Lack of Effectiveness of Cellulose Sulfate Gel for the Prevention of Vaginal HIV Transmission

Damme, Lut Van; Govinden, Roshini; Mirembe, Florence; Guédou, Fernand; Solomon, Suniti; Becker, Marissa; Banandur, Pradeep; Krishnan, Anuradha; Alary, Michel; Pande, Bina; Ramjee, Gita; Deese, Jennifer; Crucitti, Tania; Taylor, Doug

doi:10.1056/nejmoa0707957

Cited by 405 publications

(331 citation statements)

References 19 publications

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“…A large scale trial of the anionic polymer Carraguard suggested that this compound provided no protection against HIV acquisition when used as a vaginal microbicide (17). Worse yet, the results of a phase III clinical trial with another anionic polymer, cellulose sulfate, showed that women who received the compound had a higher rate of HIV acquisition relative to the placebo arm (18). On a more positive note, a clinical trial with yet another anionic polymer, Pro-2000, suggested a 30% reduction in HIV infection, but unfortunately, the results were not statistically significant (19).…”

Section: Discussionmentioning

confidence: 99%

Aminoquinoline Surfen Inhibits the Action of SEVI (Semen-derived Enhancer of Viral Infection)

Roan

Sowinski

Münch

et al. 2010

Journal of Biological Chemistry

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In semen, proteolytic peptide fragments from prostatic acid phosphatase can form amyloid fibrils termed SEVI (semen-derived enhancer of viral infection). These fibrils greatly enhance human immunodeficiency virus (HIV) infectivity by increasing the attachment of virions to target cells. Therefore, SEVI may have a significant impact on whether HIV is successfully transmitted during sexual contact. Here, we demonstrate that surfen, a small molecule heparan sulfate proteoglycan antagonist, inhibits both SEVI-and semen-mediated enhancement of HIV type 1 infection. Surfen interferes with the binding of SEVI to both target cells and HIV type 1 virions but does not deaggregate SEVI fibrils. Because SEVI can increase HIV infectivity by several orders of magnitude, supplementing current HIV microbicide candidates with SEVI inhibitors, such as surfen, might greatly increase their potency. HIV2 is primarily a sexually transmitted disease. Worldwide, estimates suggest that the majority of all HIV infections are acquired through sexual contact. This includes sexual transmission from male to female, from male to male, and from female to male. In all these routes of infection, semen is either the vehicle carrying HIV (in the case of male-to-female and male-to-male transmission) or is often present during the infection process (in the case of female-to-male transmission).Recently, semen has been reported to enhance HIV infection (1). Fractionation of semen from healthy donors led to the identification of a factor that can enhance HIV infection up to 10 5 -fold in cell culture when viral inocula are limiting. This factor, termed SEVI (semen-derived enhancer of viral infection), corresponds to amyloid fibrils composed of internal 34 -40 amino acid proteolytic fragments from prostatic acid phosphatase (PAP), a protein present at a concentration of ϳ1-2 mg/ml in semen (1, 2). The predominant peptide fragment, PAP-(248 -286), has eight basic residues, rendering it very cationic (isoelectric point ϭ 10.21). The positively charged SEVI fibrils bind to both target cells and HIV virions and augment infection by increasing physical contact between these two components (1, 3), much in the same way that synthetic cationic polymers promote retrovirus attachment to target cells (4).Although we demonstrated that the cationic nature of SEVI is important for its pro-attachment effects (3), the surface components of target cells that interact with SEVI remained unknown. We previously observed that anionic polymers, such as heparin sulfate, interfere with the binding of SEVI to target cells (3). This led us to hypothesize that the fibrils may bind target cells by interacting with cell-surface heparan sulfate proteoglycans (HSPG), naturally occurring anionic carbohydrate polymers that are closely related in structure to heparin sulfate.We therefore sought to examine whether antagonists of HSPG might inhibit the viral enhancing activity of SEVI. Bis-2-methyl-4-amino-quinolyl-6-carbamide (surfen), a recently identified small molecule antagonist of H...

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Section: Discussionmentioning

confidence: 99%

Aminoquinoline Surfen Inhibits the Action of SEVI (Semen-derived Enhancer of Viral Infection)

Roan

Sowinski

Münch

et al. 2010

Journal of Biological Chemistry

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“…[11][12][13][14][15][16][17][18][19] CS did not prevent, and, when frequently used, may have increased the risk of HIV acquisition. 20,21 N-9, also when used frequently, raised the risk of HIV infection. 7 The first promising results for a microbicide came from the CAPRISA 004 study, in which tenofovir (TFV) 1% vaginal gel used before and after heterosexual intercourse was found to be 39% effective in reducing a woman's risk of becoming infected with HIV and, unexpectedly, 51% effective in preventing genital herpes infections.…”

mentioning

confidence: 99%

Toward Early Safety Alert Endpoints: Exploring Biomarkers Suggestive of Microbicide Failure

Mauck

Lai

Weiner

et al. 2013

AIDS Research and Human Retroviruses

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TitleToward early safety alert endpoints: exploring biomarkers suggestive of microbicide failure. Several microbicides, including nonoxynol-9 (N-9) and cellulose sulfate (CS), looked promising during early trials but failed in efficacy trials. We aimed to identify Phase I mucosal safety endpoints that might explain that failure. In a blinded, randomized, parallel trial, 60 healthy premenopausal sexually abstinent women applied Universal HEC placebo, 6% CS or 4% N-9 gel twice daily for 13½ days. Endpoints included immune biomarkers in cervicovaginal lavage (CVL) and endocervical cytobrushes, inflammatory infiltrates in vaginal biopsies, epithelial integrity by naked eye, colposcopy, and histology, CVL anti-HIV activity, vaginal microflora, pH, and adverse events. Twenty women enrolled per group. Soluble/cellular markers were similar with CS and placebo, except secretory leukocyte protease inhibitor (SLPI) levels decreased in CVL, and CD3 + and CD45 + cells increased in biopsies after CS use. Increases in interleukin (IL)-8, IL-1, IL-1RA, and myeloperoxidase (MPO) and decreases in SLPI were significant with N-9. CVL anti-HIV activity was significantly higher during CS use compared to N-9 or placebo. CS users tended to have a higher prevalence of intermediate Nugent score, Escherichia coli, and Enterococcus and fewer gram-negative rods. Most Nugent scores diagnostic for bacterial vaginosis were in N-9 users. All cases of histological inflammation or deep epithelial disruption occurred in N-9 users. While the surfactant N-9 showed obvious biochemical and histological signs of inflammation, more subtle changes, including depression of SLPI, tissue influx of CD45 + and CD3 + cells, and subclinical microflora shifts were associated with CS use and may help to explain the clinical failure of nonsurfactant microbicides.

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“…7 However, failures in other recent clinical trials indicate that we must keep seeking out new effective compounds that could help us to block worldwide spreading of HIV. [8][9][10] In the last few years, nanotechnology offered a huge battery of novel nanoparticles such as dendrimers and macromolecules characterized by hyperbranched, well-defined, monodisperse, three-dimensional structures that are being developed as drug delivery vehicles or as therapeutic agents. [11][12][13][14][15][16][17] The controlled synthesis of dendrimers allows the assembly of highly defined, single molecule structures that radiate out in branches from a central initiator core.…”

Section: Introductionmentioning

confidence: 99%

Antiviral mechanism of polyanionic carbosilane dendrimers against HIV-1

Vacas-Córdoba¹,

Malý²,

Mata³

et al. 2016

IJN

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Nanotechnology-derived platforms, such as dendrimers, are very attractive in several biological applications. In the case of human immunodeficiency virus (HIV) infection, polyanionic carbosilane dendrimers have shown great potential as antiviral agents in the development of novel microbicides to prevent the sexual transmission of HIV-1. In this work, we studied the mechanism of two sulfated and naphthylsulfonated functionalized carbosilane dendrimers, G3-S16 and G2-NF16. They are able to inhibit viral infection at fusion and thus at the entry step. Both compounds impede the binding of viral particles to target cell surface and membrane fusion through the blockage of gp120–CD4 interaction. In addition, and for the first time, we demonstrate that dendrimers can inhibit cell-to-cell HIV transmission and difficult infectious synapse formation. Thus, carbosilane dendrimers’ mode of action is a multifactorial process targeting several proteins from viral envelope and from host cells that could block HIV infection at different stages during the first step of infection.

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Lack of Effectiveness of Cellulose Sulfate Gel for the Prevention of Vaginal HIV Transmission

Abstract: Cellulose sulfate did not prevent HIV infection and may have increased the risk of HIV acquisition. (ClinicalTrials.gov number, NCT00153777; and Current Controlled Trials number, ISRCTN95638385.)

Cited by 405 publications

References 19 publications

Aminoquinoline Surfen Inhibits the Action of SEVI (Semen-derived Enhancer of Viral Infection)

Aminoquinoline Surfen Inhibits the Action of SEVI (Semen-derived Enhancer of Viral Infection)

Toward Early Safety Alert Endpoints: Exploring Biomarkers Suggestive of Microbicide Failure

Antiviral mechanism of polyanionic carbosilane dendrimers against HIV-1

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