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.
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