Article

Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulation.

Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
AIDS (Impact Factor: 6.56). 08/2003; 17(11):1597-604. DOI: 10.1097/01.aids.0000072663.21517.63
Source: PubMed

ABSTRACT The development of drugs that can be used as topical microbicides is currently recognized as a priority area of research.
A preclinical evaluation of the potential effectiveness of TMC120, a non-nucleoside reverse transcriptase inhibitor (NNRTI), as a topical microbicide to prevent vaginal HIV-1 transmission in a humanized severe combined immunodeficient (hu-SCID) mouse model.
Reconstituted mice received an intravaginal application of a TMC120-containing gel 20 min prior to a non-invasive vaginal challenge with cell-associated HIV. The possible cytotoxic effect of TMC120-containing-gel on lymphocytes was assessed and their in vivo migration was followed using fluorescently labelled human lymphocytes. Systemic infection was monitored by p24 antigen detection in culture supernatant from cocultured intraperitoneal cells using antigen capture enzyme-linked immunosorbent assay test and by the presence of integrated proviral HIV-1 DNA in DNA extracted from spleen cells. In vivo migration of labelled lymphocytes was examined by analysis of cells isolated from regional lymph nodes.
In this model, systemic infection was successfully inhibited by the presence of TMC120-containing gel at vaginal level. The in vivo migration of human lymphocytes from the vagina to regional lymph nodes, following the deposition of TMC120-containing gel, excluded the possibility that inhibition of systemic infection was a result of NNRTI toxicity.
Vaginal transmission of HIV was successfully prevented by the application of a gel formulation containing TMC120. This is the first evidence of the in vivo effectiveness of a microbicide preparation containing an NNRTI against cell-associated HIV.

0 Followers
 · 
69 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Members of the interferon regulatory factor (IRF) family control the expression of numerous proteins, many of which are central to regulating host immune responses. IRF1 is one of the central mediators of the innate and adaptive immune responses required for antigen processing and presentation, Th1/Th2 differentiation, and natural killer (NK) cell and macrophage function. Many viruses have evolved mechanisms to target the IRF1 pathway in order to promote viral pathogenesis. During early HIV infection, IRF1 acts as a double-edged sword, critical for driving viral replication as well as eliciting antiviral responses. In this review, we describe the strategies that HIV-1 has evolved to modulate IRF1 in order to enhance viral replication and to disarm the host immune system. IRF1 has been shown to be an important factor in natural protection against HIV in highly exposed seronegative (HESN) individuals and is crucial in regulating the initial stages of HIV replication and HIV disease progression, as well as the establishment of latency. An understanding of how the protective effects of IRF1 responses are controlled in HESN individuals, naturally resistant to HIV infection, may provide important clues on how to regain control of HIV and tip the balance of immunity in favor of the host, or provide new opportunities to eliminate HIV in its host altogether.
    AIDS Research and Human Retroviruses 11/2013; 29(11):1428-1433. DOI:10.1089/aid.2013.0098 · 2.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Small-animal models of lentivirus transmission have repeatedly demonstrated transmission by cell-associated virus via vaginal, rectal, and oral routes. The earliest experiments were in the cat/feline immunodeficiency virus model, followed a decade later by successful vaginal transmission of cell-associated human immunodeficiency virus (HIV) in mice bearing transplanted human immune cells. After early unsuccessful attempts at cell-associated transmission in nonhuman primates, renewed investigation in diverse primate models has now confirmed the findings from the cat and humanized mouse models. Improvements in humanized mouse models have made them the preferred small-animal models to study HIV mucosal transmission. They provide complementary systems to nonhuman primate models to aid in the elucidation of the many remaining questions on the mechanism of and means to prevent both cell-associated and cell-free HIV transmission across mucosal barriers. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    The Journal of Infectious Diseases 12/2014; 210(suppl 3):S654-S659. DOI:10.1093/infdis/jiu368 · 5.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract The aim of the present study was to evaluate chitosan as a vaginal mucoadhesive gel base for econazole nitrate and miconazole nitrate. To this aim, different types of chitosan with different molecular masses and viscosity properties [low molecular mass chitosan (viscosity: 20,000 mPa s), medium molecular mass chitosan (viscosity: 200,000 mPa s), high molecular mass chitosan (viscosity: 800,000 mPa s)] have been used. First, rheological studies were conducted on chitosan gels. Mechanical, syringeability and mucoadhesive properties of chitosan gels were determined. Release profiles of econazole nitrate and miconazole nitrate from chitosan gels were obtained and evaluated kinetically. In addition, anticandidal activities of formulations were determined. Finally, vaginal retention of chitosan gels in rats was evaluated by in vivo distribution studies. Based on the results, it can be concluded that gels prepared with medium molecular mass chitosan might be effectively used for different antifungal agents in the treatment of vaginal candidiosis, since it has high mucoadhesiveness, suitable mechanical and release properties with good vaginal retention.
    Acta Pharmaceutica 06/2014; 64(2):139-156. DOI:10.2478/acph-2014-0013 · 1.03 Impact Factor

Full-text (2 Sources)

Download
103 Downloads
Available from
May 23, 2014