Restricted accessResearch articleFirst published online 2020-05
Adeno-Associated Virus D-Sequence-Mediated Suppression of Expression of a Human Major Histocompatibility Class II Gene: Implications in the Development of Adeno-Associated Virus Vectors for Modulating Humoral Immune Response
A 20-nt long sequence, termed the D-sequence, in the adeno-associated virus (AAV) inverted terminal repeat was observed to share a partial sequence homology with the X-box in the regulatory region of the human leukocyte antigen DRA (HLA-DRA) promoter of the human major histocompatibility complex class II (MHC-II) genes. The D-sequence was also shown to specifically interact with the regulatory factor binding to the X-box (RFX), binding of which to the X-box is a critical step in the MHC-II gene expression, suggesting that D-sequence might compete for RFX transcription factor binding, thereby suppressing expression from the MHC-II promoter. In DNA-mediated transfection experiments, using a reporter gene under the control of the HLA-DRA promoter, D-sequence oligonucleotides were found to inhibit expression of the reporter gene expression in HeLa and 293 cells by ∼93% and 96%, respectively. No inhibition was observed when nonspecific synthetic oligonucleotides were used. D-sequence oligonucleotides had no effect on expression from the cytomegalovirus immediate-early gene promoter. Interferon-γ-mediated activation of MHC-II gene expression was also inhibited by D-sequence oligonucleotides as well as after infection with either the wild-type AAV or transduction with recombinant AAV vectors. These studies suggest that the D-sequence-mediated downregulation of the MHC-II gene expression may be exploited toward the development of novel AAV vectors capable of dampening the host humoral response, which has important implication in the optimal use of these vectors in human gene therapy.
Get full access to this article
View all access options for this article.
References
1.
BainbridgeJW, SmithAJ, BarkerSS, et al.Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med, 2008; 358:2231–2239.
2.
MaguireAM, SimonelliF, PierceEA, et al.Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med, 2008; 358:2240–2248.
3.
HauswirthWW, AlemanTS, KaushalS, et al.Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther, 2008; 19:979–990.
4.
CideciyanAV, AlemanTS, BoyeSL, et al.Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A, 2008; 105:15112–15117.
5.
GaudetD, MethotJ, DeryS, et al.Efficacy and long-term safety of alipogene tiparvovec (AAV1- LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther, 2013; 20:361–369.
6.
NathwaniAC, RosalesC, McIntoshJ, et al.Long-term safety and efficacy following systemic administration of a self-complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther, 2011; 19:876–885.
7.
NathwaniAC, ReissUM, TuddenhamEG, et al.Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med, 2014; 371:1994–2004.
8.
MiesbachW, MeijerK, CoppensM, et al.Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood, 2018; 131:1022–1031.
9.
GeorgeLA, SullivanSK, GiermaszA, et al.Hemophilia B gene therapy with a high-specific- activity factor IX variant. N Engl J Med, 2017; 377:2215–2227.
10.
RangarajanS, WalshL, LesterW, et al.AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med, 2017; 377:2519–2530.
11.
PasiKJ, RangarajanS, MitchellN, et al.Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med, 2020; 382:29–40.
12.
HwuWL, MuramatsuS, TsengSH, et al.Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med, 2012; 4:134ra161.
13.
MacLarenRE, GroppeM, BarnardAR, et al.Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet, 2014; 383:1129–1137.
14.
GuyJ, FeuerWJ, DavisJL, et al.Gene therapy for leber hereditary optic neuropathy: low- and medium-dose visual results. Ophthalmology, 2017; 124:1621–1634.
15.
MendellJR, Al-ZaidyS, ShellR, et al.Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med, 2017; 377:1713–1722.
16.
FitzpatrickZ, LeborgneC, BarbonE, et al.Influence of pre-existing anti-capsid neutralizing and binding antibodies on AAV vector transduction. Mol Ther Methods Clin Dev, 2018; 9:119–129.
17.
CooperMD. The early history of B cells. Nat Rev Immunol, 2015; 15:191–197.
18.
RochePA, FurutaK. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol, 2015; 15:203–216.
19.
NakamuraMC. CIITA: a master regulator of adaptive immunity shows its innate side in the bone. J Bone Miner Res, 2014; 29:287–289.
20.
SrivastavaA, LusbyEW, BernsKI. Nucleotide sequence and organization of the adeno-associated virus 2 genome. J Virol, 1983; 45:555–564.
21.
SrivastavaA. Replication of the adeno-associated virus DNA termini in vitro. Intervirology, 1987; 27:138–147.
22.
LusbyE, FifeKH, BernsKI. Nucleotide sequence of the inverted terminal repetition in adeno- associated virus DNA. J Virol, 1980; 34:402–409.
23.
WangXS, PonnazhaganS, SrivastavaA. Rescue and replication signals of the adeno-associated virus 2 genome. J Mol Biol, 1995; 250:573–580.
24.
WangXS, PonnazhaganS, SrivastavaA. Rescue and replication of adeno-associated virus type 2 as well as vector DNA sequences from recombinant plasmids containing deletions in the viral inverted terminal repeats: selective encapsidation of viral genomes in progeny virions. J Virol, 1996; 70:1668-1677.
25.
WangXS, QingK, PonnazhaganS, et al.Adeno-associated virus type 2 DNA replication in vivo: mutation analyses of the D sequence in viral inverted terminal repeats. J Virol, 1997; 71:3077–3082.
26.
JulienL, ChassagneJ, PeccateC, et al.RFX1 and RFX3 transcription factors interact with the D sequence of adeno-associated virus inverted terminal repeat and regulate AAV transduction. Sci Rep, 2018; 8:210.
27.
QingK, WangXS, KubeDM, et al.Role of tyrosine phosphorylation of a cellular protein in adeno- associated virus 2-mediated transgene expression. Proc Natl Acad Sci U S A, 1997; 94:10879–10884.
28.
QingK, KhuntiratB, MahC, et al.Adeno-associated virus type 2-mediated gene transfer: correlation of tyrosine phosphorylation of the cellular single-stranded D sequence-binding protein with transgene expression in human cells in vitro and murine tissues in vivo. J Virol, 1998; 72:1593–1599.
29.
PonnazhaganS, WangXS, WoodyMJ, et al.Differential expression in human cells from the p6 promoter of human parvovirus B19 following plasmid transfection and recombinant adeno-associated virus 2 (AAV) infection: human megakaryocytic leukaemia cells are non-permissive for AAV infection. J Gen Virol, 1996; 77(Pt 6):1111–1122.
30.
PonnazhaganS, MukherjeeP, WangXS, et al.Adeno-associated virus type 2-mediated transduction in primary human bone marrow-derived CD34+ hematopoietic progenitor cells: donor variation and correlation of transgene expression with cellular differentiation. J Virol, 1997; 71:8262–8267.
31.
LingC, WangY, LuY, et al.Enhanced transgene expression from recombinant single-stranded D-sequence-substituted adeno-associated virus vectors in human cell lines in vitro and in murine hepatocytes in vivo. J Virol, 2015; 89:952–961.
32.
KubeDM, SrivastavaA. Quantitative DNA slot blot analysis: inhibition of DNA binding to membranes by magnesium ions. Nucleic Acids Res, 1997; 25:3375–3376.
33.
KayCN, RyalsRC, AslanidiGV, et al.Targeting photoreceptors via intravitreal delivery using novel, capsid-mutated AAV vectors. PLoS One, 2013; 8:e62097.
34.
ReithW, KobrM, EmeryP, et al.Cooperative binding between factors RFX and X2bp to the X and X2 boxes of MHC class II promoters. J Biol Chem, 1994; 269:20020–20025.
35.
SteimleV, DurandB, BarrasE, et al.A novel DNA-binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome). Genes Dev, 1995; 9:1021–1032.
36.
MasternakK, BarrasE, ZuffereyM, et al.A gene encoding a novel RFX-associated transactivator is mutated in the majority of MHC class II deficiency patients. Nat Genet, 1998; 20:273–277.
37.
NagarajanUM, Louis-PlenceP, DeSandroA, et al.RFX-B is the gene responsible for the most common cause of the bare lymphocyte syndrome, an MHC class II immunodeficiency. Immunity, 1999; 10:153–162.
38.
MorenoCS, BeresfordGW, Louis-PlenceP, et al.CREB regulates MHC class II expression in a CIITA-dependent manner. Immunity, 1999; 10:143–151.
39.
LeeKW, LeeY, KimDS, KwonHJ. Direct role of NF-kappaB activation in Toll-like receptor- triggered HLA-DRA expression. Eur J Immunol, 2006; 36:1254–1266.
40.
GauvreauME, CôtéMH, Bourgeois-DaigneaultMC, et al.Sorting of MHC class II molecules into exosomes through a ubiquitin-independent pathway. Traffic, 2009; 10:1518–1527.
41.
AbendrothA, SlobedmanB, LeeE, et al.Modulation of major histocompatibility class II protein expression by varicella-zoster virus. J Virol, 2000; 74:1900–1907.
42.
MahC, QingK, KhuntiratB, et al.Adeno-associated virus type 2-mediated gene transfer: role of epidermal growth factor receptor protein tyrosine kinase in transgene expression. J Virol, 1998; 72:9835–9843.
43.
DavidoffAM, GrayJT, NgCY, et al.Comparison of the ability of adeno-associated viral vectors pseudotyped with serotype 2, 5, and 8 capsid proteins to mediate efficient transduction of the liver in murine and nonhuman primate models. Mol Ther, 2005; 11:875–888.
44.
SackBK, MerchantS, MarkusicDM, et al.Transient B cell depletion or improved transgene expression by codon optimization promote tolerance to factor VIII in gene therapy. PLoS One, 2012; 7:e37671.
45.
TseLV, KlincKA, MadiganVJ, et al.Structure-guided evolution of antigenically distinct adeno- associated virus variants for immune evasion. Proc Natl Acad Sci U S A, 2017; 114:E4812–E4821.
46.
van LieshoutLP, DommJM, RindlerTN, et al.A novel triple-mutant AAV6 capsid induces rapid and potent transgene expression in the muscle and respiratory tract of mice. Mol Ther Methods Clin Dev, 2018; 9:323–329.
47.
SharplessNE. INK4a/ARF: a multifunctional tumor suppressor locus. Mutat Res, 2005; 576:22–38.
48.
de la MazaLM, CarterBJ. Inhibition of adenovirus oncogenicity in hamsters by adeno-associated virus DNA. J Natl Cancer Inst, 1981; 67:1323–1326.
49.
HermonatPL. Inhibition of H-ras expression by the adeno-associated virus Rep78 transformation suppressor gene product. Cancer Res, 1991; 51:3373–3377.
50.
HermonatPL. Inhibition of bovine papillomavirus plasmid DNA replication by adeno-associated virus. Virology, 1992; 189:329–333.
51.
HermonatPL. Down-regulation of the human c-fos and c-myc proto-oncogene promoters by adeno- associated virus Rep78. Cancer Lett, 1994; 81:129–136.
52.
HermonatPL. Adeno-associated virus inhibits human papillomavirus type 16: a viral interaction implicated in cervical cancer. Cancer Res, 1994; 54:2278–2281.
53.
MayorHD, HoulditchGS, MumfordDM. Influence of adeno-associated satellite virus on adenovirus-induced tumours in hamsters. Nat New Biol, 1973; 241:44–46.
54.
OstroveJM, DuckworthDH, BernsKI. Inhibition of adenovirus-transformed cell oncogenicity by adeno-associated virus. Virology, 1981; 113:521–533.
55.
RajK, OgstonP, BeardP. Virus-mediated killing of cells that lack p53 activity. Nature, 2001; 412:914–917.
56.
CullenPJ. Endosomal sorting and signalling: an emerging role for sorting nexins. Nat Rev Mol Cell Biol, 2008; 9:574–582.
57.
NedwinGE, NaylorSL, SakaguchiAY, et al.Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res, 1985; 13:6361–6373.
58.
KwonH-J, WeigelKA, HansenJ, et al.AAV-mediated gene transfer: effect on MHC Class II gene expression. Mol Ther, 2000; 1: S190.
59.
VillardJ, PerettiM, MasternakK, et al.A functionally essential domain of RFX5 mediates activation of major histocompatibility complex class II promoters by promoting cooperative binding between RFX and NF-Y. Mol Cell Biol, 2000; 20:3364–3376.
60.
WangZ, MaHI, LiJ, et al.Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo. Gene Ther, 2003; 10:2105–2111.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
