1932

Abstract

After cell entry, human immunodeficiency virus type 1 (HIV-1) replication involves reverse transcription of the RNA genome, nuclear import of the subviral complex without nuclear envelope breakdown, and integration of the viral complementary DNA into the host genome. Here, we discuss recent evidence indicating that completion of reverse transcription and viral genome uncoating occur in the nucleus rather than in the cytoplasm, as previously thought, and suggest a testable model for nuclear import and uncoating. Multiple recent studies indicated that the cone-shaped capsid, which encases the genome and replication proteins, not only serves as a reaction container for reverse transcription and as a shield from innate immune sensors but also may constitute the elusive HIV-1 nuclear import factor. Rupture of the capsid may be triggered in the nucleus by completion of reverse transcription, by yet-unknown nuclear factors, or by physical damage, and it appears to occur in close temporal and spatial association with the integration process.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-virology-020922-110929
2022-09-29
2024-06-17
Loading full text...

Full text loading...

/deliver/fulltext/virology/9/1/annurev-virology-020922-110929.html?itemId=/content/journals/10.1146/annurev-virology-020922-110929&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Campbell EM, Hope TJ. 2015. HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat. Rev. Microbiol. 13:8471–83
    [Crossref] [Google Scholar]
  2. 2.
    Zhang MJ, Stear JH, Jacques DA, Böcking T. 2022. Insights into HIV uncoating from single-particle imaging techniques. Biophys. Rev. 14:23–32
    [Crossref] [Google Scholar]
  3. 3.
    Guedán A, Caroe ER, Barr GCR, Bishop KN. 2021. The role of capsid in HIV-1 nuclear entry. Viruses 13:81425
    [Crossref] [Google Scholar]
  4. 4.
    Ingram Z, Fischer DK, Ambrose Z 2021. Disassembling the nature of capsid: biochemical, genetic, and imaging approaches to assess HIV-1 capsid functions. Viruses 13:112237
    [Crossref] [Google Scholar]
  5. 5.
    Novikova M, Zhang Y, Freed EO, Peng K. 2019. Multiple roles of HIV-1 capsid during the virus replication cycle. Virol. Sin. 34:2119–34
    [Crossref] [Google Scholar]
  6. 6.
    Arhel N. 2010. Revisiting HIV-1 uncoating. Retrovirology 7:196
    [Crossref] [Google Scholar]
  7. 7.
    Coffin JM, Fan H. 2016. The discovery of reverse transcriptase. Annu. Rev. Virol. 3:29–51
    [Crossref] [Google Scholar]
  8. 8.
    Hu W-S, Hughes SH. 2012. HIV-1 reverse transcription. Cold Spring Harb. Perspect. Med. 2:10a006882
    [Crossref] [Google Scholar]
  9. 9.
    Briggs JA, Wilk T, Welker R, Kräusslich H-G, Fuller SD. 2003. Structural organization of authentic, mature HIV-1 virions and cores. EMBO J 22:71707–15
    [Crossref] [Google Scholar]
  10. 10.
    Sundquist WI, Kräusslich H-G. 2012. HIV-1 assembly, budding, and maturation. Cold Spring Harb. Perspect. Med. 2:7a006924
    [Google Scholar]
  11. 11.
    Ganser BK, Li S, Klishko VY, Finch JT, Sundquist WI. 1999. Assembly and analysis of conical models for the HIV-1 core. Science 283:539880–83
    [Crossref] [Google Scholar]
  12. 12.
    Mattei S, Glass B, Hagen WJ, Kräusslich H-G, Briggs JA. 2016. The structure and flexibility of conical HIV-1 capsids determined within intact virions. Science 354:63181434–37
    [Crossref] [Google Scholar]
  13. 13.
    Yang H, Ji X, Zhao G, Ning J, Zhao Q et al. 2012. Structural insight into HIV-1 capsid recognition by rhesus TRIM5α. PNAS 109:4518372–77
    [Crossref] [Google Scholar]
  14. 14.
    Yu A, Skorupka KA, Pak AJ, Ganser-Pornillos BK, Pornillos O, Voth GA. 2020. TRIM5α self-assembly and compartmentalization of the HIV-1 viral capsid. Nat. Commun. 11:11307
    [Crossref] [Google Scholar]
  15. 15.
    Ganser-Pornillos BK, Pornillos O 2019. Restriction of HIV-1 and other retroviruses by TRIM5. Nat. Rev. Microbiol. 17:9546–56
    [Crossref] [Google Scholar]
  16. 16.
    Kim K, Dauphin A, Komurlu S, McCauley SM, Yurkovetskiy L et al. 2019. Cyclophilin A protects HIV-1 from restriction by human TRIM5α. Nat. Microbiol. 4:122044–51
    [Crossref] [Google Scholar]
  17. 17.
    Bukrinsky MI, Sharova N, McDonald TL, Pushkarskaya T, Tarpley WG, Stevenson M. 1993. Association of integrase, matrix, and reverse transcriptase antigens of human immunodeficiency virus type 1 with viral nucleic acids following acute infection. PNAS 90:136125–29
    [Crossref] [Google Scholar]
  18. 18.
    Farnet CM, Haseltine WA. 1991. Determination of viral proteins present in the human immunodeficiency virus type 1 preintegration complex. J. Virol. 65:41910–15
    [Crossref] [Google Scholar]
  19. 19.
    Fassati A, Goff SP. 2001. Characterization of intracellular reverse transcription complexes of human immunodeficiency virus type 1. J. Virol. 75:83626–35
    [Crossref] [Google Scholar]
  20. 20.
    Miller M, Farnet C, Bushman F. 1997. Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J. Virol. 71:75382–90
    [Crossref] [Google Scholar]
  21. 21.
    McDonald D, Vodicka MA, Lucero G, Svitkina TM, Borisy GG et al. 2002. Visualization of the intracellular behavior of HIV in living cells. J. Cell Biol. 159:3441–52
    [Crossref] [Google Scholar]
  22. 22.
    Campbell EM, Hope TJ. 2008. Live cell imaging of the HIV-1 life cycle. Trends Microbiol 16:12580–87
    [Crossref] [Google Scholar]
  23. 23.
    Campbell EM, Perez O, Melar M, Hope TJ. 2007. Labeling HIV-1 virions with two fluorescent proteins allows identification of virions that have productively entered the target cell. Virology 360:2286–93
    [Crossref] [Google Scholar]
  24. 24.
    Shah VB, Aiken C. 2011. In vitro uncoating of HIV-1 cores. JoVE 8:57e3384
    [Google Scholar]
  25. 25.
    Forshey BM, von Schwedler U, Sundquist WI, Aiken C. 2002. Formation of a human immunodeficiency virus type 1 core of optimal stability is crucial for viral replication. J. Virol. 76:115667–77
    [Crossref] [Google Scholar]
  26. 26.
    Welker R, Hohenberg H, Tessmer U, Huckhagel C, Kräusslich H-G. 2000. Biochemical and structural analysis of isolated mature cores of human immunodeficiency virus type 1. J. Virol. 74:31168–77
    [Crossref] [Google Scholar]
  27. 27.
    Mamede JI, Cianci GC, Anderson MR, Hope TJ. 2017. Early cytoplasmic uncoating is associated with infectivity of HIV-1. PNAS 114:34E7169–78
    [Crossref] [Google Scholar]
  28. 28.
    Hulme AE, Perez O, Hope TJ. 2011. Complementary assays reveal a relationship between HIV-1 uncoating and reverse transcription. PNAS 108:249975–80
    [Crossref] [Google Scholar]
  29. 29.
    Hulme AE, Kelley Z, Foley D, Hope TJ. 2015. Complementary assays reveal a low level of CA associated with viral complexes in the nuclei of HIV-1-infected cells. J. Virol. 89:105350–61
    [Crossref] [Google Scholar]
  30. 30.
    Rankovic S, Varadarajan J, Ramalho R, Aiken C, Rousso I. 2017. Reverse transcription mechanically initiates HIV-1 capsid disassembly. J. Virol. 91:12e00289–17
    [Crossref] [Google Scholar]
  31. 31.
    Cosnefroy O, Murray PJ, Bishop KN. 2016. HIV-1 capsid uncoating initiates after the first strand transfer of reverse transcription. Retrovirology 13:158
    [Crossref] [Google Scholar]
  32. 32.
    Yang Y, Fricke T, Diaz-Griffero F. 2013. Inhibition of reverse transcriptase activity increases stability of the HIV-1 core. J. Virol. 87:1683–87
    [Crossref] [Google Scholar]
  33. 33.
    Francis AC, Marin M, Shi J, Aiken C, Melikyan GB. 2016. Time-resolved imaging of single HIV-1 uncoating in vitro and in living cells. PLOS Pathog 12:6e1005709
    [Crossref] [Google Scholar]
  34. 34.
    Li L, Olvera JM, Yoder KE, Mitchell RS, Butler SL et al. 2001. Role of the non-homologous DNA end joining pathway in the early steps of retroviral infection. EMBO J 20:123272–81
    [Crossref] [Google Scholar]
  35. 35.
    Cavazza T, Vernos I. 2016. The RanGTP pathway: from nucleo-cytoplasmic transport to spindle assembly and beyond. Front. Cell Dev. Biol. 3:82
    [Crossref] [Google Scholar]
  36. 36.
    Bukrinsky MI, Haggerty S, Dempsey MP, Sharova N, Adzhubel A et al. 1993. A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature 365:6447666–69
    [Crossref] [Google Scholar]
  37. 37.
    Gallay P, Swingler S, Song J, Bushman F, Trono D. 1995. HIV nuclear import is governed by the phosphotyrosine-mediated binding of matrix to the core domain of integrase. Cell 83:4569–76
    [Crossref] [Google Scholar]
  38. 38.
    von Schwedler U, Kornbluth RS, Trono D. 1994. The nuclear localization signal of the matrix protein of human immunodeficiency virus type 1 allows the establishment of infection in macrophages and quiescent T lymphocytes. PNAS 91:156992–96
    [Crossref] [Google Scholar]
  39. 39.
    Gallay P, Hope T, Chin D, Trono D. 1997. HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway. PNAS 94:189825–30
    [Crossref] [Google Scholar]
  40. 40.
    Heinzinger NK, Bukinsky MI, Haggerty SA, Ragland AM, Kewalramani V et al. 1994. The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. PNAS 91:157311–15
    [Crossref] [Google Scholar]
  41. 41.
    Popov S, Rexach M, Zybarth G, Reiling N, Lee M-A et al. 1998. Viral protein R regulates nuclear import of the HIV-1 pre-integration complex. EMBO J 17:4909–17
    [Crossref] [Google Scholar]
  42. 42.
    Depienne C, Roques P, Créminon C, Fritsch L, Casseron R et al. 2000. Cellular distribution and karyophilic properties of matrix, integrase, and Vpr proteins from the human and simian immunodeficiency viruses. Exp. Cell Res. 260:2387–95
    [Crossref] [Google Scholar]
  43. 43.
    Arhel N, Munier S, Souque P, Mollier K, Charneau P. 2006. Nuclear import defect of human immunodeficiency virus type 1 DNA flap mutants is not dependent on the viral strain or target cell type. J. Virol. 80:2010262–69
    [Crossref] [Google Scholar]
  44. 44.
    Zennou V, Petit C, Guetard D, Nerhbass U, Montagnier L, Charneau P. 2000. HIV-1 genome nuclear import is mediated by a central DNA flap. Cell 101:2173–85
    [Crossref] [Google Scholar]
  45. 45.
    Freed EO, Martin MA. 1994. HIV-1 infection of non-dividing cells. Nature 369:6476107–8
    [Crossref] [Google Scholar]
  46. 46.
    Fouchier RA, Meyer BE, Simon JH, Fischer U, Malim MH. 1997. HIV-1 infection of non-dividing cells: evidence that the amino-terminal basic region of the viral matrix protein is important for Gag processing but not for post-entry nuclear import. EMBO J 16:154531–39
    [Crossref] [Google Scholar]
  47. 47.
    Freed EO, Englund G, Martin MA. 1995. Role of the basic domain of human immunodeficiency virus type 1 matrix in macrophage infection. J. Virol. 69:63949–54
    [Crossref] [Google Scholar]
  48. 48.
    Dvorin JD, Bell P, Maul GG, Yamashita M, Emerman M, Malim MH. 2002. Reassessment of the roles of integrase and the central DNA flap in human immunodeficiency virus type 1 nuclear import. J. Virol. 76:2312087–96
    [Crossref] [Google Scholar]
  49. 49.
    Petit C, Schwartz O, Mammano F. 2000. The karyophilic properties of human immunodeficiency virus type 1 integrase are not required for nuclear import of proviral DNA. J. Virol. 74:157119–26
    [Crossref] [Google Scholar]
  50. 50.
    Limón A, Nakajima N, Lu R, Ghory HZ, Engelman A. 2002. Wild-type levels of nuclear localization and human immunodeficiency virus type 1 replication in the absence of the central DNA flap. J. Virol. 76:2312078–86
    [Crossref] [Google Scholar]
  51. 51.
    Rivière L, Darlix J-L, Cimarelli A. 2010. Analysis of the viral elements required in the nuclear import of HIV-1 DNA. J. Virol. 84:2729–39
    [Crossref] [Google Scholar]
  52. 52.
    Fassati A, Görlich D, Harrison I, Zaytseva L, Mingot J-M. 2003. Nuclear import of HIV-1 intracellular reverse transcription complexes is mediated by importin 7. EMBO J 22:143675–85
    [Crossref] [Google Scholar]
  53. 53.
    Zaitseva L, Myers R, Fassati A. 2006. tRNAs promote nuclear import of HIV-1 intracellular reverse transcription complexes. PLOS Biol 4:10e332
    [Crossref] [Google Scholar]
  54. 54.
    Christ F, Thys W, De Rijck J, Gijsbers R, Albanese A et al. 2008. Transportin-SR2 imports HIV into the nucleus. Curr. Biol. 18:161192–202
    [Crossref] [Google Scholar]
  55. 55.
    Cribier A, Ségéral E, Delelis O, Parissi V, Simon A et al. 2011. Mutations affecting interaction of integrase with TNPO3 do not prevent HIV-1 cDNA nuclear import. Retrovirology 8:1104
    [Crossref] [Google Scholar]
  56. 56.
    Yang Y, Luban J, Diaz-Griffero F. 2014. The fate of HIV-1 capsid: a biochemical assay for HIV-1 uncoating. Human Retroviruses: Methods and Protocols E Vicenzi, G Poli 29–36 Totowa, NJ: Humana
    [Google Scholar]
  57. 57.
    Stremlau M, Perron M, Lee M, Li Y, Song B et al. 2006. Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5α restriction factor. PNAS 103:145514–19
    [Crossref] [Google Scholar]
  58. 58.
    Nisole S, Lynch C, Stoye JP, Yap MW. 2004. A Trim5-cyclophilin A fusion protein found in owl monkey kidney cells can restrict HIV-1. PNAS 101:3613324–28
    [Crossref] [Google Scholar]
  59. 59.
    Li Y, Kar AK, Sodroski J. 2009. Target cell type-dependent modulation of human immunodeficiency virus type 1 capsid disassembly by cyclophilin A. J. Virol. 83:2110951–62
    [Crossref] [Google Scholar]
  60. 60.
    Arhel NJ, Souquere-Besse S, Munier S, Souque P, Guadagnini S et al. 2007. HIV-1 DNA Flap formation promotes uncoating of the pre-integration complex at the nuclear pore. EMBO J 26:123025–37
    [Crossref] [Google Scholar]
  61. 61.
    Jun S, Ke D, Debiec K, Zhao G, Meng X et al. 2011. Direct visualization of HIV-1 with correlative live-cell microscopy and cryo-electron tomography. Structure 19:111573–81
    [Crossref] [Google Scholar]
  62. 62.
    Li C, Burdick RC, Nagashima K, Hu W-S, Pathak VK. 2021. HIV-1 cores retain their integrity until minutes before uncoating in the nucleus. PNAS 118:10e2019467118
    [Crossref] [Google Scholar]
  63. 63.
    Yamashita M, Emerman M. 2004. Capsid is a dominant determinant of retrovirus infectivity in nondividing cells. J. Virol. 78:115670–78
    [Crossref] [Google Scholar]
  64. 64.
    Yamashita M, Perez O, Hope TJ, Emerman M. 2007. Evidence for direct involvement of the capsid protein in HIV infection of nondividing cells. PLOS Pathog 3:101502–10
    [Crossref] [Google Scholar]
  65. 65.
    Saito A, Yamashita M. 2021. HIV-1 capsid variability: viral exploitation and evasion of capsid-binding molecules. Retrovirology 18:132
    [Crossref] [Google Scholar]
  66. 66.
    Fischer DK, Saito A, Kline C, Cohen R, Watkins SC et al. 2019. CA mutation N57A has distinct strain-specific HIV-1 capsid uncoating and infectivity phenotypes. J. Virol. 93:9e00214–19
    [Crossref] [Google Scholar]
  67. 67.
    Dismuke DJ, Aiken C. 2006. Evidence for a functional link between uncoating of the human immunodeficiency virus type 1 core and nuclear import of the viral preintegration complex. J. Virol. 80:83712–20
    [Crossref] [Google Scholar]
  68. 68.
    Wilbourne M, Zhang P. 2021. Visualizing HIV-1 capsid and its interactions with antivirals and host factors. Viruses 13:2246
    [Crossref] [Google Scholar]
  69. 69.
    Yamashita M, Engelman AN. 2017. Capsid-dependent host factors in HIV-1 infection. Trends Microbiol 25:9741–55
    [Crossref] [Google Scholar]
  70. 70.
    Rasaiyaah J, Tan CP, Fletcher AJ, Price AJ, Blondeau C et al. 2013. HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503:7476402–5
    [Crossref] [Google Scholar]
  71. 71.
    Lahaye X, Satoh T, Gentili M, Cerboni S, Conrad C et al. 2013. The capsids of HIV-1 and HIV-2 determine immune detection of the viral cDNA by the innate sensor cGAS in dendritic cells. Immunity 39:61132–42
    [Crossref] [Google Scholar]
  72. 72.
    Sumner RP, Harrison L, Touizer E, Peacock TP, Spencer M et al. 2020. Disrupting HIV-1 capsid formation causes cGAS sensing of viral DNA. EMBO J 39:20e103958
    [Crossref] [Google Scholar]
  73. 73.
    Mallery DL, Márquez CL, McEwan WA, Dickson CF, Jacques DA et al. 2018. IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis. eLife 7:e35335
    [Crossref] [Google Scholar]
  74. 74.
    Márquez CL, Lau D, Walsh J, Shah V, McGuinness C et al. 2018. Kinetics of HIV-1 capsid uncoating revealed by single-molecule analysis. eLife 7:e34772
    [Crossref] [Google Scholar]
  75. 75.
    Jacques DA, McEwan WA, Hilditch L, Price AJ, Towers GJ, James LC. 2016. HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis. Nature 536:7616349–53
    [Crossref] [Google Scholar]
  76. 76.
    Jennings J, Shi J, Varadarajan J, Jamieson PJ, Aiken C. 2020. The host cell metabolite inositol hexakisphosphate promotes efficient endogenous HIV-1 reverse transcription by stabilizing the viral capsid. mBio 11:6e02820–20
    [Crossref] [Google Scholar]
  77. 77.
    Xu C, Fischer DK, Rankovic S, Li W, Dick RA et al. 2020. Permeability of the HIV-1 capsid to metabolites modulates viral DNA synthesis. PLOS Biol 18:12e3001015
    [Crossref] [Google Scholar]
  78. 78.
    Huang P-T, Summers BJ, Xu C, Perilla JR, Malikov V et al. 2019. FEZ1 is recruited to a conserved cofactor site on capsid to promote HIV-1 trafficking. Cell Rep 28:9237385.e7
    [Crossref] [Google Scholar]
  79. 79.
    Malikov V, Da Silva ES, Jovasevic V, Bennett G, de Souza Aranha Vieira DA et al. 2015. HIV-1 capsids bind and exploit the kinesin-1 adaptor FEZ1 for inward movement to the nucleus. Nat. Commun. 6:6660
    [Crossref] [Google Scholar]
  80. 80.
    Rihn SJ, Wilson SJ, Loman NJ, Alim M, Bakker SE et al. 2013. Extreme genetic fragility of the HIV-1 capsid. PLOS Pathog 9:6e1003461
    [Crossref] [Google Scholar]
  81. 81.
    Bejarano DA, Peng K, Laketa V, Börner K, Jost KL et al. 2019. HIV-1 nuclear import in macrophages is regulated by CPSF6-capsid interactions at the nuclear pore complex. eLife 8:e41800
    [Crossref] [Google Scholar]
  82. 82.
    Peng K, Muranyi W, Glass B, Laketa V, Yant SR et al. 2015. Quantitative microscopy of functional HIV post-entry complexes reveals association of replication with the viral capsid. eLife 3:e04114
    [Crossref] [Google Scholar]
  83. 83.
    Zila V, Müller TG, Laketa V, Müller B, Kräusslich H-G. 2019. Analysis of CA content and CPSF6 dependence of early HIV-1 replication complexes in SupT1-R5 cells. mBio 10:6e02501–19
    [Crossref] [Google Scholar]
  84. 84.
    Burdick RC, Delviks-Frankenberry KA, Chen J, Janaka SK, Sastri J et al. 2017. Dynamics and regulation of nuclear import and nuclear movements of HIV-1 complexes. PLOS Pathog 13:8e1006570
    [Crossref] [Google Scholar]
  85. 85.
    Burdick RC, Li C, Munshi M, Rawson JMO, Nagashima K et al. 2020. HIV-1 uncoats in the nucleus near sites of integration. PNAS 117:105486–93
    [Crossref] [Google Scholar]
  86. 86.
    Francis AC, Melikyan GB. 2018. Single HIV-1 imaging reveals progression of infection through CA-dependent steps of docking at the nuclear pore, uncoating, and nuclear transport. Cell Host Microbe 23:4536–48.e6
    [Crossref] [Google Scholar]
  87. 87.
    Fernandez J, Machado AK, Lyonnais S, Chamontin C, Gärtner K et al. 2019. Transportin-1 binds to the HIV-1 capsid via a nuclear localization signal and triggers uncoating. Nat. Microbiol. 4:111840–50
    [Crossref] [Google Scholar]
  88. 88.
    Zurnic Bönisch I, Dirix L, Lemmens V, Borrenberghs D, De Wit F et al. 2020. Capsid-labelled HIV to investigate the role of capsid during nuclear import and integration. J. Virol. 94:7e01024–19
    [Crossref] [Google Scholar]
  89. 89.
    Zila V, Margiotta E, Turoňová B, Müller TG, Zimmerli CE et al. 2021. Cone-shaped HIV-1 capsids are transported through intact nuclear pores. Cell 184:41032–46.e18
    [Crossref] [Google Scholar]
  90. 90.
    Naghavi MH. 2021. HIV-1 capsid exploitation of the host microtubule cytoskeleton during early infection. Retrovirology 18:119
    [Crossref] [Google Scholar]
  91. 91.
    Dharan A, Campbell EM. 2018. Role of microtubules and microtubule-associated proteins in HIV-1 infection. J. Virol. 92:16e00085–18
    [Crossref] [Google Scholar]
  92. 92.
    von Appen A, Kosinski J, Sparks L, Ori A, DiGuilio AL et al. 2015. In situ structural analysis of the human nuclear pore complex. Nature 526:7571140–43
    [Crossref] [Google Scholar]
  93. 93.
    Fay N, Panté N. 2015. Nuclear entry of DNA viruses. Front. Microbiol. 6:467
    [Crossref] [Google Scholar]
  94. 94.
    Francis AC, Marin M, Prellberg MJ, Palermino-Rowland K, Melikyan GB. 2020. HIV-1 uncoating and nuclear import precede the completion of reverse transcription in cell lines and in primary macrophages. Viruses 12:111234
    [Crossref] [Google Scholar]
  95. 95.
    Chin CR, Perreira JM, Savidis G, Portmann JM, Aker AM et al. 2015. Direct visualization of HIV-1 replication intermediates shows that capsid and CPSF6 modulate HIV-1 intra-nuclear invasion and integration. Cell Rep 13:81717–31
    [Crossref] [Google Scholar]
  96. 96.
    Stultz RD, Cenker JJ, McDonald D. 2017. Imaging HIV-1 genomic DNA from entry through productive infection. J. Virol. 91:9e00034–17
    [Crossref] [Google Scholar]
  97. 97.
    Rensen E, Mueller F, Scoca V, Parmar JJ, Souque P et al. 2021. Clustering and reverse transcription of HIV-1 genomes in nuclear niches of macrophages. EMBO J 40:1e105247
    [Crossref] [Google Scholar]
  98. 98.
    Francis AC, Marin M, Singh PK, Achuthan V, Prellberg MJ et al. 2020. HIV-1 replication complexes accumulate in nuclear speckles and integrate into speckle-associated genomic domains. Nat. Commun. 11:13505
    [Crossref] [Google Scholar]
  99. 99.
    Müller TG, Zila V, Peters K, Schifferdecker S, Stanic M et al. 2021. HIV-1 uncoating by release of viral cDNA from capsid-like structures in the nucleus of infected cells. eLife 10:e64776
    [Crossref] [Google Scholar]
  100. 100.
    Schifferdecker S, Zila V, Mueller TG, Sakin V, Anders-Oesswein M et al. 2021. Direct capsid labeling of infectious HIV-1 by genetic code expansion allows detection of largely complete nuclear capsids and suggests nuclear entry of HIV-1 complexes via common routes. bioRxiv 2021.09.14.460218. https://doi.org/10.1101/2021.09.14.460218
    [Crossref] [Google Scholar]
  101. 101.
    Müller TG, Sakin V, Müller B. 2019. A spotlight on viruses—application of click chemistry to visualize virus-cell interactions. Molecules 24:3481
    [Crossref] [Google Scholar]
  102. 102.
    Bejarano DA, Puertas MC, Börner K, Martinez-Picado J, Müller B, Kräusslich H-G. 2018. Detailed characterization of early HIV-1 replication dynamics in primary human macrophages. Viruses 10:11620
    [Crossref] [Google Scholar]
  103. 103.
    Achuthan V, Perreira JM, Sowd GA, Puray-Chavez M, McDougall WM et al. 2018. Capsid-CPSF6 interaction licenses nuclear HIV-1 trafficking to sites of viral DNA integration. Cell Host Microbe 24:3392–404.e8
    [Crossref] [Google Scholar]
  104. 104.
    Li W, Singh PK, Sowd GA, Bedwell GJ, Jang S et al. 2020. CPSF6-dependent targeting of speckle-associated domains distinguishes primate from nonprimate lentiviral integration. mBio 11:5e02254–20
    [Google Scholar]
  105. 105.
    Lee K, Ambrose Z, Martin TD, Oztop I, Mulky A et al. 2010. Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe 7:3221–33
    [Crossref] [Google Scholar]
  106. 106.
    Price AJ, Fletcher AJ, Schaller T, Elliott T, Lee K et al. 2012. CPSF6 defines a conserved capsid interface that modulates HIV-1 replication. PLOS Pathog 8:8e1002896
    [Crossref] [Google Scholar]
  107. 107.
    Price AJ, Jacques DA, McEwan WA, Fletcher AJ, Essig S et al. 2014. Host cofactors and pharmacologic ligands share an essential interface in HIV-1 capsid that is lost upon disassembly. PLOS Pathog 10:10e1004459
    [Crossref] [Google Scholar]
  108. 108.
    Bhattacharya A, Alam SL, Fricke T, Zadrozny K, Sedzicki J et al. 2014. Structural basis of HIV-1 capsid recognition by PF74 and CPSF6. PNAS 111:5218625–30
    [Crossref] [Google Scholar]
  109. 109.
    Dharan A, Bachmann N, Talley S, Zwikelmaier V, Campbell EM. 2020. Nuclear pore blockade reveals that HIV-1 completes reverse transcription and uncoating in the nucleus. Nat. Microbiol. 5:91088–95
    [Crossref] [Google Scholar]
  110. 110.
    Selyutina A, Persaud M, Lee K, KewalRamani V, Diaz-Griffero F. 2020. Nuclear import of the HIV-1 core precedes reverse transcription and uncoating. Cell Rep 32:13108201
    [Crossref] [Google Scholar]
  111. 111.
    Zimmerli CE, Allegretti M, Rantos V, Goetz SK, Obarska-Kosinska A et al. 2021. Nuclear pores dilate and constrict in cellulo. Science 374:6573eabd9776
    [Crossref] [Google Scholar]
  112. 112.
    Schuller AP, Wojtynek M, Mankus D, Tatli M, Kronenberg-Tenga R et al. 2021. The cellular environment shapes the nuclear pore complex architecture. Nature 598:7882667–71
    [Crossref] [Google Scholar]
  113. 113.
    Rebensburg SV, Wei G, Larue RC, Lindenberger J, Francis AC et al. 2021. Sec24C is an HIV-1 host dependency factor crucial for virus replication. Nat. Microbiol. 6:4435–44
    [Crossref] [Google Scholar]
  114. 114.
    Gamble TR, Vajdos FF, Yoo S, Worthylake DK, Houseweart M et al. 1996. Crystal structure of human cyclophilin A bound to the amino-terminal domain of HIV-1 capsid. Cell 87:71285–94
    [Crossref] [Google Scholar]
  115. 115.
    Schaller T, Ocwieja KE, Rasaiyaah J, Price AJ, Brady TL et al. 2011. HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLOS Pathog 7:12e1002439
    [Crossref] [Google Scholar]
  116. 116.
    Dharan A, Talley S, Tripathi A, Mamede JI, Majetschak M et al. 2016. KIF5B and Nup358 cooperatively mediate the nuclear import of HIV-1 during infection. PLOS Pathog 12:6e1005700
    [Crossref] [Google Scholar]
  117. 117.
    Lau D, Walsh JC, Mousapasandi A, Ariotti N, Shah VB et al. 2020. Self-assembly of fluorescent HIV capsid spheres for detection of capsid binders. Langmuir 36:133624–32
    [Crossref] [Google Scholar]
  118. 118.
    Denning DP, Patel SS, Uversky V, Fink AL, Rexach M. 2003. Disorder in the nuclear pore complex: The FG repeat regions of nucleoporins are natively unfolded. PNAS 100:52450–55
    [Crossref] [Google Scholar]
  119. 119.
    Frey S, Görlich D. 2007. A saturated FG-repeat hydrogel can reproduce the permeability properties of nuclear pore complexes. Cell 130:3512–23
    [Crossref] [Google Scholar]
  120. 120.
    Frey S, Richter RP, Görlich D. 2006. FG-rich repeats of nuclear pore proteins form a three-dimensional meshwork with hydrogel-like properties. Science 314:5800815–17
    [Crossref] [Google Scholar]
  121. 121.
    Engelman AN. 2021. HIV capsid and integration targeting. Viruses 13:1125
    [Crossref] [Google Scholar]
  122. 122.
    Di Nunzio F, Fricke T, Miccio A, Valle-Casuso JC, Perez P et al. 2013. Nup153 and Nup98 bind the HIV-1 core and contribute to the early steps of HIV-1 replication. Virology 440:18–18
    [Crossref] [Google Scholar]
  123. 123.
    Nunzio FD, Danckaert A, Fricke T, Perez P, Fernandez J et al. 2012. Human nucleoporins promote HIV-1 docking at the nuclear pore, nuclear import and integration. PLOS ONE 7:9e46037
    [Crossref] [Google Scholar]
  124. 124.
    Matreyek KA, Yücel SS, Li X, Engelman A. 2013. Nucleoporin NUP153 phenylalanine-glycine motifs engage a common binding pocket within the HIV-1 capsid protein to mediate lentiviral infectivity. PLOS Pathog 9:10e1003693
    [Crossref] [Google Scholar]
  125. 125.
    Kane M, Rebensburg SV, Takata MA, Zang TM, Yamashita M et al. 2018. Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2. eLife 7:e35738
    [Crossref] [Google Scholar]
  126. 126.
    Sowd GA, Serrao E, Wang H, Wang W, Fadel HJ et al. 2016. A critical role for alternative polyadenylation factor CPSF6 in targeting HIV-1 integration to transcriptionally active chromatin. PNAS 113:8E1054–63
    [Crossref] [Google Scholar]
  127. 127.
    Isel C, Ehresmann C, Marquet R. 2010. Initiation of HIV reverse transcription. Viruses 2:1213–43
    [Crossref] [Google Scholar]
  128. 128.
    Christensen DE, Ganser-Pornillos BK, Johnson JS, Pornillos O, Sundquist WI. 2020. Reconstitution and visualization of HIV-1 capsid-dependent replication and integration in vitro. Science 370:6513eabc8420
    [Crossref] [Google Scholar]
  129. 129.
    Scoca V, Morin R, Tinevez J-Y, Di Nunzio F. 2021. HIV-induced membraneless organelles orchestrate post-nuclear entry steps. bioRxiv 2020.11.17.385567. https://doi.org/10.1101/2020.11.17.385567
    [Crossref] [Google Scholar]
  130. 130.
    Rouzina I, Bruinsma R. 2014. DNA confinement drives uncoating of the HIV virus. Eur. Phys. J. Spec. Top. 223:91745–54
    [Crossref] [Google Scholar]
  131. 131.
    Garcia HG, Grayson P, Han L, Inamdar M, Kondev J et al. 2007. Biological consequences of tightly bent DNA: the other life of a macromolecular celebrity. Biopolymers 85:2115–30
    [Crossref] [Google Scholar]
  132. 132.
    Chen H, Meisburger SP, Pabit SA, Sutton JL, Webb WW, Pollack L. 2012. Ionic strength-dependent persistence lengths of single-stranded RNA and DNA. PNAS 109:3799–804
    [Crossref] [Google Scholar]
  133. 133.
    Ben-Shaul A, Gelbart WM. 2015. Viral ssRNAs are indeed compact. Biophys. J. 108:114–16
    [Crossref] [Google Scholar]
  134. 134.
    Watts JM, Dang KK, Gorelick RJ, Leonard CW, Bess JW Jr. et al. 2009. Architecture and secondary structure of an entire HIV-1 RNA genome. Nature 460:7256711–16
    [Crossref] [Google Scholar]
  135. 135.
    Jiang K, Humbert N, KK S, Rouzina I, Mely Y, Westerlund F 2021. The HIV-1 nucleocapsid chaperone protein forms locally compacted globules on long double-stranded DNA. Nucleic Acids Res 49:84550–63
    [Crossref] [Google Scholar]
  136. 136.
    Geis FK, Goff SP. 2019. Unintegrated HIV-1 DNAs are loaded with core and linker histones and transcriptionally silenced. PNAS 116:4723735–42
    [Crossref] [Google Scholar]
  137. 137.
    Zhu Y, Wang GZ, Cingöz O, Goff SP. 2018. NP220 mediates silencing of unintegrated retroviral DNA. Nature 564:7735278–82
    [Crossref] [Google Scholar]
  138. 138.
    Wang GZ, Wang Y, Goff SP. 2016. Histones are rapidly loaded onto unintegrated retroviral DNAs soon after nuclear entry. Cell Host Microbe 20:6798–809
    [Crossref] [Google Scholar]
  139. 139.
    Goff SP. 2021. Silencing of unintegrated retroviral DNAs. Viruses 13:112248
    [Crossref] [Google Scholar]
  140. 140.
    Rankovic S, Ramalho R, Aiken C, Rousso I. 2018. PF74 reinforces the HIV-1 capsid to impair reverse transcription-induced uncoating. J. Virol. 92:20e00845–18
    [Crossref] [Google Scholar]
  141. 141.
    Rankovic S, Deshpande A, Harel S, Aiken C, Rousso I. 2021. HIV-1 uncoating occurs via a series of rapid biomechanical changes in the core related to individual stages of reverse transcription. J. Virol 95:10e00166–21
    [Crossref] [Google Scholar]
  142. 142.
    Zila V, Müller TG, Müller B, Kräusslich H-G. 2021. HIV-1 capsid is the key orchestrator of early viral replication. PLOS Pathog 17:12e1010109
    [Crossref] [Google Scholar]
  143. 143.
    McFadden WM, Snyder AA, Kirby KA, Tedbury PR, Raj M et al. 2021. Rotten to the core: antivirals targeting the HIV-1 capsid core. Retrovirology 18:141
    [Crossref] [Google Scholar]
  144. 144.
    Zhuang S, Torbett BE. 2021. Interactions of HIV-1 capsid with host factors and their implications for developing novel therapeutics. Viruses 13:3417
    [Crossref] [Google Scholar]
  145. 145.
    Carnes SK, Sheehan JH, Aiken C. 2018. Inhibitors of the HIV-1 capsid, a target of opportunity. Curr. Opin. HIV AIDS 13:4359–65
    [Crossref] [Google Scholar]
  146. 146.
    Blair WS, Pickford C, Irving SL, Brown DG, Anderson M et al. 2010. HIV capsid is a tractable target for small molecule therapeutic intervention. PLOS Pathog 6:12e1001220
    [Crossref] [Google Scholar]
  147. 147.
    Yant SR, Mulato A, Hansen D, Tse WC, Niedziela-Majka A et al. 2019. A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model. Nat. Med. 25:91377–84
    [Crossref] [Google Scholar]
  148. 148.
    Link JO, Rhee MS, Tse WC, Zheng J, Somoza JR et al. 2020. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature 584:7822614–18
    [Crossref] [Google Scholar]
  149. 149.
    Bester SM, Wei G, Zhao H, Adu-Ampratwum D, Iqbal N et al. 2020. Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. Science 370:6514360–64
    [Crossref] [Google Scholar]
  150. 150.
    Dick RA, Zadrozny KK, Xu C, Schur FKM, Lyddon TD et al. 2018. Inositol phosphates are assembly co-factors for HIV-1. Nature 560:7719509–12
    [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-virology-020922-110929
Loading
/content/journals/10.1146/annurev-virology-020922-110929
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error