The D-amino acid peptide D3 reduces amyloid fibril boosted HIV-1 infectivity
© Widera et al.; licensee BioMed Central Ltd. 2014
Received: 24 July 2013
Accepted: 9 January 2014
Published: 14 January 2014
Amyloid fibrils such as Semen-Derived Enhancer of Viral Infection (SEVI) or amyloid-β-peptide (Aβ) enhance HIV-1 attachment and entry. Inhibitors destroying or converting those fibrils into non-amyloidogenic aggregates effectively reduce viral infectivity. Thus, they seem to be suitable as therapeutic drugs expanding the current HIV-intervening repertoire of antiretroviral compounds.
In this study, we demonstrate that the small D-amino acid peptide D3, which was investigated for therapeutic studies on Alzheimer’s disease (AD), significantly reduces both SEVI and Aβ fibril boosted infectivity of HIV-1.
Since amyloids could play an important role in the progression of AIDS dementia complex (ADC), the treatment of HIV-1 infected individuals with D3, that inhibits Aβ fibril formation and converts preformed Aβ fibrils into non-amyloidogenic and non-fibrillar aggregates, may reduce the vulnerability of the central nervous system of HIV patients for HIV associated neurological disorders.
KeywordsHIV-1 infection SEVI D3 Amyloid-beta Alzheimer’s disease D-enantiomeric peptide Drugs Monomers Oligomers
Amyloid fibrils exhibiting a cationic surface , for example those of the Alzheimer’s disease (AD) related amyloid-β peptide (Aβ) and the Semen derived Enhancer of Viral Infection (SEVI), promote HIV infection by facilitating viral attachment through neutralization of the electrostatic repulsion between the negatively charged surface of virions and target cells [2–4]. Experimental approaches to reduce SEVI-mediated enhancement of HIV-1 infection by amyloid binding agents have already been described [5–9]. However, except for epigallocatechin-3-gallate, the major active constituent of green tea, most of these compounds were shown to bind, but not to eliminate amyloids. Recently, it was demonstrated that the small D-amino acid peptide D3 converts Aβ oligomers and fibrils into non-amyloidogenic, non-fibrillar and non-toxic aggregates and reduces the cognitive deficits of the central nervous system in transgenic AD model mice . Because many amyloid fibrils, despite their composition of different peptides or proteins, show significant structural similarities like a typical cross-beta sheet quaternary structure, we intended to analyze the inhibitory capacity of D3 to reduce other amyloid caused pathologic effects.
HIV-1 entry in female mucosa is restricted and requires overcoming at least three hurdles. These are to breach the mucosal barrier and get through the epithelium, infection and replication in sub-epithelial mononuclear cells and the initiation of a systemic infection in the lymph nodes . Since genital mononuclear cells, including dendritic cells (DCs), macrophages and lymphocytes are susceptible to HIV-1 in vivo, amyloid fibrils might help HIV-1 to penetrate the mucosa and to reach these cells. Thus, treatment with D3 could inhibit the first sub-epithelial contact and prevent viral spreading.
In addition to its activity to enhance the infectivity of HIV-1 in semen, amyloids could play an important role in the progression of AIDS dementia complex (ADC) also known as HIV encephalopathy, which develops in between 20% and 30% of HIV patients in the course of infection. Interestingly, the formation of Aβ aggregates and fibrils is thought to precede the clinical symptoms of AD by three to four decades, and such fibrils may therefore be present in many mid-aged people. Since, the D-amino acid peptide D3 drastically reduces plaque load  and cognitive deficits even in orally D3 treated AD transgenic mice , it might be suitable to additionally reduce the fibril boosted HIV-1 infectivity in vivo.
In conclusion, the application of D3 may reduce SEVI-induced enhancement of viral infectivity of HIV-1 and the vulnerability of the central nervous system of HIV infected individuals. Thus, D3 seems to be suitable as therapeutic and prophylactic drug expanding the current HIV-intervening repertoire of antiretroviral compounds.
Enzyme-linked immunosorbent assay
Fluorescence activated cell sorting
Green fluorescent protein
Human immunodeficiency virus type 1
Phosphate buffered saline
Passive lysis buffer
Relative light units
Size exclusion chromatography
Semen-derived enhancer of virus infection.
These studies were supported, in part, by the DFG (SCHA 909/3-1), the Stiftung für AIDS-Forschung, Düsseldorf (H.S.), BMBF-Kompetenznetz Degenerative Demenzen (KNDD FKZ 01GI1010A, D.W.), DFG Graduate School 1033 (S.F., D.W.) and Jürgen Manchot Stiftung (M.W., H.S., D.W.). The following reagents were obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: TZM-bl cells from Drs. John C. Kappes, Dr. Xiaoyun Wu and Tranzyme Inc., Chessie 8 from Dr. George Lewis  and Molt-4 Clone 8 from Dr. Ronald Desrosiers. We thank Dr. Michael Schreiber for providing pNL4-3 PI 952  and Dr. Valerie Bosch for pNL4-3-GFP. We also thank Dr. Jan Münch for providing SEVI-fibrils.
- Luhrs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Dobeli H, Schubert D, Riek R: 3D structure of Alzheimer’s amyloid-beta(1–42) fibrils. Proc Natl Acad Sci USA. 2005, 102: 17342-17347. 10.1073/pnas.0506723102PubMed CentralView ArticlePubMed
- Wojtowicz WM, Farzan M, Joyal JL, Carter K, Babcock GJ, Israel DI, Sodroski J, Mirzabekov T: Stimulation of enveloped virus infection by beta-amyloid fibrils. J Biol Chem. 2002, 277: 35019-35024. 10.1074/jbc.M203518200View ArticlePubMed
- Munch J, Rucker E, Standker L, Adermann K, Goffinet C, Schindler M, Wildum S, Chinnadurai R, Rajan D, Specht A: Semen-derived amyloid fibrils drastically enhance HIV infection. Cell. 2007, 131: 1059-1071. 10.1016/j.cell.2007.10.014View ArticlePubMed
- Roan NR, Munch J, Arhel N, Mothes W, Neidleman J, Kobayashi A, Smith-McCune K, Kirchhoff F, Greene WC: The cationic properties of SEVI underlie its ability to enhance human immunodeficiency virus infection. J Virol. 2009, 83: 73-80. 10.1128/JVI.01366-08PubMed CentralView ArticlePubMed
- Capule CC, Brown C, Olsen JS, Dewhurst S, Yang J: Oligovalent amyloid-binding agents reduce SEVI-mediated enhancement of HIV-1 infection. J Am Chem Soc. 2012, 134: 905-908. 10.1021/ja210931bPubMed CentralView ArticlePubMed
- Olsen JS, Brown C, Capule CC, Rubinshtein M, Doran TM, Srivastava RK, Feng C, Nilsson BL, Yang J, Dewhurst S: Amyloid-binding small molecules efficiently block SEVI (semen-derived enhancer of virus infection)- and semen-mediated enhancement of HIV-1 infection. J Biol Chem. 2010, 285: 35488-35496. 10.1074/jbc.M110.163659PubMed CentralView ArticlePubMed
- Hauber I, Hohenberg H, Holstermann B, Hunstein W, Hauber J: The main green tea polyphenol epigallocatechin-3-gallate counteracts semen-mediated enhancement of HIV infection. Proc Natl Acad Sci USA. 2009, 106: 9033-9038. 10.1073/pnas.0811827106PubMed CentralView ArticlePubMed
- Sievers SA, Karanicolas J, Chang HW, Zhao A, Jiang L, Zirafi O, Stevens JT, Munch J, Baker D, Eisenberg D: Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation. Nature. 2011, 475: 96-100. 10.1038/nature10154PubMed CentralView ArticlePubMed
- Roan NR, Sowinski S, Munch J, Kirchhoff F, Greene WC: Aminoquinoline surfen inhibits the action of SEVI (semen-derived enhancer of viral infection). J Biol Chem. 2010, 285: 1861-1869. 10.1074/jbc.M109.066167PubMed CentralView ArticlePubMed
- Funke AS, van Groen T, Kadish I, Bartnik D, Nagel-Steger L, Brener O, Sehl T, Batra-Safferling R, Moriscot C, Schoehn G: Oral treatment with the d-enantiomeric peptide D3 improves the pathology and behavior of Alzheimer’s disease transgenic mice. ACS Chem Neurosci. 2010, 1: 639-648. 10.1021/cn100057jView Article
- Polzer S, Dittmar MT, Schmitz H, Schreiber M: The N-linked glycan g15 within the V3 loop of the HIV-1 external glycoprotein gp120 affects coreceptor usage, cellular tropism, and neutralization. Virology. 2002, 304: 70-80. 10.1006/viro.2002.1760View ArticlePubMed
- Chien P, Weissman JS, DePace AH: Emerging principles of conformation-based prion inheritance. Annu Rev Biochem. 2004, 73: 617-656. 10.1146/annurev.biochem.72.121801.161837View ArticlePubMed
- Daniel MD, Li Y, Naidu YM, Durda PJ, Schmidt DK, Troup CD, Silva DP, MacKey JJ, Kestler HW, Sehgal PK: Simian immunodeficiency virus from African green monkeys. J Virol. 1988, 62: 4123-4128.PubMed CentralPubMed
- Kikukawa R, Koyanagi Y, Harada S, Kobayashi N, Hatanaka M, Yamamoto N: Differential susceptibility to the acquired immunodeficiency syndrome retrovirus in cloned cells of human leukemic T-cell line Molt-4. J Virol. 1986, 57: 1159-1162.PubMed CentralPubMed
- Abacioglu YH, Fouts TR, Laman JD, Claassen E, Pincus SH, Moore JP, Roby CA, Kamin-Lewis R, Lewis GK: Epitope mapping and topology of baculovirus-expressed HIV-1 gp160 determined with a panel of murine monoclonal antibodies. AIDS Res Hum Retroviruses. 1994, 10: 371-381. 10.1089/aid.1994.10.371View ArticlePubMed
- Widera M, Erkelenz S, Hillebrand F, Krikoni A, Widera D, Kaisers W, Deenen R, Gombert M, Dellen R, Pfeiffer T: An intronic G run within HIV-1 intron 2 is critical for splicing regulation of vif mRNA. J Virol. 2013, 87: 2707-2720. 10.1128/JVI.02755-12PubMed CentralView ArticlePubMed
- van Groen T, Wiesehan K, Funke SA, Kadish I, Nagel-Steger L, Willbold D: Reduction of Alzheimer’s disease amyloid plaque load in transgenic mice by D3, A D-enantiomeric peptide identified by mirror image phage display. Chem Med Chem. 2008, 3: 1848-1852. 10.1002/cmdc.200800273View ArticlePubMed
- Shen R, Richter HE, Smith PD: Early HIV-1 target cells in human vaginal and ectocervical mucosa. Am J Reprod Immunol. 2011, 65: 261-267. 10.1111/j.1600-0897.2010.00939.xPubMed CentralView ArticlePubMed
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