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.


Available from: Elena Germinario, Jun 14, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A dual chamber system was established to model heterosexual HIV transmission. Cell-associated, but not cell-free HIV, added to a confluent layer of cervical epithelial cells in the apical chamber, reproducibly infected monocyte-derived dendritic cells (MO-DC) and CD4(+) T cells in the basal compartment. Only minimal epithelial transmigration of HIV-infected mononuclear cells (HIV-PBMCs) was observed. Most evidence points to transepithelial migration of virus, released from HIV-PBMCs after their activation by epithelial cells. We used this model for evaluation of the therapeutic index of various potentially preventive antiviral compounds, including non-nucleoside reverse transcriptase inhibitors (NNRTIs, including UC781 and various diaryltriazines and diarylpyrimidines), poly-anionic entry inhibitors (including PRO2000, cellulose sulphate, dextrane sulphate 5000 and polystyrene sulphonate) and the fusion inhibitor T-20. The epithelium was pre-treated with compound and incubated with HIV-PBMCs for 24 h. Afterwards the apical chamber was removed and MO-DC/CD4(+) T cell co-cultures were further cultured without compound. NNRTIs, including a TMC120 gel, blocked infection of the sub-epithelial targets at sub-micromolar concentrations. Polyanionic entry inhibitors (up to 100 microg/ml) and T-20 (up to 449 microg/ml) failed to inhibit transmission. Moreover, whereas the NNRTIs used interfered with epithelial integrity with cervical epithelium only at very high concentrations, the evaluated entry inhibitors showed toxicity at concentrations that did not prevent infection.
    Antiviral Research 06/2007; 74(2):111-24. DOI:10.1016/j.antiviral.2006.10.010 · 3.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: More than three decades since its discovery, HIV infection remains one of the most aggressive epidemics worldwide, with more than 35 million people infected. In sub-Saharan Africa, heterosexual transmissions represent nearly 80% of new infections, with 50% of these occurring in women. In an effort to stop the dramatic spread of the HIV epidemic, new preventive treatments, such as microbicides, have been developed. Nanotechnology has revolutionized this field by designing and engineering novel highly effective nano-sized materials as microbicide candidates. This review illustrates the most recent advances in nanotech-derived HIV prevention strategies, as well as the main steps required to translate promising in vitro results into clinical trials. Copyright © 2014 Elsevier B.V. All rights reserved.
    Antiviral Research 11/2014; 113C:33-48. DOI:10.1016/j.antiviral.2014.10.014 · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A review of the recent outcomes regarding technologies to prevent vaginaltransmission of HIV, mainly by using antiretroviral (ARV) drugs formulated as microbicides. An introduction about the HIV transmission mechanism by the vaginal route is included together with the recent challenges faced for development of successful microbicide products. The outcomes of clinical evaluations are mentioned and the different formulation strategies studied to-date, with the requirement, advantages, disadvantages and limitations of each dosage-form type. Finally, the recent attempts to apply various types of nanotechnologies in order to develop advanced microbicide-products and overcome existing limitations, are presented. Copyright © 2015. Published by Elsevier B.V.
    Advanced drug delivery reviews 04/2015; DOI:10.1016/j.addr.2015.03.015 · 12.71 Impact Factor