Abstract
Peptide dendrimers are a class of molecules that exhibit a large array of biological effects including antiviral activity. In this report, we analyzed the antiviral activity of the peptide-derivatized SB105-A10 dendrimer, which is a tetra-branched dendrimer synthetized on a lysine core, in activated peripheral blood mononuclear cells (PBMCs) that were challenged with reference and wild-type human immunodeficiency virus type 1 (HIV-1) strains. SB105-A10 inhibited infections by HIV-1 X4 and R5 strains, interfering with the early phases of the viral replication cycle. SB105-A10 targets heparan sulfate proteoglycans (HSPGs) and, importantly, the surface plasmon resonance (SPR) assay revealed that SB105-A10 strongly binds gp41 and gp120, most likely preventing HIV-1 attachment/entry through multiple mechanisms. Interestingly, the antiviral activity of SB105-A10 was also detectable in an organ-like structure of human cervicovaginal tissue, in which SB105-A10 inhibited the HIV-1ada R5 strain infection without altering the tissue viability. These results demonstrated the strong antiviral activity of SB105-A10 and suggest a potential microbicide use of this dendrimer to prevent the heterosexual transmission of HIV-1.
Highlights
HIV induces a life-long infection, which, if untreated, progressively evolves to acquired immunodeficiency syndrome (AIDS) with the ultimate death of the infected patients [1]
The present study mainly demonstrated that: i) SB105-A10 inhibited HIV replication of all of the tested reference and human immunodeficiency virus type 1 (HIV-1) strains that were isolated from HIV-positive patients in activated peripheral blood mononuclear cells (PBMCs), as indicated by the HIV-1 p24 protein ELISA assay in the cell culture supernatants; ii) SB105-A10 interfered with the attachment/entry of HIV-1 by multiple mechanisms targeting cell membrane heparan sulfate proteoglycans (HSPGs) and HIV virions; in particular, SB105-A10 bound gp41 and gp120 as revealed by the surface plasmon resonance (SPR) analysis; and iii) SB105-A10 inhibited the HIV infection in a biologically organotypic model of cervicovaginal epithelial tissue
The antiviral effect of SB105-A10 was tested on a wide range of R5, X4 and dual tropic R5/X4 HIV-1 strains, and a significant and reliable decrease of HIV-1 p24 protein amount was detected by the HIV-1 p24 ELISA assay in supernatants of the activated
Summary
HIV induces a life-long infection, which, if untreated, progressively evolves to acquired immunodeficiency syndrome (AIDS) with the ultimate death of the infected patients [1]. To tackle the HIV infection, two traditional approaches, represented by the pharmacological treatment and prophylaxis measures, have been proposed [3,4]. The absence of a broadly protective vaccine against the various HIV subtypes indicates that the development of alternative pharmacological approaches to HIV infection prophylaxis may be considered a major avenue for controlling HIV transmission. Because approximately 85% of HIV cases originate from sexual transmission [13] and because heterosexual contact represents the major route of infection [14], the development of pharmacological topical treatments, that employ so-called microbicides, might be crucial to prevent or reduce the transmission of HIV at the level of the genital mucosa [15,16,17]. Mathematical models have predicted that 60%-effective microbicides with 20% coverage could prevent 2.5 millions new infections within three years [18,19], suggesting that the identification of novel microbicides might play an important role in HIV infection control, pending the development of a functional vaccine
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