Genetic diversity of the highly variable V1 region interferes with Human Immunodeficiency Virus type 1 envelope functionality

Retrovirology

Matteo Negroni¹  Romain Gasser¹  Etienne Simon-Loriere²  Meriem Hamoudi¹ 

[1] Architecture et Réactivité de l'ARN, CNRS, IBMC, Université de Strasbourg, 15 rue René Descartes, 67084 Strasbourg, Cedex, France;Present address: Institut Pasteur, Unité de Génétique Fonctionnelle des Maladies Infectieuses, 28 rue du Docteur Roux, 75724 Paris CEDEX 15, France; Centre National de la Recherche Scientifique, URA, CNRS3012 Paris, France

关键词: Viral entry;    Variable regions;    gp120;    Envelope;    HIV-1;   

Others  :  806960
DOI  :  10.1186/1742-4690-10-114

 received in 2013-05-17, accepted in 2013-10-13,  发布年份 2013

【 摘 要 】

Background

The HIV envelope (Env) promotes viral entry in the host cell. During this process, Env undergoes several conformational changes to ensure its function. At the same time, the gp120 component of Env is the protein of the virus presenting the largest genetic diversity. Understanding how the virus maintains the balance between the competing requirements for maintenance of functionality and antigenic variation of this protein is central for the comprehension of its strategies of evolution and can highlight vulnerable aspects of its replication cycle. We focused on the variable domains V1 and V2 of the HIV-1 gp120 that are involved in conformational changes and are critical for viral escape from antibody neutralization.

Results

Despite the extensive sequence diversity found in the epidemic for these regions and their location on the external face of the protein, we observed that replacing V1V2 of one primary isolate with that of another severely interferes with Env functionality in more than half of the cases studied. Similar results were obtained for intra- and intersubtype chimeras. These observations are indicative of an interference of genetic diversity in these regions with Env functionality. Therefore, despite the extensive sequence diversity that characterizes these regions in the epidemic, our results show that functional constraints seem to limit their genetic variation. Defects in the V1V2 chimeras were not relieved by the insertion of the V3 region from the same isolate, suggesting that the decrease in functionality is not due to perturbation of potential coevolution networks between V1V2 and V3. Within the V1V2 domain, the sequence of the hypervariable loop of the V1 domain seems to be crucial for the functionality of the protein.

Conclusions

Besides the well-documented role of V1V2 in the interplay with the immune response, this work shows that V1 is also involved in the selection of functional envelopes. By documenting a compromise between the opposing forces of sequence diversification and retention of functionality, these observations improve our understanding of the evolutionary trajectories of the HIV-1 envelope gene.

【 授权许可】

   
2013 Hamoudi et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]HIV sequence databasehttp://www.hiv.lanl.gov/content/sequence/HIV/mainpage.html webcite
• [2]Alkhatib G, Broder CC, Berger EA: Cell type-specific fusion cofactors determine human immunodeficiency virus type 1 tropism for T-cell lines versus primary macrophages. J Virol 1996, 70:5487-5494.
• [3]Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, Wu L, Mackay CR, LaRosa G, Newman W, et al.: The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 1996, 85:1135-1148.
• [4]Dalgleish AG, Beverley PC, Clapham PR, Crawford DH, Greaves MF, Weiss RA: The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature 1984, 312:763-767.
• [5]Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, et al.: Identification of a major co-receptor for primary isolates of HIV-1. Nature 1996, 381:661-666.
• [6]Doranz BJ, Rucker J, Yi Y, Smyth RJ, Samson M, Peiper SC, Parmentier M, Collman RG, Doms RW: A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 1996, 85:1149-1158.
• [7]Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP, Paxton WA: HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 1996, 381:667-673.
• [8]Feng Y, Broder CC, Kennedy PE, Berger EA: HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 1996, 272:872-877.
• [9]Klatzmann D, Champagne E, Chamaret S, Gruest J, Guetard D, Hercend T, Gluckman JC, Montagnier L: T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature 1984, 312:767-768.
• [10]Wyatt R, Sodroski J: The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science 1998, 280:1884-1888.
• [11]Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, Berger EA: CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 1996, 272:1955-1958.
• [12]Guttman M, Kahn M, Garcia NK, Hu SL, Lee KK: Solution structure, conformational dynamics, and CD4-induced activation in full-length, glycosylated, monomeric HIV gp120. J Virol 2012, 86:8750-8764.
• [13]Sullivan N, Sun Y, Sattentau Q, Thali M, Wu D, Denisova G, Gershoni J, Robinson J, Moore J, Sodroski J: CD4-Induced conformational changes in the human immunodeficiency virus type 1 gp120 glycoprotein: consequences for virus entry and neutralization. J Virol 1998, 72:4694-4703.
• [14]Thali M, Furman C, Helseth E, Repke H, Sodroski J: Lack of correlation between soluble CD4-induced shedding of the human immunodeficiency virus type 1 exterior envelope glycoprotein and subsequent membrane fusion events. J Virol 1992, 66:5516-5524.
• [15]Wyatt R, Moore J, Accola M, Desjardin E, Robinson J, Sodroski J: Involvement of the V1/V2 variable loop structure in the exposure of human immunodeficiency virus type 1 gp120 epitopes induced by receptor binding. J Virol 1995, 69:5723-5733.
• [16]Furuta RA, Wild CT, Weng Y, Weiss CD: Capture of an early fusion-active conformation of HIV-1 gp41. Nat Struct Biol 1998, 5:276-279.
• [17]He Y, Vassell R, Zaitseva M, Nguyen N, Yang Z, Weng Y, Weiss CD: Peptides trap the human immunodeficiency virus type 1 envelope glycoprotein fusion intermediate at two sites. J Virol 2003, 77:1666-1671.
• [18]Koshiba T, Chan DC: The prefusogenic intermediate of HIV-1 gp41 contains exposed C-peptide regions. J Biol Chem 2003, 278:7573-7579.
• [19]Si Z, Madani N, Cox JM, Chruma JJ, Klein JC, Schon A, Phan N, Wang L, Biorn AC, Cocklin S, et al.: Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins. Proc Natl Acad Sci U S A 2004, 101:5036-5041.
• [20]Chan DC, Fass D, Berger JM, Kim PS: Core structure of gp41 from the HIV envelope glycoprotein. Cell 1997, 89:263-273.
• [21]Lu M, Blacklow SC, Kim PS: A trimeric structural domain of the HIV-1 transmembrane glycoprotein. Nat Struct Biol 1995, 2:1075-1082.
• [22]Weissenhorn W, Dessen A, Harrison SC, Skehel JJ, Wiley DC: Atomic structure of the ectodomain from HIV-1 gp41. Nature 1997, 387:426-430.
• [23]Checkley MA, Luttge BG, Freed EO: HIV-1 envelope glycoprotein biosynthesis, trafficking, and incorporation. J Mol Biol 2011, 410:582-608.
• [24]Olshevsky U, Helseth E, Furman C, Li J, Haseltine W, Sodroski J: Identification of individual human immunodeficiency virus type 1 gp120 amino acids important for CD4 receptor binding. J Virol 1990, 64:5701-5707.
• [25]Starcich BR, Hahn BH, Shaw GM, McNeely PD, Modrow S, Wolf H, Parks ES, Parks WP, Josephs SF, Gallo RC, et al.: Identification and characterization of conserved and variable regions in the envelope gene of HTLV-III/LAV, the retrovirus of AIDS. Cell 1986, 45:637-648.
• [26]Willey RL, Rutledge RA, Dias S, Folks T, Theodore T, Buckler CE, Martin MA: Identification of conserved and divergent domains within the envelope gene of the acquired immunodeficiency syndrome retrovirus. Proc Natl Acad Sci U S A 1986, 83:5038-5042.
• [27]Wei X, Decker JM, Wang S, Hui H, Kappes JC, Wu X, Salazar-Gonzalez JF, Salazar MG, Kilby JM, Saag MS, et al.: Antibody neutralization and escape by HIV-1. Nature 2003, 422:307-312.
• [28]Mascola JR, Montefiori DC: The role of antibodies in HIV vaccines. Annu Rev Immunol 2010, 28:413-444.
• [29]Reitter JN, Means RE, Desrosiers RC: A role for carbohydrates in immune evasion in AIDS. Nat Med 1998, 4:679-684.
• [30]Chen B, Vogan EM, Gong H, Skehel JJ, Wiley DC, Harrison SC: Structure of an unliganded simian immunodeficiency virus gp120 core. Nature 2005, 433:834-841.
• [31]McLellan JS, Pancera M, Carrico C, Gorman J, Julien JP, Khayat R, Louder R, Pejchal R, Sastry M, Dai K, et al.: Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 2011, 480:336-343.
• [32]Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA: Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 1998, 393:648-659.
• [33]Bunnik EM, Euler Z, Welkers MR, Boeser-Nunnink BD, Grijsen ML, Prins JM, Schuitemaker H: Adaptation of HIV-1 envelope gp120 to humoral immunity at a population level. Nat Med 2010, 16:995-997.
• [34]Hu G, Liu J, Taylor KA, Roux KH: Structural comparison of HIV-1 envelope spikes with and without the V1/V2 loop. J Virol 2011, 85:2741-2750.
• [35]Johnson WE, Morgan J, Reitter J, Puffer BA, Czajak S, Doms RW, Desrosiers RC: A replication-competent, neutralization-sensitive variant of simian immunodeficiency virus lacking 100 amino acids of envelope. J Virol 2002, 76:2075-2086.
• [36]Kwon YD, Finzi A, Wu X, Dogo-Isonagie C, Lee LK, Moore LR, Schmidt SD, Stuckey J, Yang Y, Zhou T, et al.: Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops. Proc Natl Acad Sci U S A 2012, 109:5663-5668.
• [37]Liao HX, Lynch R, Zhou T, Gao F, Alam SM, Boyd SD, Fire AZ, Roskin KM, Schramm CA, Zhang Z, et al.: Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 2013, 496:469-476.
• [38]Cocchi F, DeVico AL, Garzino-Demo A, Cara A, Gallo RC, Lusso P: The V3 domain of the HIV-1 gp120 envelope glycoprotein is critical for chemokine-mediated blockade of infection. Nat Med 1996, 2:1244-1247.
• [39]Speck RF, Wehrly K, Platt EJ, Atchison RE, Charo IF, Kabat D, Chesebro B, Goldsmith MA: Selective employment of chemokine receptors as human immunodeficiency virus type 1 coreceptors determined by individual amino acids within the envelope V3 loop. J Virol 1997, 71:7136-7139.
• [40]Chen L, Kwon YD, Zhou T, Wu X, O’Dell S, Cavacini L, Hessell AJ, Pancera M, Tang M, Xu L, et al.: Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120. Science 2009, 326:1123-1127.
• [41]Rizzuto C, Sodroski J: Fine definition of a conserved CCR5-binding region on the human immunodeficiency virus type 1 glycoprotein 120. AIDS Res Hum Retroviruses 2000, 16:741-749.
• [42]Crublet E, Andrieu JP, Vives RR, Lortat-Jacob H: The HIV-1 envelope glycoprotein gp120 features four heparan sulfate binding domains, including the co-receptor binding site. J Biol Chem 2008, 283:15193-15200.
• [43]Zolla-Pazner S, Cardozo T: Structure-function relationships of HIV-1 envelope sequence-variable regions refocus vaccine design. Nat Rev Immunol 2010, 10:527-535.
• [44]Huang CC, Tang M, Zhang MY, Majeed S, Montabana E, Stanfield RL, Dimitrov DS, Korber B, Sodroski J, Wilson IA, et al.: Structure of a V3-containing HIV-1 gp120 core. Science 2005, 310:1025-1028.
• [45]Liao HX, Bonsignori M, Alam SM, McLellan JS, Tomaras GD, Moody MA, Kozink DM, Hwang KK, Chen X, Tsao CY, et al.: Vaccine induction of antibodies against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2. Immunity 2013, 38:176-186.
• [46]Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, et al.: Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009, 361:2209-2220.
• [47]Rolland M, Edlefsen PT, Larsen BB, Tovanabutra S, Sanders-Buell E, Hertz T, DeCamp AC, Carrico C, Menis S, Magaret CA, et al.: Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2. Nature 2012, 490:417-420.
• [48]Wyatt R, Sullivan N, Thali M, Repke H, Ho D, Robinson J, Posner M, Sodroski J: Functional and immunologic characterization of human immunodeficiency virus type 1 envelope glycoproteins containing deletions of the major variable regions. J Virol 1993, 67:4557-4565.
• [49]Cao J, Sullivan N, Desjardin E, Parolin C, Robinson J, Wyatt R, Sodroski J: Replication and neutralization of human immunodeficiency virus type 1 lacking the V1 and V2 variable loops of the gp120 envelope glycoprotein. J Virol 1997, 71:9808-9812.
• [50]Stamatatos L, Cheng-Mayer C: An envelope modification that renders a primary, neutralization-resistant clade B human immunodeficiency virus type 1 isolate highly susceptible to neutralization by sera from other clades. J Virol 1998, 72:7840-7845.
• [51]Saunders CJ, McCaffrey RA, Zharkikh I, Kraft Z, Malenbaum SE, Burke B, Cheng-Mayer C, Stamatatos L: The V1, V2, and V3 regions of the human immunodeficiency virus type 1 envelope differentially affect the viral phenotype in an isolate-dependent manner. J Virol 2005, 79:9069-9080.
• [52]Laakso MM, Lee FH, Haggarty B, Agrawal C, Nolan KM, Biscone M, Romano J, Jordan AP, Leslie GJ, Meissner EG, et al.: V3 loop truncations in HIV-1 envelope impart resistance to coreceptor inhibitors and enhanced sensitivity to neutralizing antibodies. PLoS Pathog 2007, 3:e117.
• [53]Bontjer I, Land A, Eggink D, Verkade E, Tuin K, Baldwin C, Pollakis G, Paxton WA, Braakman I, Berkhout B, Sanders RW: Optimization of human immunodeficiency virus type 1 envelope glycoproteins with V1/V2 deleted, using virus evolution. J Virol 2009, 83:368-383.
• [54]Simon-Loriere E, Galetto R, Hamoudi M, Archer J, Lefeuvre P, Martin DP, Robertson DL, Negroni M: Molecular mechanisms of recombination restriction in the envelope gene of the human immunodeficiency virus. PLoS Pathog 2009, 5:e1000418.
• [55]Edgar RC: MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 2004, 32:1792-1797.
• [56]Robertson DL, Anderson JP, Bradac JA, Carr JK, Foley B, Funkhouser RK, Gao F, Hahn BH, Kalish ML, Kuiken C, et al.: HIV-1 nomenclature proposal. Science 2000, 288:55-56.
• [57]Buonaguro L, Tornesello ML, Buonaguro FM: Human immunodeficiency virus type 1 subtype distribution in the worldwide epidemic: pathogenetic and therapeutic implications. J Virol 2007, 81:10209-10219.
• [58]Long EM, Rainwater SM, Lavreys L, Mandaliya K, Overbaugh J: HIV type 1 variants transmitted to women in Kenya require the CCR5 coreceptor for entry, regardless of the genetic complexity of the infecting virus. AIDS Res Hum Retroviruses 2002, 18:567-576.
• [59]Li M, Gao F, Mascola JR, Stamatatos L, Polonis VR, Koutsoukos M, Voss G, Goepfert P, Gilbert P, Greene KM, et al.: Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. J Virol 2005, 79:10108-10125.
• [60]Li M, Salazar-Gonzalez JF, Derdeyn CA, Morris L, Williamson C, Robinson JE, Decker JM, Li Y, Salazar MG, Polonis VR, et al.: Genetic and neutralization properties of subtype C human immunodeficiency virus type 1 molecular env clones from acute and early heterosexually acquired infections in Southern Africa. J Virol 2006, 80:11776-11790.
• [61]Mao Y, Wang L, Gu C, Herschhorn A, Xiang SH, Haim H, Yang X, Sodroski J: Subunit organization of the membrane-bound HIV-1 envelope glycoprotein trimer. Nat Struct Mol Biol 2012, 19:893-899.
• [62]Rusert P, Krarup A, Magnus C, Brandenberg OF, Weber J, Ehlert AK, Regoes RR, Gunthard HF, Trkola A: Interaction of the gp120 V1V2 loop with a neighboring gp120 unit shields the HIV envelope trimer against cross-neutralizing antibodies. J Exp Med 2011, 208:1419-1433.
• [63]Walker LM, Phogat SK, Chan-Hui PY, Wagner D, Phung P, Goss JL, Wrin T, Simek MD, Fling S, Mitcham JL, et al.: Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 2009, 326:285-289.
• [64]N-GlycoSitehttp://www.hiv.lanl.gov/content/sequence/GLYCOSITE/glycosite.html webcite
• [65]Sakamoto T, Ushijima H, Okitsu S, Suzuki E, Sakai K, Morikawa S, Muller WE: Establishment of an HIV cell-cell fusion assay by using two genetically modified HeLa cell lines and reporter gene. J Virol Methods 2003, 114:159-166.
• [66]Barroso H, Taveira N: Evidence for negative selective pressure in HIV-2 evolution in vivo. Infect Genet Evol 2005, 5:239-246.
• [67]Edwards CT, Holmes EC, Pybus OG, Wilson DJ, Viscidi RP, Abrams EJ, Phillips RE, Drummond AJ: Evolution of the human immunodeficiency virus envelope gene is dominated by purifying selection. Genetics 2006, 174:1441-1453.
• [68]Woo J, Robertson DL, Lovell SC: Constraints on HIV-1 diversity from protein structure. J Virol 2010, 84:12995-13003.
• [69]Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, Julien JP, Wang SK, Ramos A, Chan-Hui PY, Moyle M, et al.: Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 2011, 477:466-470.
• [70]Finzi A, Xiang SH, Pacheco B, Wang L, Haight J, Kassa A, Danek B, Pancera M, Kwong PD, Sodroski J: Topological layers in the HIV-1 gp120 inner domain regulate gp41 interaction and CD4-triggered conformational transitions. Mol Cell 2010, 37:656-667.
• [71]Pancera M, Majeed S, Ban YE, Chen L, Huang CC, Kong L, Kwon YD, Stuckey J, Zhou T, Robinson JE, et al.: Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility. Proc Natl Acad Sci U S A 2010, 107:1166-1171.
• [72]Njai HF, Gali Y, Vanham G, Clybergh C, Jennes W, Vidal N, Butel C, Mpoudi-Ngolle E, Peeters M, Arien KK: The predominance of Human Immunodeficiency Virus type 1 (HIV-1) circulating recombinant form 02 (CRF02_AG) in West Central Africa may be related to its replicative fitness. Retrovirology 2006, 3:40. BioMed Central Full Text
• [73]Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S: MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 2011, 28:2731-2739.