Review Article | Published:

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

Nature Reviews Microbiology volume 13, pages 471483 (2015) | Download Citation


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.

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


Protein Data Bank


  1. 1.

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

  2. 2.

    , , , & 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.

  3. 3.

    , , & Image reconstructions of helical assemblies of the HIV-1 CA protein. Nature 407, 409–413 (2000).

  4. 4.

    , & 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.

  5. 5.

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

  6. 6.

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

  7. 7.

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

  8. 8.

    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).

  9. 9.

    , & Isolation of human immunodeficiency virus type 1 cores: retention of Vpr in the absence of p6gag. J. Virol. 74, 6198–6202 (2000).

  10. 10.

    , , & Association of Nef with the human immunodeficiency virus type 1 core. J. Virol. 73, 8824–8830 (1999).

  11. 11.

    , , , & Biochemical and structural analysis of isolated mature cores of human immunodeficiency virus type 1. J. Virol. 74, 1168–1177 (2000).

  12. 12.

    , , & Formation of a human immunodeficiency virus type 1 core of optimal stability is crucial for viral replication. J. Virol. 76, 5667–5677 (2002).

  13. 13.

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

  14. 14.

    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).

  15. 15.

    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.

  16. 16.

    , , , & The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat. Immunol. 11, 1005–1013 (2010).

  17. 17.

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

  18. 18.

    & 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.

  19. 19.

    , , & Evidence for direct involvement of the capsid protein in HIV infection of nondividing cells. PLoS Pathog. 3, 1502–1510 (2007).

  20. 20.

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

  21. 21.

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

  22. 22.

    , , & 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.

  23. 23.

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

  24. 24.

    , , & 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. 25.

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

  26. 26.

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

  27. 27.

    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).

  28. 28.

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

  29. 29.

    , & HIV suppression by host restriction factors and viral immune evasion. Curr. Opin. Struct. Biol. 31, 106–114 (2015).

  30. 30.

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

  31. 31.

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

  32. 32.

    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).

  33. 33.

    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).

  34. 34.

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

  35. 35.

    & Characterization of intracellular reverse transcription complexes of human immunodeficiency virus type 1. J. Virol. 75, 3626–3635 (2001).

  36. 36.

    , & Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J. Virol. 71, 5382–5390 (1997).

  37. 37.

    & Characterization of intracellular reverse transcription complexes of Moloney murine leukemia virus. J. Virol. 73, 8919–8925 (1999).

  38. 38.

    , & Complementary assays reveal a relationship between HIV-1 uncoating and reverse transcription. Proc. Natl Acad. Sci. USA 108, 9975–9980 (2011).

  39. 39.

    , , , & HIV-1 uncoating is facilitated by dynein and kinesin-1. J. Virol. 88, 13613–13625 (2014).

  40. 40.

    , , , & 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).

  41. 41.

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

  42. 42.

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

  43. 43.

    , & A quantitative assay for HIV DNA integration in vivo. Nat. Med. 7, 631–634 (2001).

  44. 44.

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

  45. 45.

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

  46. 46.

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

  47. 47.

    & 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.

  48. 48.

    , & Role of human immunodeficiency virus type 1 integrase in uncoating of the viral core. J. Virol. 84, 5181–5190 (2010).

  49. 49.

    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).

  50. 50.

    , , , & Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication. J. Virol. 69, 2729–2736 (1995).

  51. 51.

    , & Inhibition of reverse transcriptase activity increases stability of the HIV-1 core. J. Virol. 87, 683–687 (2013).

  52. 52.

    , & 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).

  53. 53.

    , & Specific incorporation of cyclophilin A into HIV-1 virions. Nature 372, 359–362 (1994).

  54. 54.

    , , , & Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell 73, 1067–1078 (1993).

  55. 55.

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

  56. 56.

    , , & Cyclophilin interactions with incoming human immunodeficiency virus type 1 capsids with opposing effects on infectivity in human cells. J. Virol. 79, 176–183 (2005).

  57. 57.

    , & Target cell cyclophilin A modulates human immunodeficiency virus type 1 infectivity. J. Virol. 78, 12800–12808 (2004).

  58. 58.

    , , , & Abrogation of postentry restriction of HIV-1-based lentiviral vector transduction in simian cells. Proc. Natl Acad. Sci. USA 100, 1298–1303 (2003).

  59. 59.

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

  60. 60.

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

  61. 61.

    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).

  62. 62.

    , & 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).

  63. 63.

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

  64. 64.

    & 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).

  65. 65.

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

  66. 66.

    , , , & Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A. Proc. Natl Acad. Sci. USA 99, 5247–5252 (2002).

  67. 67.

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

  68. 68.

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

  69. 69.

    , & 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).

  70. 70.

    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).

  71. 71.

    & 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).

  72. 72.

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

  73. 73.

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

  74. 74.

    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).

  75. 75.

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

  76. 76.

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

  77. 77.

    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).

  78. 78.

    & Cytoplasmic dynein promotes HIV-1 uncoating. Viruses 6, 4195–4211 (2014).

  79. 79.

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

  80. 80.

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

  81. 81.

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

  82. 82.

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

  83. 83.

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

  84. 84.

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

  85. 85.

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

  86. 86.

    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.

  87. 87.

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

  88. 88.

    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).

  89. 89.

    , , , & 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).

  90. 90.

    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.

  91. 91.

    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.

  92. 92.

    , & Transportin-SR, a nuclear import receptor for SR proteins. J. Cell Biol. 145, 1145–1152 (1999).

  93. 93.

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

  94. 94.

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

  95. 95.

    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).

  96. 96.

    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).

  97. 97.

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

  98. 98.

    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).

  99. 99.

    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.

  100. 100.

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

  101. 101.

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

  102. 102.

    , & The nuclear pore complex: bridging nuclear transport and gene regulation. Nat. Rev. Mol. Cell Biol. 11, 490–501 (2010).

  103. 103.

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

  104. 104.

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

  105. 105.

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

  106. 106.

    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).

  107. 107.

    , , & Kinesin superfamily motor proteins and intracellular transport. Nat. Rev. Mol. Cell Biol. 10, 682–696 (2009).

  108. 108.

    , , & Identification of capsid mutations that alter the rate of HIV-1 uncoating in infected cells. J. Virol. 89, 643–651 (2014).

  109. 109.

    , & Intracellular nucleotide levels and the control of retroviral infections. Virology 436, 247–254 (2013).

  110. 110.

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

  111. 111.

    , , , & Small-molecule inhibition of human immunodeficiency virus type 1 infection by virus capsid destabilization. J. Virol. 85, 542–549 (2011).

  112. 112.

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

  113. 113.

    , , , & BI-2 destabilizes HIV-1 cores during infection and prevents binding of CPSF6 to the HIV-1 capsid. Retrovirology 11, 120 (2014).

  114. 114.

    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).

  115. 115.

    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.

  116. 116.

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

  117. 117.

    , & HIV-1 and interferons: who's interfering with whom? Nat. Rev. Microbiol. 13, 403–413 (2015).

  118. 118.

    & HIV latency. Cold Spring Harb. Perspect. Med. 1, a007096 (2011).

  119. 119.

    & In vitro uncoating of HIV-1 cores. J. Vis. Exp. 57, e3384 (2011).

  120. 120.

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

  121. 121.

    , & Fates of retroviral core components during unrestricted and TRIM5-restricted infection. PLoS Pathog. 9, e1003214 (2013).

  122. 122.

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

  123. 123.

    , , , & Intracytoplasmic maturation of the human immunodeficiency virus type 1 reverse transcription complexes determines their capacity to integrate into chromatin. Retrovirology 3, 4 (2006).

  124. 124.

    , & Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes. Proc. Natl Acad. Sci. USA 110, E4780–E4789 (2013).

  125. 125.

    , , & Visualization of a proteasome-independent intermediate during restriction of HIV-1 by rhesus TRIM5α. J. Cell Biol. 180, 549–561 (2008).

  126. 126.

    , , & Labeling HIV-1 virions with two fluorescent proteins allows identification of virions that have productively entered the target cell. Virology 360, 286–293 (2007).

  127. 127.

    , & Efficiency of human immunodeficiency virus type 1 postentry infection processes: evidence against disproportionate numbers of defective virions. J. Virol. 81, 4367–4370 (2007).

  128. 128.

    , , & 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.

  129. 129.

    , & Atomic-level modelling of the HIV capsid. Nature 469, 424–427 (2011).

  130. 130.

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

  131. 131.

    & 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).

  132. 132.

    , , & HIV trafficking in host cells: motors wanted! Trends Cell Biol. 23, 652–662 (2013).

Download references


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

Author information


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

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

    • Thomas J. Hope


  1. Search for Edward M. Campbell in:

  2. Search for Thomas J. Hope in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Thomas J. Hope.



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.


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.


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.


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.


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.


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.

About this article

Publication history



Further reading

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