Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

HIV-1 capsid: the multifaceted key player in HIV-1 infection

Nature Reviews Microbiology volume 13, pages 471–483 (2015)Cite this article

Subjects

Key Points

  • In a mature, infectious HIV-1 virion, the viral genome is housed within a conical capsid core made up of the viral capsid (CA) protein. During infection, the CA protein interacts with several cellular factors to enable efficient HIV-1 genome replication, timely core disassembly, nuclear import and the integration of the viral genome into the genome of the target cell.

  • Several models of capsid core uncoating have been proposed, including immediate uncoating, cytoplasmic uncoating and uncoating at nuclear pores. The first model suggests that the HIV-1 capsid core dissociates almost immediately on viral entry; the second is a model of gradual uncoating as the virus travels through the cytoplasm until it reaches the nucleus; and the final model suggests that an intact capsid core reaches the nuclear pore complexes (NPCs). These models may not be mutually exclusive and could depend on the type of cell infected and its status of activation.

  • Both viral and cellular factors are important for regulating viral uncoating. For example, the activity of viral integrase has been shown to affect the stability of the viral capsid core. The stability of the capsid core is also influenced by interactions between CA and the host protein cyclophilin A and microtubule motor proteins, such as dynein and kinesin-1.

  • The viral capsid also influences nuclear import via interactions with host proteins, such as cleavage and polyadenylation specificity factor 6 (CPSF6), transportin 3 (TNPO3) and proteins that are part of NPCs.

  • Understanding the viral uncoating process and the role of CA during infection will enable the design of new therapeutic strategies against HIV-1, including the development of compounds that affect the stability of the capsid core.

Abstract

In a mature, infectious HIV-1 virion, the viral genome is housed within a conical capsid core made from the viral capsid (CA) protein. The CA protein and the structure into which it assembles facilitate virtually every step of infection through a series of interactions with multiple host cell factors. This Review describes our understanding of the interactions between the viral capsid core and several cellular factors that enable efficient HIV-1 genome replication, timely core disassembly, nuclear import and the integration of the viral genome into the genome of the target cell. We then discuss how elucidating these interactions can reveal new targets for therapeutic interactions against HIV-1.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The early phase of the HIV-1 replication cycle.
Figure 2: Capsid structure and function.
Figure 3: Models of viral uncoating.
Figure 4: Viral and cellular factors involved in HIV-1 uncoating.
Figure 5: Mechanisms of microtubule-mediated HIV-1 uncoating.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Briggs, J. A. et al. The stoichiometry of Gag protein in HIV-1. Nat. Struct. Mol. Biol. 11, 672–675 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Ganser, B. K., Li, S., Klishko, V. Y., Finch, J. T. & Sundquist, W. I. Assembly and analysis of conical models for the HIV-1 core. Science 283, 80–83 (1999). This paper established the first molecular models to explain the fullerene-cone structure of the HIV-1 core.

    Article  CAS  PubMed  Google Scholar 

  3. Li, S., Hill, C. P., Sundquist, W. I. & Finch, J. T. Image reconstructions of helical assemblies of the HIV-1 CA protein. Nature 407, 409–413 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Ganser-Pornillos, B. K., Cheng, A. & Yeager, M. Structure of full-length HIV-1 CA: a model for the mature capsid lattice. Cell 131, 70–79 (2007).The first high-resolution structure of assembled HIV-1 CA, identifying critical interfaces that promote capsid assembly and stability.

    Article  CAS  PubMed  Google Scholar 

  5. Byeon, I. J. et al. Structural convergence between Cryo-EM and NMR reveals intersubunit interactions critical for HIV-1 capsid function. Cell 139, 780–790 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhao, G. et al. Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics. Nature 497, 643–646 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bhattacharya, A. et al. Structural basis of HIV-1 capsid recognition by PF74 and CPSF6. Proc. Natl Acad. Sci. USA 111, 18625–18630 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Price, A. J. et al. Host cofactors and pharmacologic ligands share an essential interface in HIV-1 capsid that is lost upon disassembly. PLoS Pathog. 10, e1004459 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Accola, M. A., Öhagen, A. & Göttlinger, H. G. Isolation of human immunodeficiency virus type 1 cores: retention of Vpr in the absence of p6gag. J. Virol. 74, 6198–6202 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kotov, A., Zhou, J., Flicker, P. & Aiken, C. Association of Nef with the human immunodeficiency virus type 1 core. J. Virol. 73, 8824–8830 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Welker, R., Hohenberg, H., Tessmer, U., Huckhagel, C. & Kräusslich, H. G. Biochemical and structural analysis of isolated mature cores of human immunodeficiency virus type 1. J. Virol. 74, 1168–1177 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Forshey, B. M., von Schwedler, U., Sundquist, W. I. & Aiken, C. Formation of a human immunodeficiency virus type 1 core of optimal stability is crucial for viral replication. J. Virol. 76, 5667–5677 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gao, D. et al. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341, 903–906 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Lahaye, X. et al. 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, 1132–1142 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Rasaiyaah, J. et al. HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503, 402–405 (2013). References 14 and 15 demonstrate the substantial consequences associated with slight changes in viral CA and its ability to interact with specific cellular factors during infection. Reference 15 additionally provides insight into how certain CA mutations induce IFN responses in primary cells, perhaps explaining the strong selective pressure operating against these mutations in vivo . The paper also demonstrates that interference with uncoating or engagement of certain cellular factors can induce a potent innate immune response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yan, N., Regalado-Magdos, A. D., Stiggelbout, B., Lee-Kirsch, M. A. & Lieberman, J. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat. Immunol. 11, 1005–1013 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Aiken, C. Viral and cellular factors that regulate HIV-1 uncoating. Curr. Opin. HIV AIDS 1, 194–199 (2006).

    Article  PubMed  Google Scholar 

  18. Yamashita, M. & Emerman, M. Capsid is a dominant determinant of retrovirus infectivity in nondividing cells. J. Virol. 78, 5670–5678 (2004). This paper showed that CA is the viral protein underlying the ability of HIV-1 to infect non-dividing cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yamashita, M., Perez, O., Hope, T. J. & Emerman, M. Evidence for direct involvement of the capsid protein in HIV infection of nondividing cells. PLoS Pathog. 3, 1502–1510 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Zhou, L. et al. Transportin 3 promotes a nuclear maturation step required for efficient HIV-1 integration. PLoS Pathog. 7, e1002194 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Matreyek, K. A. & Engelman, A. The requirement for nucleoporin NUP153 during human immunodeficiency virus type 1 infection is determined by the viral capsid. J. Virol. 85, 7818–7827 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Matreyek, K. A., Yucel, S. S., Li, X. & Engelman, A. Nucleoporin NUP153 phenylalanine-glycine motifs engage a common binding pocket within the HIV-1 capsid protein to mediate lentiviral infectivity. PLoS Pathog. 9, e1003693 (2013). This paper describes molecular mapping of the NUP153–CA interface; results that were ultimately confirmed by structural studies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Peng, K. et al. Quantitative microscopy of functional HIV post-entry complexes reveals association of replication with the viral capsid. eLife 3, e04114 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hulme, A. E., Kelley, Z., Foley, D. & Hope, T. J. Complementary assays reveal a low level of CA associated with viral complexes in the nuclei of HIV-1-infected cells. J. Virol. 5350–5361 (2015).

  25. Lowe, A. R. et al. Selectivity mechanism of the nuclear pore complex characterized by single cargo tracking. Nature 467, 600–603 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pante, N. & Kann, M. Nuclear pore complex is able to transport macromolecules with diameters of about 39 nm. Mol. Biol. Cell 13, 425–434 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yang, R. et al. Second-site suppressors of HIV-1 capsid mutations: restoration of intracellular activities without correction of intrinsic capsid stability defects. Retrovirology 9, 30 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rihn, S. J. et al. Extreme genetic fragility of the HIV-1 capsid. PLoS Pathog. 9, e1003461 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jia, X., Zhao, Q. & Xiong, Y. HIV suppression by host restriction factors and viral immune evasion. Curr. Opin. Struct. Biol. 31, 106–114 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mortuza, G. B. et al. High-resolution structure of a retroviral capsid hexameric amino-terminal domain. Nature 431, 481–485 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Pornillos, O. et al. X-ray structures of the hexameric building block of the HIV capsid. Cell 137, 1282–1292 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Di Nunzio, F. et al. Nup153 and Nup98 bind the HIV-1 core and contribute to the early steps of HIV-1 replication. Virology 440, 8–18 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Koh, Y. et al. Differential effects of human immunodeficiency virus type 1 capsid and cellular factors nucleoporin 153 and LEDGF/p75 on the efficiency and specificity of viral DNA integration. J. Virol. 87, 648–658 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ocwieja, K. E. et al. HIV integration targeting: a pathway involving transportin-3 and the nuclear pore protein RanBP2. PLoS Pathog. 7, e1001313 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fassati, A. & Goff, S. P. Characterization of intracellular reverse transcription complexes of human immunodeficiency virus type 1. J. Virol. 75, 3626–3635 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Miller, M. D., Farnet, C. M. & Bushman, F. D. Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J. Virol. 71, 5382–5390 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Fassati, A. & Goff, S. P. Characterization of intracellular reverse transcription complexes of Moloney murine leukemia virus. J. Virol. 73, 8919–8925 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Hulme, A. E., Perez, O. & Hope, T. J. Complementary assays reveal a relationship between HIV-1 uncoating and reverse transcription. Proc. Natl Acad. Sci. USA 108, 9975–9980 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Lukic, Z., Dharan, A., Fricke, T., Diaz-Griffero, F. & Campbell, E. M. HIV-1 uncoating is facilitated by dynein and kinesin-1. J. Virol. 88, 13613–13625 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Perez-Caballero, D., Hatziioannou, T., Zhang, F., Cowan, S. & Bieniasz, P. D. Restriction of human immunodeficiency virus type 1 by TRIM-CypA occurs with rapid kinetics and independently of cytoplasmic bodies, ubiquitin, and proteasome cctivity. J. Virol. 79, 15567–15572 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. McDonald, D. et al. Visualization of the intracellular behavior of HIV in living cells. J. Cell Biol. 159, 441–452 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Xu, H. et al. Evidence for biphasic uncoating during HIV-1 infection from a novel imaging assay. Retrovirology 10, 70 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Butler, S. L., Hansen, M. S. & Bushman, F. D. A quantitative assay for HIV DNA integration in vivo. Nat. Med. 7, 631–634 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Arhel, N. J. et al. HIV-1 DNA Flap formation promotes uncoating of the pre-integration complex at the nuclear pore. EMBO J. 26, 3025–3037 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Farnet, C. M. & Bushman, F. D. HIV-1 cDNA integration: requirement of HMG I(Y) protein for function of preintegration complexes in vitro. Cell 88, 483–492 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. Li, L. et al. Retroviral cDNA integration: stimulation by HMG I family proteins. J. Virol. 74, 10965–10974 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hilditch, L. & Towers, G. J. A model for cofactor use during HIV-1 reverse transcription and nuclear entry. Curr. Opin. Virol. 4, 32–36 (2014). This paper provides a noteworthy model of CA cofactor engagement not entirely described in this Review.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Briones, M. S., Dobard, C. W. & Chow, S. A. Role of human immunodeficiency virus type 1 integrase in uncoating of the viral core. J. Virol. 84, 5181–5190 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jurado, K. A. et al. Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Proc. Natl Acad. Sci. USA 110, 8690–8695 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Engelman, A., Englund, G., Orenstein, J. M., Martin, M. A. & Craigie, R. Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication. J. Virol. 69, 2729–2736 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Yang, Y., Fricke, T. & Diaz-Griffero, F. Inhibition of reverse transcriptase activity increases stability of the HIV-1 core. J. Virol. 87, 683–687 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhu, K., Dobard, C. & Chow, S. A. Requirement for integrase during reverse transcription of human immunodeficiency virus type 1 and the effect of cysteine mutations of integrase on its interactions with reverse transcriptase. J. Virol. 78, 5045–5055 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Franke, E. K., Yuan, H. E. & Luban, J. Specific incorporation of cyclophilin A into HIV-1 virions. Nature 372, 359–362 (1994).

    Article  CAS  PubMed  Google Scholar 

  54. Luban, J., Bossolt, K. L., Franke, E. K., Kalpana, G. V. & Goff, S. P. Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell 73, 1067–1078 (1993).

    Article  CAS  PubMed  Google Scholar 

  55. Thali, M. et al. Functional association of cyclophilin A with HIV-1 virions. Nature 372, 363–365 (1994).

    Article  CAS  PubMed  Google Scholar 

  56. Hatziioannou, T., Perez-Caballero, D., Cowan, S. & Bieniasz, P. D. Cyclophilin interactions with incoming human immunodeficiency virus type 1 capsids with opposing effects on infectivity in human cells. J. Virol. 79, 176–183 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sokolskaja, E., Sayah, D. M. & Luban, J. Target cell cyclophilin A modulates human immunodeficiency virus type 1 infectivity. J. Virol. 78, 12800–12808 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kootstra, N. A., Munk, C., Tonnu, N., Landau, N. R. & Verma, I. M. Abrogation of postentry restriction of HIV-1-based lentiviral vector transduction in simian cells. Proc. Natl Acad. Sci. USA 100, 1298–1303 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Towers, G. J. et al. Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors. Nat. Med. 9, 1138–1143 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Gamble, T. R. et al. Crystal structure of human cyclophilin A bound to the amino-terminal domain of HIV-1 capsid. Cell 87, 1285–1294 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Braaten, D. et al. Cyclosporine A-resistant human immunodeficiency virus type 1 mutants demonstrate that Gag encodes the functional target of cyclophilin A. J. Virol. 70, 5170–5176 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Braaten, D., Franke, E. K. & Luban, J. Cyclophilin A is required for an early step in the life cycle of human immunodeficiency virus type 1 before the initiation of reverse transcription. J. Virol. 70, 3551–3560 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Braaten, D. & Luban, J. Cyclophilin A regulates HIV-1 infectivity, as demonstrated by gene targeting in human T cells. EMBO J. 20, 1300–1309 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. De Iaco, A. & Luban, J. Cyclophilin A promotes HIV-1 reverse transcription but its effect on transduction correlates best with its effect on nuclear entry of viral cDNA. Retrovirology 11, 11 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Li, Y., Kar, A. K. & Sodroski, J. Target cell type-dependent modulation of human immunodeficiency virus type 1 capsid disassembly by cyclophilin A. J. Virol. 83, 10951–10962 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bosco, D. A., Eisenmesser, E. Z., Pochapsky, S., Sundquist, W. I. & Kern, D. Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A. Proc. Natl Acad. Sci. USA 99, 5247–5252 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Fricke, T. et al. Human cytosolic extracts stabilize the HIV-1 core. J. Virol. 87, 10587–10597 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Shah, V. B. et al. The host proteins transportin SR2/TNPO3 and cyclophilin A exert opposing effects on HIV-1 uncoating. J. Virol. 87, 422–432 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Aberham, C., Weber, S. & Phares, W. Spontaneous mutations in the human immunodeficiency virus type 1 gag gene that affect viral replication in the presence of cyclosporins. J. Virol. 70, 3536–3544 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Schneidewind, A. et al. Escape from the dominant HLA-B27-restricted cytotoxic T-lymphocyte response in Gag is associated with a dramatic reduction in human immunodeficiency virus type 1 replication. J. Virol. 81, 12382–12393 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yang, R. & Aiken, C. A mutation in alpha helix 3 of CA renders human immunodeficiency virus type 1 cyclosporin A resistant and dependent: rescue by a second-site substitution in a distal region of CA. J. Virol. 81, 3749–3756 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Qi, M., Yang, R. & Aiken, C. Cyclophilin A-dependent restriction of human immunodeficiency virus type 1 capsid mutants for infection of nondividing cells. J. Virol. 82, 12001–12008 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Yin, L., Braaten, D. & Luban, J. Human immunodeficiency virus type 1 replication is modulated by host cyclophilin A expression levels. J. Virol. 72, 6430–6436 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Ylinen, L. M. et al. Cyclophilin A levels dictate infection efficiency of human immunodeficiency virus type 1 capsid escape mutants A92E and G94D. J. Virol. 83, 2044–2047 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Arhel, N. et al. Quantitative four-dimensional tracking of cytoplasmic and nuclear HIV-1 complexes. Nat. Methods 3, 817–824 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Sabo, Y. et al. HIV-1 induces the formation of stable microtubules to enhance early infection. Cell Host Microbe 14, 535–546 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. Jayappa, K. D. et al. Human immunodeficiency virus type 1 employs the cellular dynein light chain 1 protein for reverse transcription through interaction with its integrase protein. J. Virol. 89, 3497–3511 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Pawlica, P. & Berthoux, L. Cytoplasmic dynein promotes HIV-1 uncoating. Viruses 6, 4195–4211 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Strunze, S. et al. Kinesin-1-mediated capsid disassembly and disruption of the nuclear pore complex promote virus infection. Cell Host Microbe 10, 210–223 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Yamashita, M. & Emerman, M. Retroviral infection of non-dividing cells: old and new perspectives. Virology 344, 88–93 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Brass, A. L. et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319, 921–926 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Konig, R. et al. Global analysis of host–pathogen interactions that regulate early-stage HIV-1 replication. Cell 135, 49–60 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lee, K. et al. Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe 7, 221–233 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhou, H. et al. Genome-scale RNAi screen for host factors required for HIV replication. Cell Host Microbe 4, 495–504 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Ambrose, Z. & Aiken, C. HIV-1 uncoating: connection to nuclear entry and regulation by host proteins. Virology, 454–455, 371–379 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. Price, A. J. et al. CPSF6 defines a conserved capsid interface that modulates HIV-1 replication. PLoS Pathog. 8, e1002896 (2012). References 7, 8 and 86 demonstrate that some assembled CA must remain associated with the viral complex when it interacts with NUP153 and CPSF6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ruepp, M. D. et al. Mammalian pre-mRNA 3′ end processing factor CF Im 68 functions in mRNA export. Mol. Biol. Cell 20, 5211–5223 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hori, T. et al. A carboxy-terminally truncated human CPSF6 lacking residues encoded by exon 6 inhibits HIV-1 cDNA synthesis and promotes capsid disassembly. J. Virol. 87, 7726–7736 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Henning, M. S., Dubose, B. N., Burse, M. J., Aiken, C. & Yamashita, M. In vivo functions of CPSF6 for HIV-1 as revealed by HIV-1 capsid evolution in HLA-B27-positive subjects. PLoS Pathog. 10, e1003868 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. De Iaco, A. et al. TNPO3 protects HIV-1 replication from CPSF6-mediated capsid stabilization in the host cell cytoplasm. Retrovirology 10, 20 (2013). An elegant molecular study establishing an assay to differentiate between 2-LTR circles and auto-integrants that is critical for understanding the roles of cellular factors and the stages in the lifecycle at which they act.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lee, K. et al. HIV-1 capsid-targeting domain of cleavage and polyadenylation specificity factor 6. J. Virol. 86, 3851–3860 (2012). A seminal study identifying truncated CPSF6 as a dominant negative inhibitor of infection, leading both to the appreciation of the role of CPSF6 in HIV-1 infection and to the N74D mutant, which remains a critical tool in studies in this area.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kataoka, N., Bachorik, J. L. & Dreyfuss, G. Transportin-SR, a nuclear import receptor for SR proteins. J. Cell Biol. 145, 1145–1152 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Christ, F. et al. Transportin-SR2 imports HIV into the nucleus. Curr. Biol. 18, 1192–1202 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Cribier, A. et al. Mutations affecting interaction of integrase with TNPO3 do not prevent HIV-1 cDNA nuclear import. Retrovirology 8, 104 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Krishnan, L. et al. The requirement for cellular transportin 3 (TNPO3 or TRN-SR2) during infection maps to human immunodeficiency virus type 1 capsid and not integrase. J. Virol. 84, 397–406 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. De Houwer, S. et al. Identification of residues in the C-terminal domain of HIV-1 integrase that mediate binding to the transportin-SR2 protein. J. Biol. Chem. 287, 34059–34068 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. De Iaco, A. & Luban, J. Inhibition of HIV-1 infection by TNPO3 depletion is determined by capsid and detectable after viral cDNA enters the nucleus. Retrovirology 8, 98 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Valle-Casuso, J. C. et al. TNPO3 is required for HIV-1 replication after nuclear import but prior to integration and binds the HIV-1 core. J. Virol. 86, 5931–5936 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Schaller, T. et al. HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLoS Pathog. 7, e1002439 (2011). This paper demonstrates the connection between HIV-1 CA associations and integration-site selection when in the nucleus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhang, R., Mehla, R. & Chauhan, A. Perturbation of host nuclear membrane component RanBP2 impairs the nuclear import of human immunodeficiency virus-1 preintegration complex (DNA). PLoS ONE 5, e15620 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Labokha, A. A. & Fassati, A. Viruses challenge selectivity barrier of nuclear pores. Viruses 5, 2410–2423 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Strambio-De-Castillia, C., Niepel, M. & Rout, M. P. The nuclear pore complex: bridging nuclear transport and gene regulation. Nat. Rev. Mol. Cell Biol. 11, 490–501 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Di Nunzio, F. et al. Human nucleoporins promote HIV-1 docking at the nuclear pore, nuclear import and integration. PLoS ONE 7, e46037 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Meehan, A. M. et al. A cyclophilin homology domain-independent role for Nup358 in HIV-1 infection. PLoS Pathog. 10, e1003969 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Bichel, K. et al. HIV-1 capsid undergoes coupled binding and isomerization by the nuclear pore protein NUP358. Retrovirology 10, 81 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Daigle, N. et al. Nuclear pore complexes form immobile networks and have a very low turnover in live mammalian cells. J. Cell Biol. 154, 71–84 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Hirokawa, N., Noda, Y., Tanaka, Y. & Niwa, S. Kinesin superfamily motor proteins and intracellular transport. Nat. Rev. Mol. Cell Biol. 10, 682–696 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Hulme, A. E., Kelley, Z., Okocha, E. A. & Hope, T. J. Identification of capsid mutations that alter the rate of HIV-1 uncoating in infected cells. J. Virol. 89, 643–651 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Amie, S. M., Noble, E. & Kim, B. Intracellular nucleotide levels and the control of retroviral infections. Virology 436, 247–254 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Blair, W. S. et al. HIV capsid is a tractable target for small molecule therapeutic intervention. PLoS Pathog. 6, e1001220 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Shi, J., Zhou, J., Shah, V. B., Aiken, C. & Whitby, K. Small-molecule inhibition of human immunodeficiency virus type 1 infection by virus capsid destabilization. J. Virol. 85, 542–549 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Lamorte, L. et al. Discovery of novel small-molecule HIV-1 replication inhibitors that stabilize capsid complexes. Antimicrob. Agents Chemother. 57, 4622–4631 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Fricke, T., Buffone, C., Opp, S., Valle-Casuso, J. & Diaz-Griffero, F. BI-2 destabilizes HIV-1 cores during infection and prevents binding of CPSF6 to the HIV-1 capsid. Retrovirology 11, 120 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Azzoni, L. et al. Pegylated interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. J. Infect. Dis. 207, 213–222 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Sandler, N. G. et al. Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature 511, 601–605 (2014). This paper provides an elegant demonstration of the potential utility of IFN response in controlling infection, showing the correlation between IFN-stimulated gene expression and control of viral infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Bosinger, S. E. & Utay, N. S. Type I interferon: understanding its role in HIV pathogenesis and therapy. Curr. HIV/AIDS Rep. 12, 41–53 (2015).

    Article  PubMed  Google Scholar 

  117. Doyle, T., Goujon, C. & Malim, M. H. HIV-1 and interferons: who's interfering with whom? Nat. Rev. Microbiol. 13, 403–413 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. Siliciano, R. F. & Greene, W. C. HIV latency. Cold Spring Harb. Perspect. Med. 1, a007096 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shah, V. B. & Aiken, C. In vitro uncoating of HIV-1 cores. J. Vis. Exp. 57, e3384 (2011).

    Google Scholar 

  120. Stremlau, M. et al. Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5α restriction factor. Proc. Natl Acad. Sci. USA 103, 5514–5519 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Kutluay, S. B., Perez-Caballero, D. & Bieniasz, P. D. Fates of retroviral core components during unrestricted and TRIM5-restricted infection. PLoS Pathog. 9, e1003214 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Fricke, T. et al. MxB binds to the HIV-1 core and prevents the uncoating process of HIV-1. Retrovirology 11, 68 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Iordanskiy, S., Berro, R., Altieri, M., Kashanchi, F. & Bukrinsky, M. Intracytoplasmic maturation of the human immunodeficiency virus type 1 reverse transcription complexes determines their capacity to integrate into chromatin. Retrovirology 3, 4 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Burdick, R. C., Hu, W. S. & Pathak, V. K. Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes. Proc. Natl Acad. Sci. USA 110, E4780–E4789 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Campbell, E. M., Perez, O., Anderson, J. L. & Hope, T. J. Visualization of a proteasome-independent intermediate during restriction of HIV-1 by rhesus TRIM5α. J. Cell Biol. 180, 549–561 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Campbell, E. M., Perez, O., Melar, M. & Hope, T. J. Labeling HIV-1 virions with two fluorescent proteins allows identification of virions that have productively entered the target cell. Virology 360, 286–293 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Thomas, J. A., Ott, D. E. & Gorelick, R. J. Efficiency of human immunodeficiency virus type 1 postentry infection processes: evidence against disproportionate numbers of defective virions. J. Virol. 81, 4367–4370 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sayah, D. M., Sokolskaja, E., Berthoux, L. & Luban, J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 430, 569–573 (2004). A paper detailing the first identification of the TRIM–Cyp restriction factor, which has become an important tool in the study of uncoating, given its ability to recognize CA and be inhibited by CsA.

    Article  CAS  PubMed  Google Scholar 

  129. Pornillos, O., Ganser-Pornillos, B. K. & Yeager, M. Atomic-level modelling of the HIV capsid. Nature 469, 424–427 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Luban, J. Cyclophilin A, TRIM5, and resistance to human immunodeficiency virus type 1 infection. J. Virol. 81, 1054–1061 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Song, C. & Aiken, C. Analysis of human cell heterokaryons demonstrates that target cell restriction of cyclosporine-resistant human immunodeficiency virus type 1 mutants is genetically dominant. J. Virol. 81, 11946–11956 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Gaudin, R., Alencar, B. C., Arhel, N. & Benaroch, P. HIV trafficking in host cells: motors wanted! Trends Cell Biol. 23, 652–662 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank O. Pornillos and J. Luban for discussions.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, 60153, Illinois, USA

    Edward M. Campbell

  2. Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA

    Thomas J. Hope

Authors
  1. Edward M. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas J. Hope
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas J. Hope.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Glossary

Lentivirus

A genus of retroviruses. Genus members include HIV-1 and related primate immunodeficiency viruses. Lentiviruses are distinguished by the expression of specific regulatory proteins and the ability to infect non-dividing cells.

Antiretroviral therapy

Treatment using a combination of pharmacological inhibitors of viral enzymes (including reverse transcriptase, protease and, more recently, integrase), which together potently suppress viral replication, reduce viral load and prevent the development of acquired immune deficiency syndrome (AIDS) in patients with HIV.

Protease

An enzyme that breaks down proteins into smaller substrates. All retroviruses express an aspartyl protease, which cleaves immature polyproteins incorporated into virions, including Gag and less-abundant Gag–Pro and Gag–Pro–Pol polyproteins. This protease is a critical target of antiretroviral therapy, as polyprotein cleavage is absolutely necessary for viral infectivity.

Fullerene cone

A closed conical structure primarily made of linked hexagonal rings. The term 'fullerene' was originally used to describe hollow carbon structures that adopt spherical or elliptical shapes. This shape is also adopted by the hexamers and pentamers of capsid protein that form the viral core of HIV.

Reverse transcriptase

An enzyme that generates cDNA from RNA. All retroviruses express a reverse transcriptase enzyme, a DNA polymerase that copies the viral genomic RNA in the process of reverse transcription. During this process, reverse transcriptase uses both RNA and DNA templates to generate a linear, double-stranded DNA genome. This enzyme is a critical target of antiretroviral therapy.

Integrase

An enzyme that catalyses the integration of DNA segments with longer DNA chains. All retroviruses express an integrase enzyme, which is responsible for inserting the double-stranded DNA genome generated by reverse transcriptase into the host-cell DNA.

Cyclic GMP–AMP synthase

(cGAS). An intrinsic sensor of cytosolic DNA that, when activated, initiates the expression of interferon-dependent genes associated with the antiviral state.

Three-prime repair exonuclease 1

(TREX1). A cytosolic exonuclease that degrades HIV-1 DNA accumulated in target cells. Despite this seemingly antiviral function, TREX1-mediated degradation of viral DNA products correlates with an inhibition of innate immune sensors leading to type I interferon activation.

Reverse transcription complex

(RTC). The term used for viral ribonucleoprotein after it has entered the target cell and begun reverse transcription of its RNA genome. As reverse transcription is thought to initiate rapidly after fusion, we use this term to generically describe the infectious viral complex following fusion.

Simple retroviruses

Basic retroviruses, such as murine leukaemia virus, that contain only the genes gag (which encodes viral structural proteins, such as matrix and capsid), pro (which encodes the viral protease), pol (which encodes the reverse transcriptase and integrase proteins) and env (which encodes the viral protein envelope).

Nuclear pore complexes

(NPCs). Large (∼50 mDa) multiprotein assemblies that govern transport across the nuclear envelope. NPCs are made up of approximately 30 different proteins, termed nucleoporins.

Restriction factors

Proteins with antiviral activity when expressed in cells. Generally, such antiviral proteins exhibit signs of positive selective pressure and viruses show clear evidence of adaptation designed to mitigate the antiviral activity.

Antiviral state

A generalized description of the state induced following induction of interferon-stimulated genes, which collectively act to reduce infection by a broad range of viruses.

Pre-integration complex

(PIC). Following the completion of reverse transcription, integrase-mediated endonuclease priming of the 5′- and 3′-ends of the genome generates a replicative intermediate capable of integrating into target DNA. We use the term PIC when the ability to integrate into surrogate DNA has been demonstrated in specific studies.

Dynein

A microtubule motor protein in cells that couples ATP hydrolysis with mechanical movement of cellular cargos. Dynein transports cargos towards the minus end of the microtubule, which is typically at the microtubule-organizing centre adjacent to the nucleus.

Microtubule

A component of the cytoskeleton that is formed from polymerized tubulin. It provides the framework necessary for dynein and kinesin motors to transport numerous cargos, including viruses, that are otherwise too large to diffuse through the protein-dense cytoplasm.

Kinesin-1

A motor protein that couples ATP hydrolysis with mechanical movement of cargos, in a manner similar to dynein. However, unlike dynein, there are many types of kinesins, and these motors typically traffic cargos towards the plus ends of microtubules, away from the nucleus.

Two-long-terminal-repeat circles

(2-LTR circles). Loops of genome and LTRs. The completely reverse-transcribed HIV-1 genome is flanked on either side by LTRs, which ultimately define the genomic boundaries of the provirus following successful integration. At a low frequency, the cellular non-homologous end joining (NHEJ) repair pathway joins the LTRs, resulting in 2-LTR circles. As the NHEJ pathway is active only in the nucleus, the presence of 2-LTR circles is used as a surrogate for nuclear entry of the pre-integration complex.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Campbell, E., Hope, T. HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat Rev Microbiol 13, 471–483 (2015). https://doi.org/10.1038/nrmicro3503

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro3503

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing