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.

HIV-1 assembly, release and maturation

Key Points

  • The HIV-1 Gag polyprotein precursor is necessary and sufficient for the formation of virus-like particles in Gag-expressing cells. Gag contains domains that are required for virus assembly and release: the matrix (MA) domain directs Gag to the plasma membrane and promotes the incorporation of the viral envelope (Env) glycoproteins; the capsid (CA) domain drives Gag–Gag interactions during assembly; the nucleocapsid (NC) domain packages the viral genomic RNA; and the p6 domain is required for efficient particle release.

  • HIV-1 recruits several host factors to promote virus assembly and release. For example, the endosomal sorting complex required for transport (ESCRT) machinery is recruited by the p6 domain of Gag to mediate the pinching off of virus particles from the cell.

  • Shortly after virus release from the cell, the viral protease cleaves the Gag precursor into the mature Gag proteins MA, CA, NC and p6. Gag processing is a highly ordered multistep sequential process that triggers the morphological rearrangement of viral protein structure, which is known as maturation.

  • The Gag protein has been the focus of drug discovery efforts aimed at developing inhibitors that are distinct from those targeting the viral enzymes protease, reverse transcriptase and integrase. Of particular promise are small-molecule inhibitors of capsid function, and maturation inhibitors, which target a late step in Gag processing.

Abstract

Major advances have occurred in recent years in our understanding of HIV-1 assembly, release and maturation, as work in this field has been propelled forwards by developments in imaging technology, structural biology, and cell and molecular biology. This increase in basic knowledge is being applied to the development of novel inhibitors designed to target various aspects of virus assembly and maturation. This Review highlights recent progress in elucidating the late stages of the HIV-1 replication cycle and the related interplay between virology, cell and molecular biology, and drug discovery.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The late stages of the HIV-1 replication cycle.
Figure 2: Gag structure and functions.
Figure 3: Models of viral envelope glycoprotein incorporation.
Figure 4: HIV-1 budding and release.
Figure 5: HIV-1 maturation.

Accession codes

Accessions

Protein Data Bank

References

  1. 1

    Massiah, M. A. et al. Three-dimensional structure of the human immunodeficiency virus type 1 matrix protein. J. Mol. Biol. 244, 198–223 (1994).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Tang, C. et al. Entropic switch regulates myristate exposure in the HIV-1 matrix protein. Proc. Natl Acad. Sci. USA 101, 517–522 (2004).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Gitti, R. K. et al. Structure of the amino-terminal core domain of the HIV-1 capsid protein. Science 273, 231–235 (1996).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    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).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Gamble, T. R. et al. Structure of the carboxyl-terminal dimerization domain of the HIV-1 capsid protein. Science 278, 849–853 (1997).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Tang, C., Ndassa, Y. & Summers, M. F. Structure of the N-terminal 283-residue fragment of the immature HIV-1 Gag polyprotein. Nat. Struct. Biol. 9, 537–543 (2002).

    CAS  PubMed  Google Scholar 

  7. 7

    Summers, M. F. et al. Nucleocapsid zinc fingers detected in retroviruses: EXAFS studies of intact viruses and the solution-state structure of the nucleocapsid protein from HIV-1. Protein Sci. 1, 563–574 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Fossen, T. et al. Solution structure of the human immunodeficiency virus type 1 p6 protein. J. Biol. Chem. 280, 42515–42527 (2005).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Ono, A. & Freed, E. O. Cell-type-dependent targeting of human immunodeficiency virus type 1 assembly to the plasma membrane and the multivesicular body. J. Virol. 78, 1552–1563 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Ono, A., Ablan, S. D., Lockett, S. J., Nagashima, K. & Freed, E. O. Phosphatidylinositol (4,5) bisphosphate regulates HIV-1 Gag targeting to the plasma membrane. Proc. Natl Acad. Sci. USA 101, 14889–14894 (2004). Demonstrates that the phospholipid PtdIns(4,5)P 2 plays a central part in directing Gag to the plasma membrane.

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Saad, J. S. et al. Structural basis for targeting HIV-1 Gag proteins to the plasma membrane for virus assembly. Proc. Natl Acad. Sci. USA 103, 11364–11369 (2006). Provides structural evidence for a direct interaction between HIV-1 matrix and PtdIns(4,5)P 2.

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Shkriabai, N. et al. Interactions of HIV-1 Gag with assembly cofactors. Biochemistry 45, 4077–4083 (2006).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Kutluay, S. B. et al. Global changes in the RNA binding specificity of HIV-1 Gag regulate virion genesis. Cell 159, 1096–1109 (2014). Uses CLIP sequencing to probe interactions between Gag and RNA during assembly and maturation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Alfadhli, A., Still, A. & Barklis, E. Analysis of human immunodeficiency virus type 1 matrix binding to membranes and nucleic acids. J. Virol. 83, 12196–12203 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Chukkapalli, V., Oh, S. J. & Ono, A. Opposing mechanisms involving RNA and lipids regulate HIV-1 Gag membrane binding through the highly basic region of the matrix domain. Proc. Natl Acad. Sci. USA 107, 1600–1605 (2010).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Balasubramaniam, M. & Freed, E. O. New insights into HIV assembly and trafficking. Physiology 26, 236–251 (2011).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Hogue, I. B., Grover, J. R., Soheilian, F., Nagashima, K. & Ono, A. Gag induces the coalescence of clustered lipid rafts and tetraspanin-enriched microdomains at HIV-1 assembly sites on the plasma membrane. J. Virol. 85, 9749–9766 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Nguyen, D. H. & Hildreth, J. E. Evidence for budding of human immunodeficiency virus type 1 selectively from glycolipid-enriched membrane lipid rafts. J. Virol. 74, 3264–3272 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Ono, A. & Freed, E. O. Plasma membrane rafts play a critical role in HIV-1 assembly and release. Proc. Natl Acad. Sci. USA 98, 13925–13930 (2001).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Brugger, B. et al. The HIV lipidome: a raft with an unusual composition. Proc. Natl Acad. Sci. USA 103, 2641–2646 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. 21

    Chan, R. et al. Retroviruses human immunodeficiency virus and murine leukemia virus are enriched in phosphoinositides. J. Virol. 82, 11228–11238 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Jolly, C. & Sattentau, Q. J. Human immunodeficiency virus type 1 virological synapse formation in T cells requires lipid raft integrity. J. Virol. 79, 12088–12094 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Zapp, M. L. & Green, M. R. Sequence-specific RNA binding by the HIV-1 Rev protein. Nature 342, 714–716 (1989).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Cullen, B. R. Nuclear RNA export. J. Cell Sci. 116, 587–597 (2003).

    Article  PubMed  Google Scholar 

  25. 25

    Chen, J. et al. High efficiency of HIV-1 genomic RNA packaging and heterozygote formation revealed by single virion analysis. Proc. Natl Acad. Sci. USA 106, 13535–13540 (2009).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Coffin, J. M. Structure, replication, and recombination of retrovirus genomes: some unifying hypotheses. J. Gen. Virol. 42, 1–26 (1979).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Hu, W. S. & Hughes, S. H. HIV-1 reverse transcription. Cold Spring Harb. Perspect. Med. 2, a006882 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Moore, M. D. et al. Probing the HIV-1 genomic RNA trafficking pathway and dimerization by genetic recombination and single virion analyses. PLoS Pathog. 5, e1000627 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Nikolaitchik, O. A. et al. Dimeric RNA recognition regulates HIV-1 genome packaging. PLoS Pathog. 9, e1003249 (2013). Provides compelling data supporting the hypothesis that Gag recognizes an RNA dimer.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Levin, J. G., Guo, J., Rouzina, I. & Musier-Forsyth, K. Nucleic acid chaperone activity of HIV-1 nucleocapsid protein: critical role in reverse transcription and molecular mechanism. Prog. Nucleic Acid Res. Mol. Biol. 80, 217–286 (2005).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Lu, K., Heng, X. & Summers, M. F. Structural determinants and mechanism of HIV-1 genome packaging. J. Mol. Biol. 410, 609–633 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Lu, K. et al. NMR detection of structures in the HIV-1 5′-leader RNA that regulate genome packaging. Science 334, 242–245 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Jouvenet, N., Simon, S. M. & Bieniasz, P. D. Imaging the interaction of HIV-1 genomes and Gag during assembly of individual viral particles. Proc. Natl Acad. Sci. USA 106, 19114–19119 (2009).

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Kutluay, S. B. & Bieniasz, P. D. Analysis of the initiating events in HIV-1 particle assembly and genome packaging. PLoS Pathog. 6, e1001200 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Chen, J. et al. Cytoplasmic HIV-1 RNA is mainly transported by diffusion in the presence or absence of Gag protein. Proc. Natl Acad. Sci. USA 111, E5205–E5213 (2014).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Tedbury, P. R., Ablan, S. D. & Freed, E. O. Global rescue of defects in HIV-1 envelope glycoprotein incorporation: implications for matrix structure. PLoS Pathog. 9, e1003739 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Hill, C. P., Worthylake, D., Bancroft, D. P., Christensen, A. M. & Sundquist, W. I. Crystal structures of the trimeric human immunodeficiency virus type 1 matrix protein: implications for membrane association and assembly. Proc. Natl Acad. Sci. USA 93, 3099–3104 (1996). Solves the crystal structure of the HIV-1 matrix protein.

    CAS  Article  PubMed  Google Scholar 

  38. 38

    Alfadhli, A., Barklis, R. L. & Barklis, E. HIV-1 matrix organizes as a hexamer of trimers on membranes containing phosphatidylinositol-(4,5)-bisphosphate. Virology 387, 466–472 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Briggs, J. A. et al. Structure and assembly of immature HIV. Proc. Natl Acad. Sci. USA 106, 11090–11095 (2009).

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Fuller, S. D., Wilk, T., Gowen, B. E., Krausslich, H. G. & Vogt, V. M. Cryo-electron microscopy reveals ordered domains in the immature HIV-1 particle. Curr. Biol. 7, 729–738 (1997).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Wright, E. R. et al. Electron cryotomography of immature HIV-1 virions reveals the structure of the CA and SP1 Gag shells. EMBO J. 26, 2218–2226 (2007). Provides early insights into the structure of the immature Gag lattice.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Bharat, T. A. et al. Structure of the immature retroviral capsid at 8 Å resolution by cryo-electron microscopy. Nature 487, 385–389 (2012).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Schur, F. K. et al. Structure of the immature HIV-1 capsid in intact virus particles at 8.8 Å resolution. Nature 517, 505–508 (2015). Presents what is currently the most refined model for the structure of the Gag lattice in the immature HIV-1 virion.

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Checkley, M. A., Luttge, B. G. & Freed, E. O. HIV-1 envelope glycoprotein biosynthesis, trafficking, and incorporation. J. Mol. Biol. 410, 582–608 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Tedbury, P. R. & Freed, E. O. The role of matrix in HIV-1 envelope glycoprotein incorporation. Trends Microbiol. 22, 372–378 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Murakami, T. & Freed, E. O. Genetic evidence for an interaction between human immunodeficiency virus type 1 matrix and α-helix 2 of the gp41 cytoplasmic tail. J. Virol. 74, 3548–3554 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Murakami, T., Ablan, S., Freed, E. O. & Tanaka, Y. Regulation of human immunodeficiency virus type 1 Env-mediated membrane fusion by viral protease activity. J. Virol. 78, 1026–1031 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Wyma, D. J. et al. Coupling of human immunodeficiency virus type 1 fusion to virion maturation: a novel role of the gp41 cytoplasmic tail. J. Virol. 78, 3429–3435 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Chojnacki, J. et al. Maturation-dependent HIV-1 surface protein redistribution revealed by fluorescence nanoscopy. Science 338, 524–528 (2012).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Wyma, D. J., Kotov, A. & Aiken, C. Evidence for a stable interaction of gp41 with Pr55Gag in immature human immunodeficiency virus type 1 particles. J. Virol. 74, 9381–9387 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Frank, G. A. et al. Maturation of the HIV-1 core by a non-diffusional phase transition. Nat. Commun. 6, 5854 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Gottlinger, H. G., Dorfman, T., Sodroski, J. G. & Haseltine, W. A. Effect of mutations affecting the p6 gag protein on human immunodeficiency virus particle release. Proc. Natl Acad. Sci. USA 88, 3195–3199 (1991). Shows for the first time that the p6 domain of HIV-1 Gag has a central role in virus release.

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Huang, M., Orenstein, J. M., Martin, M. A. & Freed, E. O. p6Gag is required for particle production from full-length human immunodeficiency virus type 1 molecular clones expressing protease. J. Virol. 69, 6810–6818 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Votteler, J. & Sundquist, W. I. Virus budding and the ESCRT pathway. Cell Host Microbe 14, 232–241 (2013).

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Demirov, D. G., Ono, A., Orenstein, J. M. & Freed, E. O. Overexpression of the N-terminal domain of TSG101 inhibits HIV-1 budding by blocking late domain function. Proc. Natl Acad. Sci. USA 99, 955–960 (2002).

    CAS  Article  PubMed  Google Scholar 

  56. 56

    Garrus, J. E. et al. Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell 107, 55–65 (2001). Uses RNA-mediated interference to demonstrate that TSG101 plays an important part in HIV-1 budding.

    CAS  Article  PubMed  Google Scholar 

  57. 57

    Martin-Serrano, J., Zang, T. & Bieniasz, P. D. HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress. Nat. Med. 7, 1313–1319 (2001).

    CAS  Article  PubMed  Google Scholar 

  58. 58

    VerPlank, L. et al. Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55Gag. Proc. Natl Acad. Sci. USA 98, 7724–7729 (2001). Together with references 55–57, establishes the role for the ESCRT machinery in virus budding.

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Fujii, K. et al. Functional role of Alix in HIV-1 replication. Virology 391, 284–292 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Morita, E. et al. ESCRT-III protein requirements for HIV-1 budding. Cell Host Microbe 9, 235–242 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Joshi, A., Munshi, U., Ablan, S. D., Nagashima, K. & Freed, E. O. Functional replacement of a retroviral late domain by ubiquitin fusion. Traffic 9, 1972–1983 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Sette, P., Nagashima, K., Piper, R. C. & Bouamr, F. Ubiquitin conjugation to Gag is essential for ESCRT-mediated HIV-1 budding. Retrovirology 10, 79 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Mercenne, G., Alam, S. L., Arii, J., Lalonde, M. S. & Sundquist, W. I. Angiomotin functions in HIV-1 assembly and budding. eLife 4, e03778 (2015).

    Article  CAS  PubMed Central  Google Scholar 

  64. 64

    Hanson, P. I., Roth, R., Lin, Y. & Heuser, J. E. Plasma membrane deformation by circular arrays of ESCRT-III protein filaments. J. Cell Biol. 180, 389–402 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Shen, Q. T. et al. Structural analysis and modeling reveals new mechanisms governing ESCRT-III spiral filament assembly. J. Cell Biol. 206, 763–777 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Wollert, T., Wunder, C., Lippincott-Schwartz, J. & Hurley, J. H. Membrane scission by the ESCRT-III complex. Nature 458, 172–177 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Ivanchenko, S. et al. Dynamics of HIV-1 assembly and release. PLoS Pathog. 5, e1000652 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Jouvenet, N., Bieniasz, P. D. & Simon, S. M. Imaging the biogenesis of individual HIV-1 virions in live cells. Nature 454, 236–240 (2008). Applies advanced microscopy techniques to visualize the kinetics of individual HIV-1 particle assembly in real time.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Jouvenet, N., Zhadina, M., Bieniasz, P. D. & Simon, S. M. Dynamics of ESCRT protein recruitment during retroviral assembly. Nat. Cell Biol. 13, 394–401 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Van Engelenburg, S. B. et al. Distribution of ESCRT machinery at HIV assembly sites reveals virus scaffolding of ESCRT subunits. Science 343, 653–656 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Bleck, M. et al. Temporal and spatial organization of ESCRT protein recruitment during HIV-1 budding. Proc. Natl Acad. Sci. USA 111, 12211–12216 (2014).

    CAS  Article  PubMed  Google Scholar 

  72. 72

    Wlodawer, A. & Erickson, J. W. Structure-based inhibitors of HIV-1 protease. Annu. Rev. Biochem. 62, 543–585 (1993).

    CAS  Article  PubMed  Google Scholar 

  73. 73

    Pettit, S. C. et al. The p2 domain of human immunodeficiency virus type 1 Gag regulates sequential proteolytic processing and is required to produce fully infectious virions. J. Virol. 68, 8017–8027 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Kaplan, A. H. et al. Partial inhibition of the human immunodeficiency virus type 1 protease results in aberrant virus assembly and the formation of noninfectious particles. J. Virol. 67, 4050–4055 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Keller, P. W. et al. A two-pronged structural analysis of retroviral maturation indicates that core formation proceeds by a disassembly-reassembly pathway rather than a displacive transition. J. Virol. 87, 13655–13664 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    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). Proposes that the HIV-1 core is arranged on the principles of fullerene geometry, with a hexameric lattice closed off at both ends by a total of 12 pentameric 'defects'.

    CAS  Article  PubMed  Google Scholar 

  77. 77

    Sundquist, W. I. & Krausslich, H. G. HIV-1 assembly, budding, and maturation. Cold Spring Harb. Perspect. Med. 2, a006924 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Gres, A.T. et al. X-ray crystal structures of native HIV-1 capsid protein reveal conformational variability. Science http://dx.doi.org/10.1126/science.aaa5936 (2015).

  80. 80

    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).

    CAS  Article  PubMed  Google Scholar 

  81. 81

    Campbell, E. M. & Hope, T. J. HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat. Rev. Microbiol. (in the press).

  82. 82

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Tedbury, P. R. & Freed, E. O. HIV-1 Gag: an emerging target for antiretroviral therapy. Curr. Top. Microbiol. Immunol. 389, 171–201 (2015).

    CAS  PubMed  Google Scholar 

  84. 84

    Ternois, F., Sticht, J., Duquerroy, S., Krausslich, H. G. & Rey, F. A. The HIV-1 capsid protein C-terminal domain in complex with a virus assembly inhibitor. Nat. Struct. Mol. Biol. 12, 678–682 (2005).

    CAS  Article  PubMed  Google Scholar 

  85. 85

    Zhang, H. et al. A cell-penetrating helical peptide as a potential HIV-1 inhibitor. J. Mol. Biol. 378, 565–580 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Kelly, B. N. et al. Structure of the antiviral assembly inhibitor CAP-1 complex with the HIV-1 CA protein. J. Mol. Biol. 373, 355–366 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Tang, C. et al. Antiviral inhibition of the HIV-1 capsid protein. J. Mol. Biol. 327, 1013–1020 (2003).

    CAS  Article  PubMed  Google Scholar 

  88. 88

    Lemke, C. T. et al. Distinct effects of two HIV-1 capsid assembly inhibitor families that bind the same site within the N-terminal domain of the viral CA protein. J. Virol. 86, 6643–6655 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    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 

  90. 90

    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).

    CAS  Article  PubMed  Google Scholar 

  91. 91

    Matreyek, K. A. & Engelman, A. Viral and cellular requirements for the nuclear entry of retroviral preintegration nucleoprotein complexes. Viruses 5, 2483–2511 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    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 

  93. 93

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

    CAS  Article  PubMed  Google Scholar 

  94. 94

    Garg, D. & Torbett, B. E. Advances in targeting nucleocapsid-nucleic acid interactions in HIV-1 therapy. Virus Res. 193, 135–143 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Li, F. et al. PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proc. Natl Acad. Sci. USA 100, 13555–13560 (2003). Provides the first description of the mechanism of action of an HIV-1 maturation inhibitor.

    CAS  Article  PubMed  Google Scholar 

  96. 96

    Zhou, J. et al. Small-molecule inhibition of human immunodeficiency virus type 1 replication by specific targeting of the final step of virion maturation. J. Virol. 78, 922–929 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Adamson, C. S. et al. In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). J. Virol. 80, 10957–10971 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    Nguyen, A. T. et al. The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles. Retrovirology 8, 101 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Zhou, J., Huang, L., Hachey, D. L., Chen, C. H. & Aiken, C. Inhibition of HIV-1 maturation via drug association with the viral Gag protein in immature HIV-1 particles. J. Biol. Chem. 280, 42149–42155 (2005).

    CAS  Article  PubMed  Google Scholar 

  100. 100

    Waki, K. et al. Structural and functional insights into the HIV-1 maturation inhibitor binding pocket. PLoS Pathog. 8, e1002997 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Salzwedel, K., Martin, D. E. & Sakalian, M. Maturation inhibitors: a new therapeutic class targets the virus structure. AIDS Rev. 9, 162–172 (2007).

    PubMed  Google Scholar 

  102. 102

    Adamson, C. S., Sakalian, M., Salzwedel, K. & Freed, E. O. Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV- 1 maturation inhibitor bevirimat. Retrovirology 7, 36 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Neil, S. J., Zang, T. & Bieniasz, P. D. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451, 425–430 (2008).

    CAS  Article  PubMed  Google Scholar 

  104. 104

    Van Damme, N. et al. The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe 3, 245–252 (2008). Together with reference 103, shows that tetherin blocks the release of mature particles from the plasma membrane and is counteracted by Vpu.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    Murakami, T. & Freed, E. O. The long cytoplasmic tail of gp41 is required in a cell type-dependent manner for HIV-1 envelope glycoprotein incorporation into virions. Proc. Natl Acad. Sci. USA 97, 343–348 (2000). Demonstrates that the cytoplasmic tail of HIV-1 gp41 is required for Env incorporation in physiologically relevant cell types.

    CAS  Article  PubMed  Google Scholar 

  106. 106

    Qi, M. et al. Rab11-FIP1C and Rab14 direct plasma membrane sorting and particle incorporation of the HIV-1 envelope glycoprotein complex. PLoS Pathog. 9, e1003278 (2013). Determines that the host cell factor Rab11-FIP1C plays an important part in HIV-1 Env trafficking and incorporation into virions.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Carlton, J. G. & Martin-Serrano, J. Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery. Science 316, 1908–1912 (2007).

    CAS  Article  PubMed  Google Scholar 

  108. 108

    Morita, E. et al. Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis. EMBO J. 26, 4215–4227 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Samson, R. Y., Obita, T., Freund, S. M., Williams, R. L. & Bell, S. D. A role for the ESCRT system in cell division in archaea. Science 322, 1710–1713 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Snyder, J. C., Samson, R. Y., Brumfield, S. K., Bell, S. D. & Young, M. J. Functional interplay between a virus and the ESCRT machinery in archaea. Proc. Natl Acad. Sci. USA 110, 10783–10787 (2013).

    CAS  Article  PubMed  Google Scholar 

  111. 111

    Sengupta, P., Van Engelenburg, S. & Lippincott-Schwartz, J. Visualizing cell structure and function with point-localization superresolution imaging. Dev. Cell 23, 1092–1102 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    Milne, J. L. et al. Cryo-electron microscopy—a primer for the non-microscopist. FEBS J. 280, 28–45 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Martin-Fernandez, M. L., Tynan, C. J. & Webb, S. E. A 'pocket guide' to total internal reflection fluorescence. J. Microsc. 252, 16–22 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    Sekar, R. B. & Periasamy, A. Fluorescence resonance energy transfer (FRET) microscopy imaging of live cell protein localizations. J. Cell Biol. 160, 629–633 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Deshmukh, L. et al. Structure and dynamics of full-length HIV-1 capsid protein in solution. J. Am. Chem. Soc. 135, 16133–16147 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Morellet, N. et al. Structure of the complex between the HIV-1 nucleocapsid protein NCp7 and the single-stranded pentanucleotide d(ACGCC). J. Mol. Biol. 283, 419–434 (1998).

    CAS  Article  PubMed  Google Scholar 

  117. 117

    Cashikar, A. G. et al. Structure of cellular ESCRT-III spirals and their relationship to HIV budding. eLife 3, e02184 (2014).

    Article  CAS  PubMed Central  Google Scholar 

  118. 118

    Ganser-Pornillos, B. K., Yeager, M. & Sundquist, W. I. The structural biology of HIV assembly. Curr. Opin. Struct. Biol. 18, 203–217 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author thanks A. Ono, W.-S. Hu, S. Van Engelenburg and members of the Freed laboratory for critical review of the manuscript and helpful discussions. Work in the Freed laboratory is supported by the Intramural Research Program of the Center for Cancer Research (National Cancer Institute, US National Institutes of Health (NIH)) and by the Intramural AIDS Targeted Antiviral Program of the NIH.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Eric O. Freed.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

DATABASES

1BJ6

1HIW

2C55

2M8N

PowerPoint slides

Glossary

Capsid

The electron-dense structure at the centre of the mature virus particle. The capsid is composed of an outer layer of capsid protein surrounding the viral RNA genome and the viral enzymes reverse transcriptase and integrase.

Maturation

The morphological transition from the immature virus particle, in which uncleaved Gag proteins are aligned in a radial manner inside the viral membrane, to the mature particle, which contains a condensed, conical core.

Envelope glycoproteins

(Env glycoproteins). The heterotrimeric complexes of surface glycoprotein (gp120) and transmembrane glycoprotein (gp41) that are packaged into the viral membrane and mediate receptor–co-receptor binding and fusion in the next round of infection.

Assembly

The process by which viral proteins and nucleic acids come together in an infected cell to produce new virus particles.

Protease

The viral enzyme that cleaves multiple sites in Gag and GagPol during maturation.

Reverse transcriptase

The viral enzyme that converts the single-stranded viral RNA genome to double-stranded DNA after virus entry into the cell.

Integrase

The viral enzyme that is responsible for catalysing the insertion of the newly synthesized viral DNA into the host cell genome.

Endosomal sorting complex required for transport

(ESCRT). A multi-complex machinery that comprises ESCRT-0, ESCRT-I, ESCRT-II and ESCRT-III, and that promotes membrane scission reactions (for example, during vesicle budding, cytokinesis and enveloped-virus budding).

310 helix

A structural element within a protein; it is composed of a right-handed helix with three residues per turn, in which the first and third residues hydrogen bond with each other. The 310 helix is more tightly wound than the more common α-helix.

Cyclophilin A

(CYPA). A member of the family of peptidyl prolyl isomerases that facilitate protein folding.

Multivesicular body

(MVB). A late endosome containing intraluminal vesicles.

Phosphatidylinositol-4,5-bisphosphate

(PtdIns(4,5)P2). A phospholipid that plays an important part in the association of HIV-1 Gag with the inner leaflet of the plasma membrane.

Virus-like particles

(VLPs). Non-infectious particles formed by the expression of Gag alone, or newly budded particles before maturation.

Maturation inhibitors

Small molecules that block virus maturation by preventing a specific late step in the Gag processing cascade.

Late domains

Small peptide motifs in retroviral Gag proteins that recruit cellular machinery (that is, endosomal sorting complexes required for transport) to the site of budding to promote virus release.

Angiomotin

A cellular protein that is implicated in endothelial cell migration and in the formation of tight junctions.

Fullerene-like geometry

The structural arrangement of atoms as observed in certain elemental forms of carbon; in their spherical arrangement, fullerenes (such as buckminsterfullerene) are composed of hexagonal rings of carbon with 12 pentameric rings, allowing the structure to adopt a closed conformation. An analogous arrangement of hexameric and pentameric rings is observed in the soccer ball (football, for the non-American reader) and in the retroviral core.

Hydrocarbon stapling

A chemical method of circularizing peptides, thereby stabilizing their conformation and enhancing their cellular penetration.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Freed, E. HIV-1 assembly, release and maturation. Nat Rev Microbiol 13, 484–496 (2015). https://doi.org/10.1038/nrmicro3490

Download citation

Further reading

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