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Mol Biol Int. 2012; 2012: 426840.
Published online May 30, 2012. doi:  10.1155/2012/426840
PMCID: PMC3369500
TRIM5 and the Regulation of HIV-1 Infectivity
Jeremy Luban *
Department of Microbiology and Molecular Medicine, University of Geneva, 1211 Geneva, Switzerland
*Jeremy Luban: jeremy.luban/at/unige.ch
Academic Editor: Abraham Brass
Received February 27, 2012; Accepted April 8, 2012.
The past ten years have seen an explosion of information concerning host restriction factors that inhibit the replication of HIV-1 and other retroviruses. Among these factors is TRIM5, an innate immune signaling molecule that recognizes the capsid lattice as soon as the retrovirion core is released into the cytoplasm of otherwise susceptible target cells. Recognition of the capsid lattice has several consequences that include multimerization of TRIM5 into a complementary lattice, premature uncoating of the virion core, and activation of TRIM5 E3 ubiquitin ligase activity. Unattached, K63-linked ubiquitin chains are generated that activate the TAK1 kinase complex and downstream inflammatory mediators. Polymorphisms in the capsid recognition domain of TRIM5 explain the observed species-specific differences among orthologues and the relatively weak anti-HIV-1 activity of human TRIM5. Better understanding of the complex interaction between TRIM5 and the retrovirus capsid lattice may someday lead to exploitation of this interaction for the development of potent HIV-1 inhibitors.
HIV-1 was identified only two years after the first report of AIDS in 1981 [1]. The HIV-1 genome was cloned and sequenced, ORFs were identified, and functions of the gene products pinpointed. At a time when few antivirals were in clinical use, HIV-1 proteins were isolated, their activities were described, their structures were determined, and inhibitors were identified [25]. The first anti-HIV-1 drug, AZT, was approved for patients in 1987, and effective combinations of anti-HIV-1 drugs were in the clinic by the mid-1990s. Thanks to these anti-HIV-1 drugs, the number of AIDS cases plummeted in countries like the United States. HIV-1 infection became an outpatient disease. Yet, despite the impact of basic science on disease in individuals with HIV-1 infection, the AIDS pandemic has not gone away.
Failure to control the AIDS pandemic may be attributable to a number of factors, including the need for improvement in drugs and more ready access to those drugs that already exist. Aside from one extraordinary case of a person who underwent bone marrow transplantation with cells from a CCR5-defective donor [6], there has been no documented cure of HIV-1 infection. Aside from a small effect in one vaccination trial [7], there is no evidence for prevention of HIV-1 infection in people by a vaccine. Without prospects for curative drugs or a preventive vaccine, the cost of HIV-1 infection to individuals and to society will remain high. In New York City there are currently ~110,000 people living with HIV-1 and ~1,600 HIV-related deaths annually (NYC Dept of Health). The toll of AIDS is much greater in medically underserved regions of the world, despite improved distribution of anti-HIV-1 drugs in these places. According to the UNAIDS report concluding in 2010 (http://www.unaids.org/en/), 34 million people were living with HIV infection, and in that year alone there were 2.7 million new infections.
Much remains to be learned about the function of each of the HIV-1 gene products and the optimization of drugs that inhibit their function. In recent years the focus of much HIV-1 molecular biology research has shifted to host factors that regulate HIV-1 infection. Initially these studies involved searches for host factors that physically interact with individual viral proteins. The cellular proteins cyclophilin A and LEDGF, for example, were found to interact with HIV-1 capsid (CA) and HIV-1 integrase (IN), respectively, [8, 9]. Both of these protein-protein interactions have been studied extensively and have offered novel approaches to HIV-1 inhibition and potential new anti-HIV-1 drug candidates [912].
Functional screens have also yielded information concerning host factors that regulate infection by HIV-1 and other retroviruses [1316]. More recently, several groups have reported human genome-wide RNAi screens to identify factors that regulate HIV-1 infectivity [1721]. Among host factors identified in these screens are host proteins such as TNPO3 that play critical roles in the poorly understood early events of HIV-1 infection that culminate in establishment of the provirus [15, 2225]. Ultimately, information springing from the study of any one of these host factors has the potential to be exploited towards the development of drugs that disrupt HIV-1 in people.
Over the past 10 years, in addition to the identification of host factors that promote HIV-1 infectivity, several host factors have been discovered that block HIV-1 infection [26]. Comparative analysis of the genes encoding these proteins, which have been called restriction factors, indicates that some of them have evolved in response to challenge with pathogenic retroviruses [27, 28]. Study of these factors has offered a wealth of information concerning requirements for HIV-1 replication, novel ways that HIV-1 might be targeted therapeutically, potential paths to cure HIV-1 infection, and ways in which innate immune detection of HIV-1 might be amplified to improve vaccination protocols.
When HIV-1 and other retroviruses undergo membrane fusion with susceptible target cells, the virion core is released into the target cell cytoplasm. The core of the virion consists of a capsid-protein lattice, within which there are two copies of the viral genome, along with the reverse transcriptase and IN proteins. An extraordinary series of experiments spanning several decades demonstrated that the retroviral CA protein lattice is the viral determinant of sensitivity to a murine-specific restriction factor called Fv1 [29, 30]. Curiously, Fv1 encodes a retroviral Gag polyprotein [29]. The mechanism of Fv1 restriction is still unknown, but these studies established the concept of retrovirus CA-specific restriction and inspired the search for similar factors targeting HIV-1 CA.
Cyclophilin A was the first HIV-1 CA-specific host factor that was identified [9, 31]. Though cyclophilin A is not a restriction factor itself, it controls the accessibility of CA to other host factors that inhibit reverse transcription and other processes essential to the early steps of the infection cycle [32]. One apparent effect of these host factors is to influence these early steps via effects on stability of the HIV-1 virion core [15, 3236]. The identity of these cyclophilin-regulated host factors is unknown. Additional screens have identified CPSF6 as a conditional regulator of HIV-1 infection, that acts in a capsid-specific manner [15, 37]. CPSF6 is a possible candidate for one such cyclophilin A-regulated restriction factor.
Cyclophilin A cDNAs have retrotransposed many times in evolution, in several cases creating new genes that regulate HIV-1 infectivity in a capsid-specific manner. The first of the cyclophilin A-targeted restriction factors to be identified was the TRIM5-cyclophilin A fusion protein found in South American owl monkeys [38]. A similar, though independently derived, TRIM5-cyclophilin A fusion gene that acts as a capsid-specific restriction factor was created in Asian macaques [3942]. Nup358/RanBP2, a nuclear pore protein that possesses a cyclophilin A domain also plays a role in HIV-1 infectivity [15, 17, 19, 43].
Early studies with HIV-1 showed that infection of cells from nonhuman primates is too inefficient to establish spreading infection [4448]. It was then shown that dominant-acting inhibitors were present in these species, and that the viral capsid was the main determinant for sensitivity [4951]. In 2004, two groups independently identified TRIM5 orthologues as being responsible for these species-specific, capsid-specific blocks [38, 52]. The owl monkey orthologue (known as TRIM5-Cyp) targets HIV-1 capsid via its carboxy-terminal cyclophilin A domain [38, 53], and the rhesus macaque orthologue (the alpha isoform) targets HIV-1 capsid via its carboxy-terminal PRY-SPRY domain [52]. Human TRIM5alpha potently restricts EIAV and N-tropic MLV, but it only weakly inhibits HIV-1 lab strains. Differences in specificity between human and macaque TRIM5alpha map to a small block of residues in the PRY-SPRY domain [28, 32, 54, 55]. Though standard HIV-1 lab strains are only weakly inhibited by human TRIM5alpha, some primary HIV-1 isolates are much more sensitive [56, 57].
One of the biggest ongoing challenges for researchers studying TRIM5 is to understand the structural basis for CA recognition. TRIM5 is a multimer, and CA recognition does not occur via a simple protein-protein interaction. Rather, TRIM5 recognizes a complex surface involving the CA lattice [58, 59]. In fact, TRIM5 spontaneously forms a hexameric protein lattice, and this propensity to form a lattice is greatly stimulated in the presence of the CA lattice [60] (Figure 1). This explains why a simple binding assay has not been developed. Extensive efforts have been made by several groups to develop soluble subdomains of the CA lattice that might be used in binding studies [61, 62]. The soluble hexamer unit, for example, seems not to bind to TRIM5 [63, 64]. In contrast, promising results have been obtained with a CA trimer [64]. A requirement for additional host factors such as SUMO-1 may complicate the situation with CA recognition even further [65].
Figure 1
Figure 1
Schematic diagram showing current models of TRIM5-mediated restriction. Free TRIM5 probably exists as a dimer in the target cell cytoplasm. Upon interaction with the capsid of a restriction-sensitive retrovirus, the propensity of TRIM5 to form a complementary (more ...)
At latest count, the human TRIM family comprises ~100 genes [66]. Like other members of this large family, TRIM5 possesses an N-terminal RING domain, a B-box domain, and a coiled-coil domain. The B box and coiled-coil domains promote multimerization of TRIM5 required for restriction activity [67, 68]. The TRIM5 RING domain confers E3 ubiquitin ligase activity, and, in cooperation with certain E2 enzymes, TRIM5 is autocatalytic, covalently attaching ubiquitin to itself [69]. Mutations on the putative E2-interacting face which disrupt this autocatalytic activity block restriction activity [70]. Ubiquitination of TRIM5 contributes to the short half-life of this protein [71], and challenge of cells with viruses bearing restriction-sensitive capsids promotes the proteasome-dependent degradation of TRIM5 [72]. Though TRIM5-stimulated ubiquitination of viral proteins has not been detected, TRIM5 may contribute to the restriction mechanism by recruiting viral components to the proteasome for degradation (Figure 1). TRIM5 interacts biochemically with the proteasome component PSMC2 and colocalizes with proteasomes in infected cells [73]. TRIM5 also associates with the proteasomal adaptor protein p62 [74] though p62 seems to stabilize TRIM5 protein levels.
In certain experimental conditions, restriction activity has been reported in the absence of the RING domain or in the absence of ubiquitination. There are several possible explanations for these discrepancies. One possibility is that, when avidity for a particular CA is great enough, TRIM5 binding to the CA is sufficient to disassemble the virion core prior to reverse transcription [59] (Figure 1). Another possible explanation stems from the fact that TRIM5 blocks multiple steps in the restriction pathway [75]. Disruption of the RING domain rescues the TRIM5-mediated block to reverse transcription and premature uncoating but not subsequent blocks in the infection cycle that lead up to integration [76, 77].
In combination with the heterodimeric E2, UBC13/UEV1A, TRIM5 catalyzes the synthesis of unattached, K63-linked ubiquitin chains that multimerize and activate the TAK1 kinase complex [63]. These K63-linked ubiquitin chains are not generated by TRIM5 when other E2 enzymes are substituted for UBC13/UEV1A. Disruption of TAK1 or of UBC13/UEV1A prevents restriction activity. Taken together, these observations suggest that the activated TAK1 complex contributes to TRIM5-mediated restriction activity via phosphorylation of a critical cofactor (Figure 1). The identity of this putative cofactor is not known, and direct phosphorylation of CA by TAK1 has not been detected.
Coming at it from another direction, the synthesis of K63-linked ubiquitin chains that activate TAK1 is stimulated by TRIM5 interaction with a restricted capsid lattice [63]. TAK1 activation leads to NFκB and AP-1 signaling which activate inflammatory cytokine transcription. In other words, TRIM5 functions as a pattern recognition receptor specific for the retrovirus capsid lattice. The consequence of TRIM5-mediated signaling for HIV-1-associated inflammation and pathology is only now being considered.
If a robust assay was developed for TRIM5 interaction with the retrovirus capsid lattice, it would inform attempts to influence HIV-1 CA recognition by TRIM5, and perhaps to develop HIV-1 inhibitors that increase the avidity of this specific interaction. If the avidity of human TRIM5 for the HIV-1 capsid lattice could be increased experimentally, the resulting increase in capsid-stimulated signaling might also be exploited as an adjuvant for anti-HIV-1 immunization.
Recent publicity concerning the apparent cure from HIV-1 infection of a leukemia patient in Berlin with transplantation of cells from a CCR5-mutant donor [6, 78] has generated excitement concerning prospects for curing HIV-1 infection. This case has also renewed interest in basic research concerning gene therapy against HIV-1 and the regulation of HIV-1 latency in people who are already infected with HIV-1. Concerning gene therapy, the most promising approaches at this point involve either disruption of CCR5 [79] or transduction of hematopoietic stem cells with potent HIV-1 restriction factors such as engineered, human TRIM5-cyclophilin A fusion proteins [80].
Acknowledgments
This work was supported by NIH Grant RO1AI59159 and Swiss National Science Foundation Grant 3100A0-128655.
1. Barré-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS) Science. 1983;220:868–871. [PubMed]
2. Chen JC-H, Krucinski J, Miercke LJW, et al. Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: a model for viral DNA binding. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(15):8233–8238. [PubMed]
3. Kim EE, Baker CT, Dwyer MD, et al. Crystal structure of HIV-1 protease in complex with VX-478, a potent and orally bioavailable inhibitor of the enzyme. Journal of the American Chemical Society. 1995;117(3):1181–1182.
4. Sarafianos SG, Das K, Tantillo C, et al. Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA:DNA. EMBO Journal. 2001;20(6):1449–1461. [PubMed]
5. Turner BG, Summers MF. Structural biology of HIV. Journal of Molecular Biology. 1999;285(1):1–32. [PubMed]
6. Hütter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation. The New England Journal of Medicine. 2009;360(7):692–698. [PubMed]
7. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. The New England Journal of Medicine. 2009;361(23):2209–2220. [PubMed]
8. Cherepanov P, Maertens G, Proost P, et al. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. Journal of Biological Chemistry. 2003;278(1):372–381. [PubMed]
9. Luban J, Bossolt KL, Franke EK, Kalpana GV, Goff SP. Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell. 1993;73(6):1067–1078. [PubMed]
10. Christ F, Voet A, Marchand A, et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nature Chemical Biology. 2010;6(6):442–448. [PubMed]
11. Franke EK, Luban J. Inhibition of HIV-1 replication by cyclosporine A or related compounds correlates with the ability to disrupt the Gag-cyclophilin A interaction. Virology. 1996;222(1):279–282. [PubMed]
12. Thali M, Bukovsky A, Kondo E, et al. Functional association of cyclophilin A with HIV-1 virions. Nature. 1994;372(6504):363–365. [PubMed]
13. Gao G, Goff SP. Somatic cell mutants resistant to retrovirus replication: intracellular blocks during the early stages of infection. Molecular Biology of the Cell. 1999;10(6):1705–1717. [PMC free article] [PubMed]
14. Gao G, Guo X, Goff SP. Inhibition of retroviral RNA production by ZAP, a CCCH-type zinc finger protein. Science. 2002;297(5587):1703–1706. [PubMed]
15. Lee K, Ambrose Z, Martin TD, et al. Flexible Use of Nuclear Import Pathways by HIV-1. Cell Host and Microbe. 2010;7(3):221–233. [PMC free article] [PubMed]
16. Valente ST, Gilmartin GM, Venkatarama K, Arriagada G, Goff SP. HIV-1 mRNA 3′ end processing is distinctively regulated by eIF3f, CDK11, and splice factor 9G8. Molecular Cell. 2009;36(2):279–289. [PMC free article] [PubMed]
17. Brass AL, Dykxhoorn DM, Benita Y, et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science. 2008;319(5865):921–926. [PubMed]
18. Bushman FD, Malani N, Fernandes J, et al. Host cell factors in HIV replication: meta-analysis of genome-wide studies. PLoS Pathogens. 2009;5(5) Article ID e1000437. [PMC free article] [PubMed]
19. König R, Zhou Y, Elleder D, et al. Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell. 2008;135(1):49–60. [PMC free article] [PubMed]
20. Yeung ML, Houzet L, Yedavalli VSRK, Jeang K-T. A genome-wide short hairpin RNA screening of Jurkat T-cells for human proteins contributing to productive HIV-1 replication. Journal of Biological Chemistry. 2009;284(29):19463–19473. [PubMed]
21. Zhou H, Xu M, Huang Q, et al. Genome-scale RNAi screen for host factors required for HIV replication. Cell Host and Microbe. 2008;4(5):495–504. [PubMed]
22. Christ F, Thys W, De Rijck J, et al. Transportin-SR2 Imports HIV into the nucleus. Current Biology. 2008;18(16):1192–1202. [PubMed]
23. 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. 2011;8, article 98 [PMC free article] [PubMed]
24. Krishnan L, Matreyek KA, Oztop I, 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. Journal of Virology. 2010;84(1):397–406. [PMC free article] [PubMed]
25. Zhou L, Sokolskaja E, Jolly C, James W, Cowley SA, Fassati A. Transportin 3 promotes a nuclear maturation step required for efficient HIV-1 integration. PLoS Pathogens. 7 Article ID e1002194. [PMC free article] [PubMed]
26. Strebel K, Luban J, Jeang K-T. Human cellular restriction factors that target HIV-1 replication. BMC Medicine. 2009;7, article 48 [PMC free article] [PubMed]
27. Sawyer SL, Emerman M, Malik HS. Ancient adaptive evolution of the primate antiviral DNA-editing enzyme APOBEC3G. PLoS Biology. 2004;2(9) Article ID E275. [PMC free article] [PubMed]
28. Sawyer SL, Wu LI, Emerman M, Malik HS. Positive selection of primate TRIM5α identifies a critical species-specific retroviral restriction domain. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(8):2832–2837. [PubMed]
29. Best S, Tissier PL, Towers G, Stoye JP. Positional cloning of the mouse retrovirus restriction gene Fv1. Nature. 1996;382(6594):826–829. [PubMed]
30. Pincus T, Rowe WP, Lilly F. A major genetic locus affecting resistance to infection with murine leukemia viruses. II. Apparent identity to a major locus described for resistance to friend murine leukemia virus. Journal of Experimental Medicine. 1971;133(6):1234–1241. [PMC free article] [PubMed]
31. Franke EK, Yuan HEH, Luban J. Specific incorporation of cyclophilin A into HIV-1 virions. Nature. 1994;372(6504):359–362. [PubMed]
32. Luban J. Cyclophilin A, TRIM5, and resistance to human immunodeficiency virus type 1 infection. Journal of Virology. 2007;81(3):1054–1061. [PMC free article] [PubMed]
33. Yuan L, Kar AK, Sodroski J. Target cell type-dependent modulation of human immunodeficiency virus type 1 capsid disassembly by cyclophilin A. Journal of Virology. 2009;83(21):10951–10962. [PMC free article] [PubMed]
34. Luban J. Absconding with the chaperone: essential cyclophilin-gag interaction in HIV-1 virions. Cell. 1996;87(7):1157–1159. [PubMed]
35. Qi M, Yang R, Aiken C. Cyclophilin A-dependent restriction of human immunodeficiency virus type 1 capsid mutants for infection of nondividing cells. Journal of Virology. 2008;82(24):12001–12008. [PMC free article] [PubMed]
36. 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. Journal of Virology. 2007;81(21):11946–11956. [PMC free article] [PubMed]
37. Lee K, Mulky A, Yuen W, et al. HIV-1 capsid targeting domain of cleavage and polyadenylation specificity factor 6. Journal of Virology. 2012;86(7):3851–3860. [PMC free article] [PubMed]
38. Sayah DM, Sokolskaja E, Berthoux L, Luban J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature. 2004;430(6999):569–573. [PubMed]
39. Brennan G, Kozyrev Y, Hu S-L. TRIMCyp expression in old world primates macaca nemestrina and macaca fascicularis. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(9):3569–3574. [PubMed]
40. Newman RM, Hall L, Kirmaier A, et al. Evolution of a TRIM5-CypA splice isoform in old world monkeys. PLoS Pathogens. 2008;4(2) Article ID e1000003. [PMC free article] [PubMed]
41. Virgen CA, Kratovac Z, Bieniasz PD, Hatziioannou T. Independent genesis of chimeric TRIM5-cyclophilin proteins in two primate species. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(9):3563–3568. [PubMed]
42. Wilson SJ, Webb BLJ, Ylinen LMJ, Verschoor E, Heeney JL, Towers GJ. Independent evolution of an antiviral TRIMCyp in rhesus macaques. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(9):3557–3562. [PubMed]
43. Schaller T, Ocwieja KE, Rasaiyaah J, et al. HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLoS Pathogens. 2011;7 Article ID e1002439. [PMC free article] [PubMed]
44. Balzarini J, De Clercq E, Uberla K. SIV/HIV-1 hybrid virus expressing the reverse transcriptase gene of HIV-1 remains sensitive to HIV-1-specific reverse transcriptase inhibitors after passage in rhesus macaques. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. 1997;15(1):1–4. [PubMed]
45. Himathongkham S, Luciw PA. Restriction of HIV-1 (subtype B) replication at the entry step in rhesus macaque cells. Virology. 1996;219(2):485–488. [PubMed]
46. Hofmann W, Schubert D, LaBonte J, et al. Species-specific, postentry barriers to primate immunodeficiency virus infection. Journal of Virology. 1999;73(12):10020–10028. [PMC free article] [PubMed]
47. Li J, Lord CI, Haseltine W, Letvin NL, Sodroski J. Infection of cynomolgus monkeys with a chimeric HIV-1/SIV(mac) virus that expresses the HIV-1 envelope glycoproteins. Journal of Acquired Immune Deficiency Syndromes. 1992;5(7):639–646. [PubMed]
48. Shibata R, Kawamura M, Sakai H, Hayami M, Ishimoto A, Adachi A. Generation of a chimeric human and simian immunodeficiency virus infectious to monkey peripheral blood mononuclear cells. Journal of Virology. 1991;65(7):3514–3520. [PMC free article] [PubMed]
49. Besnier C, Takeuchi Y, Towers G. Restriction of lentivirus in monkeys. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(18):11920–11925. [PubMed]
50. Cowan S, Hatziioannou T, Cunningham T, Muesing MA, Gottlinger HG, Bieniasz PD. Cellular inhibitors with Fv1-like activity restrict human and simian immunodeficiency virus tropism. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(18):11914–11919. [PubMed]
51. Münk C, Brandt SM, Lucero G, Landau NR. A dominant block to HIV-1 replication at reverse transcription in simian cells. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(21):13843–13848. [PubMed]
52. Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P, Sodroski J. The cytoplasmic body component TRIM5α restricts HIV-1 infection in old world monkeys. Nature. 2004;427(6977):848–853. [PubMed]
53. Nisole S, Lynch C, Stoye JP, Yap MW. A Trim5-cyclophilin A fusion protein found in owl monkey kidney cells can restrict HIV-1. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(36):13324–13328. [PubMed]
54. Stremlau M, Perron M, Welikala S, Sodroski J. Species-specific variation in the B30.2(SPRY) domain of TRIM5α determines the potency of human immunodeficiency virus restriction. Journal of Virology. 2005;79(5):3139–3145. [PMC free article] [PubMed]
55. Yap MW, Nisole S, Stoye JP. A single amino acid change in the SPRY domain of human Trim5α leads to HIV-1 restriction. Current Biology. 2005;15(1):73–78. [PubMed]
56. Battivelli E, Lecossier D, Matsuoka S, Migraine J, Clavel F, Hance AJ. Strain-specific differences in the impact of human TRIM5α, different TRIM5α alleles, and the inhibition of capsid-cyclophilin a interactions on the infectivity of HIV-1. Journal of Virology. 2010;84(21):11010–11019. [PMC free article] [PubMed]
57. Battivelli E, Migraine J, Lecossier D, Yeni P, Clavel F, Hance AJ. Gag cytotoxic T lymphocyte escape mutations can increase sensitivity of HIV-1 to human TRIM5alpha, linking intrinsic and acquired immunity. Journal of Virology. 2011;85:11846–11854. [PMC free article] [PubMed]
58. Sebastian S, Luban J. TRIM5α selectively binds a restriction-sensitive retroviral capsid. Retrovirology. 2005;2, article 40 [PMC free article] [PubMed]
59. Stremlau M, Perron M, Lee M, et al. Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5α restriction factor. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(14):5514–5519. [PubMed]
60. Ganser-Pornillos BK, Chandrasekaran V, Pornillos O, Sodroski JG, Sundquist WI, Yeager M. Hexagonal assembly of a restricting TRIM5alpha protein. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(2):534–539. [PubMed]
61. Byeon I-JL, Meng X, Jung J, et al. Structural convergence between Cryo-EM and NMR reveals intersubunit interactions critical for HIV-1 capsid function. Cell. 2009;139(4):780–790. [PMC free article] [PubMed]
62. Pornillos O, Ganser-Pornillos BK, Kelly BN, et al. X-ray structures of the hexameric building block of the hiv capsid. Cell. 2009;137(7):1282–1292. [PMC free article] [PubMed]
63. Pertel T, Hausmann S, Morger D, et al. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature. 2011;472(7343):361–365. [PMC free article] [PubMed]
64. Zhao G, Ke D, Vu T, et al. Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces. PLoS Pathogens. 2011;7(3) Article ID e1002009. [PMC free article] [PubMed]
65. Arriagada G, Muntean LN, Goff SP. SUMO-interacting motifs of human TRIM5α are important for antiviral activity. PLoS Pathogens. 2011;7(4) Article ID e1002019. [PMC free article] [PubMed]
66. Han K, Lou DI, Sawyer SL. Identification of a genomic reservoir for new trim genes in primate genomes. PLoS Genetics. 7 Article ID e1002388. [PMC free article] [PubMed]
67. Diaz-Griffero F, Qin X-R, Hayashi F, et al. A B-box 2 surface patch important for TRIM5α self-association, capsid binding avidity, and retrovirus restriction. Journal of Virology. 2009;83(20):10737–10751. [PMC free article] [PubMed]
68. Li X, Sodroski J. The TRIM5α B-box 2 domain promotes cooperative binding to the retroviral capsid by mediating higher-order self-association. Journal of Virology. 2008;82(23):11495–11502. [PMC free article] [PubMed]
69. Xu L, Yang L, Moitra PK, et al. BTBD1 and BTBD2 colocalize to cytoplasmic bodies with the RBCC/tripartite motif protein, TRIM5δ Experimental Cell Research. 2003;288(1):84–93. [PubMed]
70. Lienlaf M, Hayashi F, Di Nunzio F, et al. Contribution of E3-ubiquitin ligase activity to HIV-1 restriction by TRIM5alpha(rh): structure of the RING domain of TRIM5alpha. Journal of Virology. 2011;85:8725–8737. [PMC free article] [PubMed]
71. Diaz-Griffero F, Li X, Javanbakht H, et al. Rapid turnover and polyubiquitylation of the retroviral restriction factor TRIM5. Virology. 2006;349(2):300–315. [PubMed]
72. Rold CJ, Aiken C. Proteasomal degradation of TRIM5α during retrovirus restriction. PLoS Pathogens. 2008;4(5) Article ID e1000074. [PMC free article] [PubMed]
73. Lukic Z, Hausmann S, Sebastian S, et al. TRIM5alpha associates with proteasomal subunits in cells while in complex with HIV-1 virions. Retrovirology. 2011;8, article 93 [PMC free article] [PubMed]
74. O’Connor C, Pertel T, Gray S, et al. p62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5α Journal of Virology. 2010;84(12):5997–6006. [PMC free article] [PubMed]
75. Berthoux L, Sebastian S, Sokolskaja E, Luban J. Lv1 inhibition of human immunodeficiency virus type 1 is counteracted by factors that stimulate synthesis or nuclear translocation of viral cDNA. Journal of Virology. 2004;78(21):11739–11750. [PMC free article] [PubMed]
76. Roa A, Hayashi F, Yang Y, et al. Ring domain mutations uncouple TRIM5α restriction of HIV-1 from inhibition of reverse transcription and acceleration of uncoating. Journal of Virology. 2012;86:1717–1727. [PMC free article] [PubMed]
77. Wu X, Anderson JL, Campbell EM, Joseph AM, Hope TJ. Proteasome inhibitors uncouple rhesus TRIM5α restriction of HIV-1 reverse transcription and infection. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(19):7465–7470. [PubMed]
78. Allers K, Hütter G, Hofmann J, et al. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood. 2011;117(10):2791–2799. [PubMed]
79. Holt N, Wang J, Kim K, et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nature Biotechnology. 2010;28(8):839–847. [PMC free article] [PubMed]
80. Neagu MR, Ziegler P, Pertel T, et al. Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components. Journal of Clinical Investigation. 2009;119(10):3035–3047. [PMC free article] [PubMed]
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