Oligovalent Amyloid-Binding
Agents Reduce SEVI-Mediated
Enhancement of HIV-1 Infection
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Abstract
This paper evaluates the use of oligovalent amyloid-binding
molecules
as potential agents that can reduce the enhancement of human immunodeficiency
virus-1 (HIV-1) infection in cells by semen-derived enhancer of virus
infection (SEVI) fibrils. These naturally occurring amyloid fibrils
found in semen have been implicated as mediators that can facilitate
the attachment and internalization of HIV-1 virions to immune cells.
Molecules that are capable of reducing the role of SEVI in HIV-1 infection
may, therefore, represent a novel strategy to reduce the rate of sexual
transmission of HIV-1 in humans. Here, we evaluated a set of synthetic,
oligovalent derivatives of benzothiazole aniline (BTA, a known amyloid-binding
molecule) for their capability to bind cooperatively to aggregated
amyloid peptides and to neutralize the effects of SEVI in HIV-1 infection.
We demonstrate that these BTA derivatives exhibit a general trend
of increased binding to aggregated amyloids as a function of increasing
valence number of the oligomer. Importantly, we find that oligomers
of BTA show improved capability to reduce SEVI-mediated infection
of HIV-1 in cells compared to a BTA monomer, with the pentamer exhibiting
a 65-fold improvement in efficacy compared to a previously reported
monomeric BTA derivative. These results, thus, support the use of
amyloid-targeting molecules as potential supplements for microbicides
to curb the spread of HIV-1 through sexual contact