Advertisement

The HIV-1 Capsid: More than Just a Delivery Package

  • Leo C. JamesEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1215)

Abstract

Productive HIV infection requires integration of viral genes into the host genome. But how viral DNA gets to the nucleus in the first place remains one of the most controversial yet deceptively simple questions in HIV post-entry biology. This is illustrated in cartoons of viral entry, which often depict the entry process as an ‘explosion’ of the HIV capsid in the cytosol and independent movement of viral DNA through nuclear pores and into the nucleus. HIV enters the cell cytosol with two encapsidated RNA strands and must undergo reverse transcription (RT) to synthesise DNA. Even here there is no consensus for where, when or how RT happens. HIV must get into the nucleus, which in a non-dividing cell requires transport through the nuclear pore. Finally, the virus must ‘uncoat’: shed its protein capsid to allow its DNA to be spliced with that of the host. Where the virus uncoats and whether this is a single or multi-step process are similarly hotly debated. Understanding these processes is further complicated by three broad factors. First, that there are inter-relationships between these processes that may ensure HIV undergoes the right step at the right place at the right time. Second, the host has cofactors which the virus is dependent upon and must recruit but also immune factors that can sense and inhibit virus and so must be avoided. Third, HIV post-entry biology is cell-type dependent—meaning that factors which are essential in one cell type can be redundant in another.

Keywords

HIV Capsid Pore Reverse transcription Uncoating Entry Nucleotide Non-membranous compartment Sequestration Nuclear pore complex Host factors Infection Nuclear import DNA 

References

  1. 1.
    Luban J, Bossolt KL et al (1993) Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell 73(6):1067–1078CrossRefGoogle Scholar
  2. 2.
    Lang K, Schmid FX et al (1987) Catalysis of protein folding by prolyl isomerase. Nature 329(6136):268–270CrossRefGoogle Scholar
  3. 3.
    Dolinski K, Muir S et al (1997) All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 94(24):13093–13098CrossRefGoogle Scholar
  4. 4.
    Braaten D, Franke EK et al (1996a) 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(6):3551–3560PubMedPubMedCentralGoogle Scholar
  5. 5.
    Braaten D, Franke EK et al (1996b) Cyclophilin A is required for the replication of group M human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus SIV(CPZ)GAB but not group O HIV-1 or other primate immunodeficiency viruses. J Virol 70(7):4220–4227PubMedPubMedCentralGoogle Scholar
  6. 6.
    Sokolskaja E, Sayah DM et al (2004) Target cell cyclophilin A modulates human immunodeficiency virus type 1 infectivity. J Virol 78(23):12800–12808CrossRefGoogle Scholar
  7. 7.
    Goldstone DC, Yap MW et al (2010) Structural and functional analysis of prehistoric lentiviruses uncovers an ancient molecular interface. Cell Host Microbe 8(3):248–259CrossRefGoogle Scholar
  8. 8.
    Li Y, Kar AK et al (2009) Target cell type-dependent modulation of human immunodeficiency virus type 1 capsid disassembly by cyclophilin A. J Virol 83(21):10951–10962CrossRefGoogle Scholar
  9. 9.
    Bosco DA, Eisenmesser EZ et al (2002) Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A. Proc Natl Acad Sci USA 99(8):5247–5252CrossRefGoogle Scholar
  10. 10.
    Lammers M, Neumann H et al (2010) Acetylation regulates Cyclophilin A catalysis, immunosuppression and HIV isomerization. Nat Chem Biol 6:331–337CrossRefGoogle Scholar
  11. 11.
    Grattinger M, Hohenberg H et al (1999) In vitro assembly properties of wild-type and cyclophilin-binding defective human immunodeficiency virus capsid proteins in the presence and absence of cyclophilin A. Virology 257(1):247–260CrossRefGoogle Scholar
  12. 12.
    Rasaiyaah J, Tan CP et al (2013) HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503(7476):402–405CrossRefGoogle Scholar
  13. 13.
    Braaten D, Luban J (2001) Cyclophilin A regulates HIV-1 infectivity, as demonstrated by gene targeting in human T cells. EMBO J 20(6):1300–1309CrossRefGoogle Scholar
  14. 14.
    Manel N, Hogstad B et al (2010) A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature 467(7312):214–217CrossRefGoogle Scholar
  15. 15.
    Schreiber SL, Crabtree GR (1992) The mechanism of action of cyclosporin A and FK506. Immunol Today 13(4):136–142CrossRefGoogle Scholar
  16. 16.
    Aberham C, Weber S et al (1996) Spontaneous mutations in the human immunodeficiency virus type 1 gag gene that affect viral replication in the presence of cyclosporins. J Virol 70(6):3536–3544PubMedPubMedCentralGoogle Scholar
  17. 17.
    Ylinen LM, Schaller T et al (2009) Cyclophilin A levels dictate infection efficiency of human immunodeficiency virus type 1 capsid escape mutants A92E and G94D. J Virol 83(4):2044–2047CrossRefGoogle Scholar
  18. 18.
    Franke EK, Yuan HE et al (1994) Specific incorporation of cyclophilin A into HIV-1 virions. Nature 372(6504):359–362CrossRefGoogle Scholar
  19. 19.
    Billich A, Hammerschmid F et al (1995) Mode of action of SDZ NIM 811, a nonimmunosuppressive cyclosporin A analog with activity against human immunodeficiency virus (HIV) type 1: interference with HIV protein-cyclophilin A interactions. J Virol 69(4):2451–2461PubMedPubMedCentralGoogle Scholar
  20. 20.
    Price AJ, Marzetta F et al (2009) Active site remodeling switches HIV specificity of antiretroviral TRIMCyp. Nat Struct Mol Biol 16(10):1036–1042CrossRefGoogle Scholar
  21. 21.
    Wiegers K, Krausslich HG (2002) Differential dependence of the infectivity of HIV-1 group O isolates on the cellular protein cyclophilin A. Virology 294(2):289–295CrossRefGoogle Scholar
  22. 22.
    Aiken C (1997) Pseudotyping human immunodeficiency virus type 1 (HIV-1) by the glycoprotein of vesicular stomatitis virus targets HIV-1 entry to an endocytic pathway and suppresses both the requirement for Nef and the sensitivity to cyclosporin A. J Virol 71(8):5871–5877PubMedPubMedCentralGoogle Scholar
  23. 23.
    Brass AL, Dykxhoorn DM et al (2008) Identification of host proteins required for HIV infection through a functional genomic screen. Science 319(5865):921–926CrossRefGoogle Scholar
  24. 24.
    Konig R, Zhou Y et al (2008) Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 135(1):49–60CrossRefGoogle Scholar
  25. 25.
    Bichel K, Price AJ et al (2013) HIV-1 capsid undergoes coupled binding and isomerization by the nuclear pore protein NUP358. Retrovirology 10(1):81CrossRefGoogle Scholar
  26. 26.
    Sayah DM, Sokolskaja E et al (2004) Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 430(6999):569–573CrossRefGoogle Scholar
  27. 27.
    Wilson SJ, Webb BL et al (2008) Independent evolution of an antiviral TRIMCyp in rhesus macaques. Proc Natl Acad Sci USA 105(9):3557–3562CrossRefGoogle Scholar
  28. 28.
    Caines ME, Bichel K et al (2012) Diverse HIV viruses are targeted by a conformationally dynamic antiviral. Nat Struct Mol Biol 19(4):411–416CrossRefGoogle Scholar
  29. 29.
    Ylinen LM, Price AJ et al (2010) Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity. PLoS Pathog 6(8):e1001062CrossRefGoogle Scholar
  30. 30.
    Lee K, Ambrose Z et al (2010) Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe 7(3):221–233CrossRefGoogle Scholar
  31. 31.
    Hori T, Takeuchi H et al (2013) A carboxy-terminally truncated human CPSF6 lacking residues encoded by exon 6 inhibits HIV-1 cDNA synthesis and promotes capsid disassembly. J Virol 87(13):7726–7736CrossRefGoogle Scholar
  32. 32.
    Price AJ, Fletcher AJ et al (2012) CPSF6 defines a conserved capsid interface that modulates HIV-1 replication. PLoS Pathog 8(8):e1002896CrossRefGoogle Scholar
  33. 33.
    Schaller T, Ocwieja KE et al (2011) HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLoS Pathog 7(12):e1002439CrossRefGoogle Scholar
  34. 34.
    Ocwieja KE, Brady TL et al (2011) HIV integration targeting: a pathway involving transportin-3 and the nuclear pore protein RanBP2. PLoS Pathog 7(3):e1001313CrossRefGoogle Scholar
  35. 35.
    Maertens GN, Cook NJ et al (2014) Structural basis for nuclear import of splicing factors by human Transportin 3. Proc Natl Acad Sci USA 111(7):2728–2733CrossRefGoogle Scholar
  36. 36.
    Matreyek KA, Engelman A (2011) The requirement for nucleoporin NUP153 during human immunodeficiency virus type 1 infection is determined by the viral capsid. J Virol 85(15):7818–7827CrossRefGoogle Scholar
  37. 37.
    Cardarelli F, Lanzano L et al (2012) Capturing directed molecular motion in the nuclear pore complex of live cells. Proc Natl Acad Sci USA 109(25):9863–9868CrossRefGoogle Scholar
  38. 38.
    Bastos R, Lin A et al (1996) Targeting and function in mRNA export of nuclear pore complex protein Nup153. J Cell Biol 134(5):1141–1156CrossRefGoogle Scholar
  39. 39.
    Matreyek KA, Yucel SS et al (2013) Nucleoporin NUP153 phenylalanine-glycine motifs engage a common binding pocket within the HIV-1 capsid protein to mediate lentiviral infectivity. PLoS Pathog 9(10):e1003693CrossRefGoogle Scholar
  40. 40.
    Price AJ, Jacques DA et al (2014) Host cofactors and pharmacologic ligands share an essential interface in HIV-1 capsid that is lost upon disassembly. PLoS Pathog 10(10):e1004459CrossRefGoogle Scholar
  41. 41.
    Blair WS, Pickford C et al (2010) HIV capsid is a tractable target for small molecule therapeutic intervention. PLoS Pathog 6(12):e1001220CrossRefGoogle Scholar
  42. 42.
    Lamorte L, Titolo S et al (2013) Discovery of novel small-molecule HIV-1 replication inhibitors that stabilize capsid complexes. Antimicrob Agents Chemother 57(10):4622–4631CrossRefGoogle Scholar
  43. 43.
    Shah VB, Shi J et al (2013) The host proteins transportin SR2/TNPO3 and cyclophilin A exert opposing effects on HIV-1 uncoating. J Virol 87(1):422–432CrossRefGoogle Scholar
  44. 44.
    Jacques DA, McEwan WA et al (2016) HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis. Nature 536(7616):349–353CrossRefGoogle Scholar
  45. 45.
    Mallery DL, Márquez CL et al (2018) IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis. eLife. pii: e35335.  https://doi.org/10.7554/eLife.35335
  46. 46.
    Dick RA, Zadrozny KK, Xu C, Schur FKM, Lyddon TD, Ricana CL, Wagner JM, Perilla JR, Ganser-Pornillos BK, Johnson MC, Pornillos O, Vogt VM (2018) Inositol phosphates are assembly co-factors for HIV-1. Nature.  https://doi.org/10.1038/s41586-018-0396-4. [Epub ahead of print]CrossRefGoogle Scholar
  47. 47.
    Campbell S, Fisher RJ et al (2001) Modulation of HIV-like particle assembly in vitro by inositol phosphates. Proc Natl Acad Sci USA 98(19):10875–10879CrossRefGoogle Scholar
  48. 48.
    Saito A, Ferhadian D et al (2016) Roles of capsid-interacting host factors in multimodal inhibition of HIV-1 by PF74. J Virol 90(12):5808–5823CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Medical Research Council Laboratory of Molecular BiologyCambridgeUK

Personalised recommendations