Sequence and Functional Variation in the HIV-1 Rev Regulatory Axis

Author(s): Patrick E.H. Jackson*, Godfrey Dzhivhuho, David Rekosh, Marie-Louise Hammarskjold.

Journal Name: Current HIV Research

Volume 18 , Issue 2 , 2020

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Graphical Abstract:


Abstract:

Background: To complete its replication cycle, HIV-1 requires the nucleocytoplasmic export of intron-containing viral mRNAs. This process is ordinarily restricted by the cell, but HIV overcomes the block by means of a viral protein, Rev, and an RNA secondary structure found in all unspliced and incompletely spliced viral mRNAs called the Rev Response Element (RRE). In vivo activity of the Rev-RRE axis requires Rev binding to the RRE, oligomerization of Rev to form a competent ribonucleoprotein complex, and recruitment of cellular factors including Crm1 and RanGTP in order to export the targeted transcript. Sequence variability is observed among primary isolates in both Rev and the RRE, and the activity of both can be modulated through relatively small sequence changes. Primary isolates show differences in Rev-RRE activity and a few studies have found a correlation between lower Rev-RRE activity and slower progression of clinical disease. Lower Rev-RRE activity has also been associated with the evasion of cytotoxic T lymphocyte mediated killing.

Conclusion: The HIV-1 Rev-RRE regulatory axis is an understudied mechanism by which viral adaptation to diverse immune milieus may take place. There is evidence that this adaptation plays a role in HIV pathogenesis, particularly in immune evasion and latency, but further studies with larger sample sizes are warranted.

Keywords: HIV Rev, HIV Rev Response Element, HIV sequence variation, HIV latency, RNA splicing, post-transcriptional gene regulation.

[1]
Gallo R, Wong-Staal F, Montagnier L, Haseltine WA, Yoshida M. HIV/HTLV gene nomenclature. Nature 1988; 333(6173): 504.
[http://dx.doi.org/10.1038/333504a0] [PMID: 2836736]
[2]
Frankel AD, Young JA. HIV-1: fifteen proteins and an RNA. Annu Rev Biochem 1998; 67: 1-25.
[http://dx.doi.org/10.1146/annurev.biochem.67.1.1] [PMID: 9759480]
[3]
Hammarskjöld ML. Regulation of retroviral RNA export. Semin Cell Dev Biol 1997; 8(1): 83-90.
[http://dx.doi.org/10.1006/scdb.1996.0127] [PMID: 15001110]
[4]
Emery A, Zhou S, Pollom E, Swanstrom R. Characterizing HIV-1 Splicing by Using Next-Generation Sequencing. J Virol 2017; 91(6): e02515-6.
[http://dx.doi.org/10.1128/JVI.02515-16] [PMID: 28077653]
[5]
Purcell DF, Martin MA. Alternative splicing of human immunodeficiency virus type 1 mRNA modulates viral protein expression, replication, and infectivity. J Virol 1993; 67(11): 6365-78.
[PMID: 8411338]
[6]
Schwartz S, Felber BK, Benko DM, Fenyö EM, Pavlakis GN. Cloning and functional analysis of multiply spliced mRNA species of human immunodeficiency virus type 1. J Virol 1990; 64(6): 2519-29.
[PMID: 2335812]
[7]
Legrain P, Seraphin B, Rosbash M. Early commitment of yeast pre-mRNA to the spliceosome pathway. Mol Cell Biol 1988; 8(9): 3755-60.
[http://dx.doi.org/10.1128/MCB.8.9.3755] [PMID: 3065622]
[8]
Reed R, Hurt E. A conserved mRNA export machinery coupled to pre-mRNA splicing. Cell 2002; 108(4): 523-31.
[http://dx.doi.org/10.1016/S0092-8674(02)00627-X] [PMID: 11909523]
[9]
Erkmann JA, Kutay U. Nuclear export of mRNA: from the site of transcription to the cytoplasm. Exp Cell Res 2004; 296(1): 12-20.
[http://dx.doi.org/10.1016/j.yexcr.2004.03.015] [PMID: 15120988]
[10]
Rekosh D, Hammarskjold ML. Intron retention in viruses and cellular genes: Detention, border controls and passports. Wiley Interdiscip Rev RNA 2018; 9(3): e1470
[http://dx.doi.org/10.1002/wrna.1470] [PMID: 29508942]
[11]
Liu H, Luo M, Wen JK. mRNA stability in the nucleus. J Zhejiang Univ Sci B 2014; 15(5): 444-54.
[http://dx.doi.org/10.1631/jzus.B1400088] [PMID: 24793762]
[12]
Terribilini M, Lee JH, Yan C, et al. Identifying interaction sites in “recalcitrant” proteins: predicted protein and RNA binding sites in rev proteins of HIV-1 and EIAV agree with experimental data. Pac Symp Biocomput 2006; 415-26.
[PMID: 17094257]
[13]
LeBlanc JJ, Uddowla S, Abraham B, Clatterbuck S, Beemon KL. Tap and Dbp5, but not Gag, are involved in DR-mediated nuclear export of unspliced Rous sarcoma virus RNA. Virology 2007; 363(2): 376-86.
[http://dx.doi.org/10.1016/j.virol.2007.01.026] [PMID: 17328934]
[14]
Bray M, Prasad S, Dubay JW, et al. A small element from the Mason-Pfizer monkey virus genome makes human immunodeficiency virus type 1 expression and replication Rev-independent. Proc Natl Acad Sci USA 1994; 91(4): 1256-60.
[http://dx.doi.org/10.1073/pnas.91.4.1256] [PMID: 8108397]
[15]
Grüter P, Tabernero C, von Kobbe C, et al. TAP, the human homolog of Mex67p, mediates CTE-dependent RNA export from the nucleus. Mol Cell 1998; 1(5): 649-59.
[http://dx.doi.org/10.1016/S1097-2765(00)80065-9] [PMID: 9660949]
[16]
Li Y, Bor YC, Fitzgerald MP, Lee KS, Rekosh D, Hammarskjold ML. An NXF1 mRNA with a retained intron is expressed in hippocampal and neocortical neurons and is translated into a protein that functions as an Nxf1 cofactor. Mol Biol Cell 2016; 27(24): 3903-12.
[http://dx.doi.org/10.1091/mbc.E16-07-0515] [PMID: 27708137]
[17]
Li Y, Bor YC, Misawa Y, Xue Y, Rekosh D, Hammarskjöld ML. An intron with a constitutive transport element is retained in a Tap messenger RNA. Nature 2006; 443(7108): 234-7.
[http://dx.doi.org/10.1038/nature05107] [PMID: 16971948]
[18]
Wang B, Rekosh D, Hammarskjold ML. Evolutionary conservation of a molecular machinery for export and expression of mRNAs with retained introns. RNA 2015; 21(3): 426-37.
[http://dx.doi.org/10.1261/rna.048520.114] [PMID: 25605961]
[19]
Bor YC, Swartz J, Morrison A, Rekosh D, Ladomery M, Hammarskjöld ML. The Wilms’ tumor 1 (WT1) gene (+KTS isoform) functions with a CTE to enhance translation from an unspliced RNA with a retained intron. Genes Dev 2006; 20(12): 1597-608.
[http://dx.doi.org/10.1101/gad.1402306] [PMID: 16738405]
[20]
Zolotukhin AS, Valentin A, Pavlakis GN, Felber BK. Continuous propagation of RRE(-) and Rev(-)RRE(-) human immunodeficiency virus type 1 molecular clones containing a cis-acting element of simian retrovirus type 1 in human peripheral blood lymphocytes. J Virol 1994; 68(12): 7944-52.
[PMID: 7966585]
[21]
Ogert RA, Beemon KL, Eds. Identification of a constitutive transport element in the 3′ untranslated region of the Rous Sarcoma virus RNA Retroviruses. Cold Spring Harbor: Cold Springs Harbor Laboratory 1995.
[22]
Pessel-Vivares L, Ferrer M, Lainé S, Mougel M. MLV requires Tap/NXF1-dependent pathway to export its unspliced RNA to the cytoplasm and to express both spliced and unspliced RNAs. Retrovirology 2014; 11: 21.
[http://dx.doi.org/10.1186/1742-4690-11-21] [PMID: 24597485]
[23]
Sakuma T, Davila JI, Malcolm JA, Kocher JP, Tonne JM, Ikeda Y. Murine leukemia virus uses NXF1 for nuclear export of spliced and unspliced viral transcripts. J Virol 2014; 88(8): 4069-82.
[http://dx.doi.org/10.1128/JVI.03584-13] [PMID: 24478440]
[24]
Sodroski J, Goh WC, Rosen C, Dayton A, Terwilliger E, Haseltine W. A second post-transcriptional trans-activator gene required for HTLV-III replication. Nature 1986; 321(6068): 412-7.
[http://dx.doi.org/10.1038/321412a0] [PMID: 3012355]
[25]
Malim MH, Hauber J, Le SY, Maizel JV, Cullen BR. The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA. Nature 1989; 338(6212): 254-7.
[http://dx.doi.org/10.1038/338254a0] [PMID: 2784194]
[26]
Hadzopoulou-Cladaras M, Felber BK, Cladaras C, Athanassopoulos A, Tse A, Pavlakis GN. The rev (trs/art) protein of human immunodeficiency virus type 1 affects viral mRNA and protein expression via a cis-acting sequence in the env region. J Virol 1989; 63(3): 1265-74.
[PMID: 2783738]
[27]
Hammarskjöld ML, Heimer J, Hammarskjöld B, Sangwan I, Albert L, Rekosh D. Regulation of human immunodeficiency virus env expression by the rev gene product. J Virol 1989; 63(5): 1959-66.
[PMID: 2704072]
[28]
Cullen BR. Nuclear mRNA export: insights from virology. Trends Biochem Sci 2003; 28(8): 419-24.
[http://dx.doi.org/10.1016/S0968-0004(03)00142-7] [PMID: 12932730]
[29]
Sadaie MR, Benter T, Wong-Staal F. Site-directed mutagenesis of two trans-regulatory genes (tat-III,trs) of HIV-1. Science 1988; 239(4842): 910-3.
[http://dx.doi.org/10.1126/science.3277284] [PMID: 3277284]
[30]
Pollard VW, Malim MH. The HIV-1 Rev protein. Annu Rev Microbiol 1998; 52: 491-532.
[http://dx.doi.org/10.1146/annurev.micro.52.1.491] [PMID: 9891806]
[31]
Daly TJ, Cook KS, Gray GS, Maione TE, Rusche JR. Specific binding of HIV-1 recombinant Rev protein to the Rev-responsive element in vitro. Nature 1989; 342(6251): 816-9.
[http://dx.doi.org/10.1038/342816a0] [PMID: 2481237]
[32]
Daefler S, Klotman ME, Wong-Staal F. Trans-activating rev protein of the human immunodeficiency virus 1 interacts directly and specifically with its target RNA. Proc Natl Acad Sci USA 1990; 87(12): 4571-5.
[http://dx.doi.org/10.1073/pnas.87.12.4571] [PMID: 2191294]
[33]
Heaphy S, Dingwall C, Ernberg I, et al. HIV-1 regulator of virion expression (Rev) protein binds to an RNA stem-loop structure located within the Rev response element region. Cell 1990; 60(4): 685-93.
[http://dx.doi.org/10.1016/0092-8674(90)90671-Z] [PMID: 1689218]
[34]
Holland SM, Ahmad N, Maitra RK, Wingfield P, Venkatesan S. Human immunodeficiency virus rev protein recognizes a target sequence in rev-responsive element RNA within the context of RNA secondary structure. J Virol 1990; 64(12): 5966-75.
[PMID: 2243382]
[35]
Fernandes J, Jayaraman B, Frankel A. The HIV-1 Rev response element: an RNA scaffold that directs the cooperative assembly of a homo-oligomeric ribonucleoprotein complex. RNA Biol 2012; 9(1): 6-11.
[http://dx.doi.org/10.4161/rna.9.1.18178] [PMID: 22258145]
[36]
Fernandes JD, Booth DS, Frankel AD. A structurally plastic ribonucleoprotein complex mediates post-transcriptional gene regulation in HIV-1. Wiley Interdiscip Rev RNA 2016; 7(4): 470-86.
[http://dx.doi.org/10.1002/wrna.1342] [PMID: 26929078]
[37]
Hope TJ. The ins and outs of HIV Rev. Arch Biochem Biophys 1999; 365(2): 186-91.
[http://dx.doi.org/10.1006/abbi.1999.1207] [PMID: 10328811]
[38]
Henderson BR, Percipalle P. Interactions between HIV Rev and nuclear import and export factors: the Rev nuclear localisation signal mediates specific binding to human importin-beta. J Mol Biol 1997; 274(5): 693-707.
[http://dx.doi.org/10.1006/jmbi.1997.1420] [PMID: 9405152]
[39]
Fornerod M, Ohno M, Yoshida M, Mattaj IW. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 1997; 90(6): 1051-60.
[http://dx.doi.org/10.1016/S0092-8674(00)80371-2] [PMID: 9323133]
[40]
Neville M, Stutz F, Lee L, Davis LI, Rosbash M. The importin-beta family member Crm1p bridges the interaction between Rev and the nuclear pore complex during nuclear export. Curr Biol 1997; 7(10): 767-75.
[http://dx.doi.org/10.1016/S0960-9822(06)00335-6] [PMID: 9368759]
[41]
Ossareh-Nazari B, Bachelerie F, Dargemont C. Evidence for a role of CRM1 in signal-mediated nuclear protein export. Science 1997; 278(5335): 141-4.
[http://dx.doi.org/10.1126/science.278.5335.141] [PMID: 9311922]
[42]
Fukuda M, Asano S, Nakamura T, et al. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature 1997; 390(6657): 308-11.
[http://dx.doi.org/10.1038/36894] [PMID: 9384386]
[43]
Karn J, Stoltzfus CM. Transcriptional and posttranscriptional regulation of HIV-1 gene expression. Cold Spring Harb Perspect Med 2012; 2(2): a006916
[http://dx.doi.org/10.1101/cshperspect.a006916] [PMID: 22355797]
[44]
Daelemans D, Costes SV, Lockett S, Pavlakis GN. Kinetic and molecular analysis of nuclear export factor CRM1 association with its cargo in vivo. Mol Cell Biol 2005; 25(2): 728-39.
[http://dx.doi.org/10.1128/MCB.25.2.728-739.2005] [PMID: 15632073]
[45]
Askjaer P, Jensen TH, Nilsson J, Englmeier L, Kjems J. The specificity of the CRM1-Rev nuclear export signal interaction is mediated by RanGTP. J Biol Chem 1998; 273(50): 33414-22.
[http://dx.doi.org/10.1074/jbc.273.50.33414] [PMID: 9837918]
[46]
Dlamini Z, Hull R. Can the HIV-1 splicing machinery be targeted for drug discovery? HIV AIDS (Auckl) 2017; 9: 63-75.
[http://dx.doi.org/10.2147/HIV.S120576] [PMID: 28331370]
[47]
Rausch JW, Le Grice SF. HIV Rev Assembly on the Rev Response Element (RRE): A Structural Perspective. Viruses 2015; 7(6): 3053-75.
[http://dx.doi.org/10.3390/v7062760] [PMID: 26075509]
[48]
Malim MH, Tiley LS, McCarn DF, Rusche JR, Hauber J, Cullen BR. HIV-1 structural gene expression requires binding of the Rev trans-activator to its RNA target sequence. Cell 1990; 60(4): 675-83.
[http://dx.doi.org/10.1016/0092-8674(90)90670-A] [PMID: 2406030]
[49]
Smith AJ, Cho MI, Hammarskjöld ML, Rekosh D. Human immunodeficiency virus type 1 Pr55gag and Pr160gag-pol expressed from a simian virus 40 late replacement vector are efficiently processed and assembled into viruslike particles. J Virol 1990; 64(6): 2743-50.
[PMID: 1692347]
[50]
Watts NR, Eren E, Zhuang X, Wang YX, Steven AC, Wingfield PT. A new HIV-1 Rev structure optimizes interaction with target RNA (RRE) for nuclear export. J Struct Biol 2018; 203(2): 102-8.
[http://dx.doi.org/10.1016/j.jsb.2018.03.011] [PMID: 29605570]
[51]
Cochrane A. HIV-1 Rev function and RNA nuclear-cytoplasmic export. Methods Mol Biol 2014; 1087: 103-14.
[http://dx.doi.org/10.1007/978-1-62703-670-2_9] [PMID: 24158817]
[52]
Swenarchuk L, Harakidas P, Cochrane A. Regulated expression of HIV-1 Rev function in mammalian cell lines. Can J Microbiol 1999; 45(6): 480-90.
[http://dx.doi.org/10.1139/w99-011] [PMID: 10453476]
[53]
Booth DS, Cheng Y, Frankel AD. The export receptor Crm1 forms a dimer to promote nuclear export of HIV RNA. eLife 2014; 3e04121.
[http://dx.doi.org/10.7554/eLife.04121] [PMID: 25486595]
[54]
Yue Y, Coskun AK, Jawanda N, Auer J, Sutton RE. Differential interaction between human and murine Crm1 and lentiviral Rev proteins. Virology 2018; 513: 1-10.
[http://dx.doi.org/10.1016/j.virol.2017.09.027] [PMID: 29028476]
[55]
Jayaraman B, Fernandes JD, Yang S, Smith C, Frankel AD. Highly Mutable Linker Regions Regulate HIV-1 Rev Function and Stability. Sci Rep 2019; 9(1): 5139.
[http://dx.doi.org/10.1038/s41598-019-41582-7] [PMID: 30914719]
[56]
Kjems J, Frankel AD, Sharp PA. Specific regulation of mRNA splicing in vitro by a peptide from HIV-1 Rev. Cell 1991; 67(1): 169-78.
[http://dx.doi.org/10.1016/0092-8674(91)90580-R] [PMID: 1913815]
[57]
Battiste JL, Mao H, Rao NS, et al. Alpha helix-RNA major groove recognition in an HIV-1 rev peptide-RRE RNA complex. Science 1996; 273(5281): 1547-51.
[http://dx.doi.org/10.1126/science.273.5281.1547] [PMID: 8703216]
[58]
Jain C, Belasco JG. Structural model for the cooperative assembly of HIV-1 Rev multimers on the RRE as deduced from analysis of assembly-defective mutants. Mol Cell 2001; 7(3): 603-14.
[http://dx.doi.org/10.1016/S1097-2765(01)00207-6] [PMID: 11463385]
[59]
Fischer U, Huber J, Boelens WC, Mattaj IW, Lührmann R. The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell 1995; 82(3): 475-83.
[http://dx.doi.org/10.1016/0092-8674(95)90436-0] [PMID: 7543368]
[60]
Mann DA, Mikaélian I, Zemmel RW, et al. A molecular rheostat. Co-operative rev binding to stem I of the rev-response element modulates human immunodeficiency virus type-1 late gene expression. J Mol Biol 1994; 241(2): 193-207.
[http://dx.doi.org/10.1006/jmbi.1994.1488] [PMID: 8057359]
[61]
Daugherty MD, D’Orso I, Frankel AD. A solution to limited genomic capacity: using adaptable binding surfaces to assemble the functional HIV Rev oligomer on RNA. Mol Cell 2008; 31(6): 824-34.
[http://dx.doi.org/10.1016/j.molcel.2008.07.016] [PMID: 18922466]
[62]
Sherpa C, Rausch JW, Le Grice SF, Hammarskjold ML, Rekosh D. The HIV-1 Rev response element (RRE) adopts alternative conformations that promote different rates of virus replication. Nucleic Acids Res 2015; 43(9): 4676-86.
[http://dx.doi.org/10.1093/nar/gkv313] [PMID: 25855816]
[63]
Lusvarghi S, Sztuba-Solinska J, Purzycka KJ, Pauly GT, Rausch JW, Grice SF. The HIV-2 Rev-response element: determining secondary structure and defining folding intermediates. Nucleic Acids Res 2013; 41(13): 6637-49.
[http://dx.doi.org/10.1093/nar/gkt353] [PMID: 23640333]
[64]
O’Carroll IP, Thappeta Y, Fan L, et al. Contributions of Individual Domains to Function of the HIV-1 Rev Response Element. J Virol 2017; 91(21): e00746-17.
[http://dx.doi.org/10.1128/JVI.00746-17] [PMID: 28814520]
[65]
Fang X, Wang J, O’Carroll IP, et al. An unusual topological structure of the HIV-1 Rev response element. Cell 2013; 155(3): 594-605.
[http://dx.doi.org/10.1016/j.cell.2013.10.008] [PMID: 24243017]
[66]
Jayaraman B, Crosby DC, Homer C, Ribeiro I, Mavor D, Frankel AD. RNA-directed remodeling of the HIV-1 protein Rev orchestrates assembly of the Rev-Rev response element complex. eLife 2014; 3: e04120
[http://dx.doi.org/10.7554/eLife.04120] [PMID: 25486594]
[67]
DiMattia MA, Watts NR, Cheng N, et al. The Structure of HIV-1 Rev Filaments Suggests a Bilateral Model for Rev-RRE Assembly. Structure 2016; 24(7): 1068-80.
[http://dx.doi.org/10.1016/j.str.2016.04.015] [PMID: 27265851]
[68]
Jayaraman B, Mavor D, Gross JD, Frankel AD. Thermodynamics of Rev-RNA interactions in HIV-1 Rev-RRE assembly. Biochemistry 2015; 54(42): 6545-54.
[http://dx.doi.org/10.1021/acs.biochem.5b00876] [PMID: 26422686]
[69]
Tanamura S, Terakado H, Harada K. Cooperative dimerization of a stably folded protein directed by a flexible RNA in the assembly of the HIV Rev dimer-RRE stem II complex. J Mol Recognit 2016; 29(5): 199-209.
[http://dx.doi.org/10.1002/jmr.2518] [PMID: 26620599]
[70]
Malim MH, Cullen BR. HIV-1 structural gene expression requires the binding of multiple Rev monomers to the viral RRE: implications for HIV-1 latency. Cell 1991; 65(2): 241-8.
[http://dx.doi.org/10.1016/0092-8674(91)90158-U] [PMID: 2015625]
[71]
Heaphy S, Finch JT, Gait MJ, Karn J, Singh M. Human immunodeficiency virus type 1 regulator of virion expression, rev, forms nucleoprotein filaments after binding to a purine-rich “bubble” located within the rev-responsive region of viral mRNAs. Proc Natl Acad Sci USA 1991; 88(16): 7366-70.
[http://dx.doi.org/10.1073/pnas.88.16.7366] [PMID: 1871141]
[72]
Iwai S, Pritchard C, Mann DA, Karn J, Gait MJ. Recognition of the high affinity binding site in rev-response element RNA by the human immunodeficiency virus type-1 rev protein. Nucleic Acids Res 1992; 20(24): 6465-72.
[http://dx.doi.org/10.1093/nar/20.24.6465] [PMID: 1282702]
[73]
Hammarskjold MH, Rekosh D. A long-awaited structure is rev-ealed. Viruses 2011; 3(5): 484-92.
[http://dx.doi.org/10.3390/v3050484] [PMID: 21941623]
[74]
Daugherty MD, Booth DS, Jayaraman B, Cheng Y, Frankel AD. HIV Rev response element (RRE) directs assembly of the Rev homooligomer into discrete asymmetric complexes. Proc Natl Acad Sci USA 2010; 107(28): 12481-6.
[http://dx.doi.org/10.1073/pnas.1007022107] [PMID: 20616058]
[75]
Kjems J, Brown M, Chang DD, Sharp PA. Structural analysis of the interaction between the human immunodeficiency virus Rev protein and the Rev response element. Proc Natl Acad Sci USA 1991; 88(3): 683-7.
[http://dx.doi.org/10.1073/pnas.88.3.683] [PMID: 1992459]
[76]
Bai Y, Tambe A, Zhou K, Doudna JA. RNA-guided assembly of Rev-RRE nuclear export complexes. eLife 2014; 3: e03656
[http://dx.doi.org/10.7554/eLife.03656] [PMID: 25163983]
[77]
Pond SJ, Ridgeway WK, Robertson R, Wang J, Millar DP. HIV-1 Rev protein assembles on viral RNA one molecule at a time. Proc Natl Acad Sci USA 2009; 106(5): 1404-8.
[http://dx.doi.org/10.1073/pnas.0807388106] [PMID: 19164515]
[78]
Zapp ML, Hope TJ, Parslow TG, Green MR. Oligomerization and RNA binding domains of the type 1 human immunodeficiency virus Rev protein: a dual function for an arginine-rich binding motif. Proc Natl Acad Sci USA 1991; 88(17): 7734-8.
[http://dx.doi.org/10.1073/pnas.88.17.7734] [PMID: 1715576]
[79]
Stade K, Ford CS, Guthrie C, Weis K. Exportin 1 (Crm1p) is an essential nuclear export factor. Cell 1997; 90(6): 1041-50.
[http://dx.doi.org/10.1016/S0092-8674(00)80370-0] [PMID: 9323132]
[80]
Sherer NM, Swanson CM, Hué S, Roberts RG, Bergeron JR, Malim MH. Evolution of a species-specific determinant within human CRM1 that regulates the post-transcriptional phases of HIV-1 replication. PLoS Pathog 2011; 7(11): e1002395
[http://dx.doi.org/10.1371/journal.ppat.1002395] [PMID: 22114565]
[81]
Daugherty MD, Liu B, Frankel AD. Structural basis for cooperative RNA binding and export complex assembly by HIV Rev. Nat Struct Mol Biol 2010; 17(11): 1337-42.
[http://dx.doi.org/10.1038/nsmb.1902] [PMID: 20953181]
[82]
Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL. eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol 2006; 175(3): 415-26.
[http://dx.doi.org/10.1083/jcb.200607020] [PMID: 17074885]
[83]
Siddiqui N, Borden KL. mRNA export and cancer. Wiley Interdiscip Rev RNA 2012; 3(1): 13-25.
[http://dx.doi.org/10.1002/wrna.101] [PMID: 21796793]
[84]
Fries B, Heukeshoven J, Hauber I, et al. Analysis of nucleocytoplasmic trafficking of the HuR ligand APRIL and its influence on CD83 expression. J Biol Chem 2007; 282(7): 4504-15.
[http://dx.doi.org/10.1074/jbc.M608849200] [PMID: 17178712]
[85]
Kimura T, Hashimoto I, Nagase T, Fujisawa J. CRM1-dependent, but not ARE-mediated, nuclear export of IFN-alpha1 mRNA. J Cell Sci 2004; 117(Pt 11): 2259-70.
[http://dx.doi.org/10.1242/jcs.01076] [PMID: 15126627]
[86]
Schütz S, Chemnitz J, Spillner C, Frohme M, Hauber J, Kehlenbach RH. Stimulated expression of mRNAs in activated T cells depends on a functional CRM1 nuclear export pathway. J Mol Biol 2006; 358(4): 997-1009.
[http://dx.doi.org/10.1016/j.jmb.2006.02.041] [PMID: 16580684]
[87]
Groom HC, Anderson EC, Lever AM. Rev: beyond nuclear export. J Gen Virol 2009; 90(Pt 6): 1303-18.
[http://dx.doi.org/10.1099/vir.0.011460-0] [PMID: 19321757]
[88]
Arrigo SJ, Chen IS. Rev is necessary for translation but not cytoplasmic accumulation of HIV-1 vif, vpr, and env/vpu 2 RNAs. Genes Dev 1991; 5(5): 808-19.
[http://dx.doi.org/10.1101/gad.5.5.808] [PMID: 1827422]
[89]
Jin L, Guzik BW, Bor YC, Rekosh D, Hammarskjöld ML. Tap and NXT promote translation of unspliced mRNA. Genes Dev 2003; 17(24): 3075-86.
[http://dx.doi.org/10.1101/gad.1155703] [PMID: 14701875]
[90]
Coyle JH, Guzik BW, Bor Y-C, et al. Sam68 enhances the cytoplasmic utilization of intron-containing RNA and is functionally regulated by the nuclear kinase Sik/BRK. Mol Cell Biol 2003; 23(1): 92-103.
[http://dx.doi.org/10.1128/MCB.23.1.92-103.2003] [PMID: 12482964]
[91]
D’Agostino DM, Felber BK, Harrison JE, Pavlakis GN. The Rev protein of human immunodeficiency virus type 1 promotes polysomal association and translation of gag/pol and vpu/env mRNAs. Mol Cell Biol 1992; 12(3): 1375-86.
[http://dx.doi.org/10.1128/MCB.12.3.1375] [PMID: 1545819]
[92]
Kimura T, Hashimoto I, Nishikawa M, Fujisawa JI. A role for Rev in the association of HIV-1 gag mRNA with cytoskeletal β-actin and viral protein expression. Biochimie 1996; 78(11-12): 1075-80.
[http://dx.doi.org/10.1016/S0300-9084(97)86732-6] [PMID: 9150887]
[93]
Brandt S, Blissenbach M, Grewe B, Konietzny R, Grunwald T, Uberla K. Rev proteins of human and simian immunodeficiency virus enhance RNA encapsidation. PLoS Pathog 2007; 3(4): e54
[http://dx.doi.org/10.1371/journal.ppat.0030054] [PMID: 17432934]
[94]
Blissenbach M, Grewe B, Hoffmann B, Brandt S, Uberla K. Nuclear RNA export and packaging functions of HIV-1 Rev revisited. J Virol 2010; 84(13): 6598-604.
[http://dx.doi.org/10.1128/JVI.02264-09] [PMID: 20427541]
[95]
Moore MD, Nikolaitchik OA, Chen J, Hammarskjöld M-L, Rekosh D, Hu W-S. Probing the HIV-1 genomic RNA trafficking pathway and dimerization by genetic recombination and single virion analyses. PLoS Pathog 2009; 5(10): e1000627
[http://dx.doi.org/10.1371/journal.ppat.1000627] [PMID: 19834549]
[96]
Daniels RS, Smith MH, Fisher AG. Molecular characterization of biologically diverse envelope variants of human immunodeficiency virus type 1 derived from an individual. J Virol 1991; 65(10): 5574-8.
[PMID: 1895406]
[97]
Li G, Piampongsant S, Faria NR, et al. An integrated map of HIV genome-wide variation from a population perspective. Retrovirology 2015; 12: 18.
[http://dx.doi.org/10.1186/s12977-015-0148-6] [PMID: 25808207]
[98]
Mansky LM, Temin HM. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 1995; 69(8): 5087-94.
[PMID: 7541846]
[99]
Cuevas JM, Geller R, Garijo R, López-Aldeguer J, Sanjuán R. Extremely High Mutation Rate of HIV-1 In Vivo. PLoS Biol 2015; 13(9): e1002251
[http://dx.doi.org/10.1371/journal.pbio.1002251] [PMID: 26375597]
[100]
Yu Q, König R, Pillai S, et al. Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome. Nat Struct Mol Biol 2004; 11(5): 435-42.
[http://dx.doi.org/10.1038/nsmb758] [PMID: 15098018]
[101]
Biswas N, Wang T, Ding M, et al. ADAR1 is a novel multi targeted anti-HIV-1 cellular protein. Virology 2012; 422(2): 265-77.
[http://dx.doi.org/10.1016/j.virol.2011.10.024] [PMID: 22104209]
[102]
Rossenkhan R, Novitsky V, Sebunya TK, Musonda R, Gashe BA, Essex M. Viral diversity and diversification of major non-structural genes vif, vpr, vpu, tat exon 1 and rev exon 1 during primary HIV-1 subtype C infection. PLoS One 2012; 7(5): e35491
[http://dx.doi.org/10.1371/journal.pone.0035491] [PMID: 22590503]
[103]
Ramakrishnan R, Hussain M, Holzer A, Mehta R, Sundaravaradan V, Ahmad N. Evaluations of HIV type 1 rev gene diversity and functional domains following perinatal transmission. AIDS Res Hum Retroviruses 2005; 21(12): 1035-45.
[http://dx.doi.org/10.1089/aid.2005.21.1035] [PMID: 16379607]
[104]
Guillon C, Stankovic K, Ataman-Onal Y, Biron F, Verrier B. Evidence for CTL-mediated selection of Tat and Rev mutants after the onset of the asymptomatic period during HIV type 1 infection. AIDS Res Hum Retroviruses 2006; 22(12): 1283-92.
[http://dx.doi.org/10.1089/aid.2006.22.1283] [PMID: 17209772]
[105]
Salazar-Gonzalez JF, Bailes E, Pham KT, et al. Deciphering human immunodeficiency virus type 1 transmission and early envelope diversification by single-genome amplification and sequencing. J Virol 2008; 82(8): 3952-70.
[http://dx.doi.org/10.1128/JVI.02660-07] [PMID: 18256145]
[106]
Fernandes JD, Faust TB, Strauli NB, et al. Functional Segregation of Overlapping Genes in HIV. Cell 2016; 167(7): 1762-73.
[http://dx.doi.org/10.1016/j.cell.2016.11.031]
[107]
Martins LP, Chenciner N, Asjö B, Meyerhans A, Wain-Hobson S. Independent fluctuation of human immunodeficiency virus type 1 rev and gp41 quasispecies in vivo. J Virol 1991; 65(8): 4502-7.
[PMID: 2072461]
[108]
Phuphuakrat A, Auewarakul P. Heterogeneity of HIV-1 Rev response element. AIDS Res Hum Retroviruses 2003; 19(7): 569-74.
[http://dx.doi.org/10.1089/088922203322230932] [PMID: 12908934]
[109]
Ramakrishnan R, Ahmad N. Derivation of primary sequences and secondary structures of rev responsive element from HIV-1 infected mothers and infants following vertical transmission. Virology 2007; 359(1): 201-11.
[http://dx.doi.org/10.1016/j.virol.2006.09.003] [PMID: 17045321]
[110]
Dayton ET, Konings DA, Powell DM, et al. Extensive sequence-specific information throughout the CAR/RRE, the target sequence of the human immunodeficiency virus type 1 Rev protein. J Virol 1992; 66(2): 1139-51.
[PMID: 1731093]
[111]
Werstuck G, Zapp ML, Green MR. A non-canonical base pair within the human immunodeficiency virus rev-responsive element is involved in both rev and small molecule recognition. Chem Biol 1996; 3(2): 129-37.
[http://dx.doi.org/10.1016/S1074-5521(96)90289-6] [PMID: 8807838]
[112]
Aoyama S, Sugaya M, Kobayashi C, Masuda K, Maeda T, Sakamoto T, et al. An isostructural G-G to A-A substitution within the HIV RRE RNA switches the specificity towards arginine-rich peptides. Nucleic Acids Symp Ser (Oxf) 2009; 53: 271-2.
[http://dx.doi.org/10.1093/nass/nrp136]
[113]
Sugaya M, Nishimura F, Katoh A, Harada K. Tailoring the peptide-binding specificity of an RNA by combinations of specificity-altering mutations. Nucleosides Nucleotides Nucleic Acids 2008; 27(5): 534-45.
[http://dx.doi.org/10.1080/15257770801944493] [PMID: 18569791]
[114]
Iwazaki T, Li X, Harada K. Evolvability of the mode of peptide binding by an RNA. RNA 2005; 11(9): 1364-73.
[http://dx.doi.org/10.1261/rna.2560905] [PMID: 16043495]
[115]
Harada K, Sugaya M, Nishimura F, Katoh A. Manipulation of the peptide-binding specificity of an RNA in a rational manner by combinations of specificity-altering mutations. Nucleic Acids Symp Ser (Oxf) 2008; 52: 13-4.
[http://dx.doi.org/10.1093/nass/nrn007]
[116]
Abdallah EY, Smith CA. Diverse mutants of HIV RRE IIB recognize wild-type Rev ARM or Rev ARM R35G-N40V. J Mol Recognit 2015; 28(12): 710-21.
[http://dx.doi.org/10.1002/jmr.2485] [PMID: 26130028]
[117]
Harada K, Iwazaki T, Li X, Yuda A, Kobayashi K. The variability of the peptide-binding specificity of RNA. Nucleic Acids Res Suppl 2003; 3: 201-2.
[http://dx.doi.org/10.1093/nass/3.1.201]
[118]
Chu CC, Plangger R, Kreutz C, Al-Hashimi HM. Dynamic ensemble of HIV-1 RRE stem IIB reveals non-native conformations that disrupt the Rev-binding site. Nucleic Acids Res 2019; 47(13): 7105-17.
[http://dx.doi.org/10.1093/nar/gkz498] [PMID: 31199872]
[119]
Lichinchi G, Gao S, Saletore Y, et al. Dynamics of the human and viral m(6)A RNA methylomes during HIV-1 infection of T cells. Nat Microbiol 2016; 1: 16011.
[http://dx.doi.org/10.1038/nmicrobiol.2016.11] [PMID: 27572442]
[120]
Kennedy EM, Bogerd HP, Kornepati AV, et al. Posttranscriptional m6A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe 2016; 19(5): 675-85.
[http://dx.doi.org/10.1016/j.chom.2016.04.002] [PMID: 27117054]
[121]
Tirumuru N, Zhao BS, Lu W, Lu Z, He C, Wu LN. (6)-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression. eLife 2016; 5e: 15528.
[http://dx.doi.org/10.7554/eLife.15528] [PMID: 27371828]
[122]
Sherpa C, Jackson PEH, Gray LR, et al. Evolution of the HIV-1 Rev Response Element during Natural Infection Reveals Nucleotide Changes That Correlate with Altered Structure and Increased Activity over Time. J Virol 2019; 93(11): e02102-18.
[http://dx.doi.org/10.1128/JVI.02102-18] [PMID: 30867301]
[123]
Sloan EA, Kearney MF, Gray LR, et al. Limited nucleotide changes in the Rev response element (RRE) during HIV-1 infection alter overall Rev-RRE activity and Rev multimerization. J Virol 2013; 87(20): 11173-86.
[http://dx.doi.org/10.1128/JVI.01392-13] [PMID: 23926352]
[124]
Malim MH, Böhnlein S, Hauber J, Cullen BR. Functional dissection of the HIV-1 Rev trans-activator--derivation of a trans-dominant repressor of Rev function. Cell 1989; 58(1): 205-14.
[http://dx.doi.org/10.1016/0092-8674(89)90416-9] [PMID: 2752419]
[125]
Woffendin C, Ranga U, Yang Z, Xu L, Nabel GJ. Expression of a protective gene-prolongs survival of T cells in human immunodeficiency virus-infected patients. Proc Natl Acad Sci USA 1996; 93(7): 2889-94.
[http://dx.doi.org/10.1073/pnas.93.7.2889] [PMID: 8610137]
[126]
Ranga U, Woffendin C, Verma S, et al. Enhanced T cell engraftment after retroviral delivery of an antiviral gene in HIV-infected individuals. Proc Natl Acad Sci USA 1998; 95(3): 1201-6.
[http://dx.doi.org/10.1073/pnas.95.3.1201] [PMID: 9448309]
[127]
Hamm TE, Rekosh D, Hammarskjöld ML. Selection and characterization of human immunodeficiency virus type 1 mutants that are resistant to inhibition by the transdominant negative RevM10 protein. J Virol 1999; 73(7): 5741-7.
[PMID: 10364325]
[128]
Legiewicz M, Badorrek CS, Turner KB, et al. Resistance to RevM10 inhibition reflects a conformational switch in the HIV-1 Rev response element. Proc Natl Acad Sci USA 2008; 105(38): 14365-70.
[http://dx.doi.org/10.1073/pnas.0804461105] [PMID: 18776047]
[129]
Jiang S, Zhao Q, Debnath AK. Peptide and non-peptide HIV fusion inhibitors. Curr Pharm Des 2002; 8(8): 563-80.
[http://dx.doi.org/10.2174/1381612024607180] [PMID: 11945159]
[130]
Nameki D, Kodama E, Ikeuchi M, et al. Mutations conferring resistance to human immunodeficiency virus type 1 fusion inhibitors are restricted by gp41 and Rev-responsive element functions. J Virol 2005; 79(2): 764-70.
[http://dx.doi.org/10.1128/JVI.79.2.764-770.2005] [PMID: 15613304]
[131]
Ueno M, Kodama EN, Shimura K, et al. Synonymous mutations in stem-loop III of Rev responsive elements enhance HIV-1 replication impaired by primary mutations for resistance to enfuvirtide. Antiviral Res 2009; 82(1): 67-72.
[http://dx.doi.org/10.1016/j.antiviral.2009.02.002] [PMID: 19428597]
[132]
Possik EJ, Bou Sleiman MS, Ghattas IR, Smith CA. Randomized codon mutagenesis reveals that the HIV Rev arginine-rich motif is robust to substitutions and that double substitution of two critical residues alters specificity. J Mol Recognit 2013; 26(6): 286-96.
[http://dx.doi.org/10.1002/jmr.2272] [PMID: 23595810]
[133]
Edgcomb SP, Aschrafi A, Kompfner E, Williamson JR, Gerace L, Hennig M. Protein structure and oligomerization are important for the formation of export-competent HIV-1 Rev-RRE complexes. Protein Sci 2008; 17(3): 420-30.
[http://dx.doi.org/10.1110/ps.073246608] [PMID: 18218716]
[134]
Faust O, Bigman L, Friedler A. A role of disordered domains in regulating protein oligomerization and stability. Chem Commun (Camb) 2014; 50(74): 10797-800.
[http://dx.doi.org/10.1039/C4CC03863K] [PMID: 25054624]
[135]
Wolff H, Hadian K, Ziegler M, et al. Analysis of the influence of subcellular localization of the HIV Rev protein on Rev-dependent gene expression by multi-fluorescence live-cell imaging. Exp Cell Res 2006; 312(4): 443-56.
[http://dx.doi.org/10.1016/j.yexcr.2005.11.020] [PMID: 16368434]
[136]
Hua J, Caffrey JJ, Cullen BR. Functional consequences of natural sequence variation in the activation domain of HIV-1 Rev. Virology 1996; 222(2): 423-9.
[http://dx.doi.org/10.1006/viro.1996.0439] [PMID: 8806526]
[137]
Jackson PE, Tebit DM, Rekosh D, Hammarskjold ML. Rev-RRE Functional Activity Differs Substantially Among Primary HIV-1 Isolates. AIDS Res Hum Retroviruses 2016; 32(9): 923-34.
[http://dx.doi.org/10.1089/aid.2016.0047] [PMID: 27147495]
[138]
Svicher V, Alteri C, D’Arrigo R, et al. Treatment with the fusion inhibitor enfuvirtide influences the appearance of mutations in the human immunodeficiency virus type 1 regulatory protein rev. Antimicrob Agents Chemother 2009; 53(7): 2816-23.
[http://dx.doi.org/10.1128/AAC.01067-08] [PMID: 19124665]
[139]
Cunyat F, Beerens N, García E, Clotet B, Kjems J, Cabrera C. Functional analyses reveal extensive RRE plasticity in primary HIV-1 sequences selected under selective pressure. PLoS One 2014; 9(8): e106299
[http://dx.doi.org/10.1371/journal.pone.0106299] [PMID: 25170621]
[140]
Learmont J, Tindall B, Evans L, et al. Long-term symptomless HIV-1 infection in recipients of blood products from a single donor. Lancet 1992; 340(8824): 863-7.
[http://dx.doi.org/10.1016/0140-6736(92)93281-Q] [PMID: 1357294]
[141]
Zaunders J, Dyer WB, Churchill M. The Sydney Blood Bank Cohort: implications for viral fitness as a cause of elite control. Curr Opin HIV AIDS 2011; 6(3): 151-6.
[http://dx.doi.org/10.1097/COH.0b013e3283454d5b] [PMID: 21378562]
[142]
Oelrichs R, Tsykin A, Rhodes D, et al. Genomic sequence of HIV type 1 from four members of the Sydney Blood Bank Cohort of long-term nonprogressors. AIDS Res Hum Retroviruses 1998; 14(9): 811-4.
[http://dx.doi.org/10.1089/aid.1998.14.811] [PMID: 9643382]
[143]
Churchill MJ, Chiavaroli L, Wesselingh SL, Gorry PR. Persistence of attenuated HIV-1 rev alleles in an epidemiologically linked cohort of long-term survivors infected with nef-deleted virus. Retrovirology 2007; 4: 43.
[http://dx.doi.org/10.1186/1742-4690-4-43] [PMID: 17601342]
[144]
Papathanasopoulos MA, Patience T, Meyers TM, McCutchan FE, Morris L. Full-length genome characterization of HIV type 1 subtype C isolates from two slow-progressing perinatally infected siblings in South Africa. AIDS Res Hum Retroviruses 2003; 19(11): 1033-7.
[http://dx.doi.org/10.1089/088922203322588396] [PMID: 14686322]
[145]
Rodenburg CM, Li Y, Trask SA, et al. UNAIDS and NIAID Networks for HIV Isolation and Characterization. Near full-length clones and reference sequences for subtype C isolates of HIV type 1 from three different continents. AIDS Res Hum Retroviruses 2001; 17(2): 161-8.
[http://dx.doi.org/10.1089/08892220150217247] [PMID: 11177395]
[146]
Iversen AK, Shpaer EG, Rodrigo AG, et al. Persistence of attenuated rev genes in a human immunodeficiency virus type 1-infected asymptomatic individual. J Virol 1995; 69(9): 5743-53.
[PMID: 7637019]
[147]
Phuphuakrat A, Paris RM, Nittayaphan S, Louisirirotchanakul S, Auewarakul P. Functional variation of HIV-1 Rev Response Element in a longitudinally studied cohort. J Med Virol 2005; 75(3): 367-73.
[http://dx.doi.org/10.1002/jmv.20279] [PMID: 15648073]
[148]
Phuphuakrat A, Auewarakul P. Functional variability of Rev response element in HIV-1 primary isolates. Virus Genes 2005; 30(1): 23-9.
[http://dx.doi.org/10.1007/s11262-004-4578-9] [PMID: 15744559]
[149]
Bobbitt KR, Addo MM, Altfeld M, et al. Rev activity determines sensitivity of HIV-1-infected primary T cells to CTL killing. Immunity 2003; 18(2): 289-99.
[http://dx.doi.org/10.1016/S1074-7613(03)00031-1] [PMID: 12594955]
[150]
Carpenter S, Dobbs D. Molecular and biological characterization of equine infectious anemia virus Rev. Curr HIV Res 2010; 8(1): 87-93.
[http://dx.doi.org/10.2174/157016210790416424] [PMID: 20210784]
[151]
Ihm Y, Sparks WO, Lee JH, et al. Structural model of the Rev regulatory protein from equine infectious anemia virus. PLoS One 2009; 4(1): e4178
[http://dx.doi.org/10.1371/journal.pone.0004178] [PMID: 19137065]
[152]
Carpenter S, Chen WC, Dorman KS. Rev variation during persistent lentivirus infection. Viruses 2011; 3(1): 1-11.
[http://dx.doi.org/10.3390/v3010001] [PMID: 21994723]
[153]
Belshan M, Baccam P, Oaks JL, et al. Genetic and biological variation in equine infectious anemia virus Rev correlates with variable stages of clinical disease in an experimentally infected pony. Virology 2001; 279(1): 185-200.
[http://dx.doi.org/10.1006/viro.2000.0696] [PMID: 11145901]
[154]
Baccam P, Thompson RJ, Li Y, et al. Subpopulations of equine infectious anemia virus Rev coexist in vivo and differ in phenotype. J Virol 2003; 77(22): 12122-31.
[http://dx.doi.org/10.1128/JVI.77.22.12122-12131.2003] [PMID: 14581549]
[155]
Sparks WO, Dorman KS, Liu S, Carpenter S. Naturally arising point mutations in non-essential domains of equine infectious anemia virus Rev alter Rev-dependent nuclear-export activity. J Gen Virol 2008; 89(Pt 4): 1043-8.
[http://dx.doi.org/10.1099/vir.0.83195-0] [PMID: 18343848]
[156]
Carlson JM, Schaefer M, Monaco DC, et al. HIV transmission. Selection bias at the heterosexual HIV-1 transmission bottleneck. Science 2014; 345(6193): 1254031
[http://dx.doi.org/10.1126/science.1254031] [PMID: 25013080]
[157]
Blackard JT. HIV compartmentalization: a review on a clinically important phenomenon. Curr HIV Res 2012; 10(2): 133-42.
[http://dx.doi.org/10.2174/157016212799937245] [PMID: 22329519]
[158]
Pomerantz RJ, Seshamma T, Trono D. Efficient replication of human immunodeficiency virus type 1 requires a threshold level of Rev: potential implications for latency. J Virol 1992; 66(3): 1809-13.
[PMID: 1738210]
[159]
Lassen KG, Ramyar KX, Bailey JR, Zhou Y, Siliciano RF. Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells. PLoS Pathog 2006; 2(7): e68
[http://dx.doi.org/10.1371/journal.ppat.0020068] [PMID: 16839202]
[160]
Siliciano RF, Greene WC. HIV latency. Cold Spring Harb Perspect Med 2011; 1(1): a007096
[http://dx.doi.org/10.1101/cshperspect.a007096] [PMID: 22229121]
[161]
Margolis DM, Hazuda DJ. Combined approaches for HIV cure. Curr Opin HIV AIDS 2013; 8(3): 230-5.
[http://dx.doi.org/10.1097/COH.0b013e32835ef089] [PMID: 23446138]
[162]
Bates DO, Morris JC, Oltean S, Donaldson LF. Pharmacology of Modulators of Alternative Splicing. Pharmacol Rev 2017; 69(1): 63-79.
[http://dx.doi.org/10.1124/pr.115.011239] [PMID: 28034912]


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