawer M J, Gray R H, Sewankambo N K, Serwadda D, Li X, Laeyendecker O, Kiwanuka N, Kigozi G, Kiddugavu M, Lutalo T, Nalugoda F, Wabwire-Mangen F, Meehan M P, Quinn T C. 2005. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis, 191: 1403–1409.

    Article  PubMed  Google Scholar 

  • Wurm F M. 2004. Production of recombinant protein therapeutics in cultivated mammalian cells. Nat Biotechnol, 22: 1393–1398.

    Article  CAS  PubMed  Google Scholar 

  • Wyatt R, Kwong P D, Desjardins E, Sweet R W, Robinson J, Hendrickson W A, Sodroski J G. 1998. The antigenic structure of the HIV gp120 envelope glycoprotein. Nature, 393: 705–711.

    Article  CAS  PubMed  Google Scholar 

  • Yu Y, Zhu J, Mi L Z, Walz T, Sun H, Chen J, Springer T A. 2012. S tructural specializations of α4β7, an integrin that mediates rolling adhesion. J Cell Biol, 196: 131–146.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zeller Y, Mechtersheimer S, Altevogt P. 2001. Critical amino acid re sidues of the α4 subunit for α4β7 integrin function. J Cell Biochem, 83: 304–319.

    Article  CAS  PubMed  Google Scholar 

  • Zhang Z Q, Wietgrefe S W, Li Q, Shore M D, Duan L, Reilly C, Lifson J D, Haase A T. 2004. Roles of substrate availability and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection. Proc Natl Acad Sci USA, 101: 5640–5645.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China

    Chang Li, Wei Jin, Tao Du, Yalan Liu & Qinxue Hu

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Chang Li & Wei Jin

  3. Department of General Surgery, Wuhan No.1 Hospital, Wuhan, 430022, China

    Biao Wu

  4. Section of Infectious Diseases, Faculty of Medicine, Imperial College London, St. Mary’s Campus, London, W21PG, UK

    Robin J. Shattock

  5. Institute for Infection and Immunity, St George’s University of London, London, SW170RE, UK

    Qinxue Hu

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  1. Chang Li
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  2. Wei Jin
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Li, C., Jin, W., Du, T. et al. Binding of HIV-1 virions to α4β7 expressing cells and impact of antagonizing α4β7 on HIV-1 infection of primary CD4+ T cells. Virol. Sin. 29, 381–392 (2014). https://doi.org/10.1007/s12250-014-3525-8

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