Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulation.
OBJECTIVE
The development of drugs that can be used as topical microbicides is currently recognized as a priority area of research.


METHODS
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Di Fabio
Simonetta
S
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
Van Roey
Jens
J
Giannini
Giacomo
G
van den Mooter
Guy
G
Spada
Massimo
M
Binelli
Andrea
A
Pirillo
Maria F
MF
Germinario
Elena
E
Belardelli
Filippo
F
de Bethune
Marie-Pierre
MP
Vella
Stefano
S
D000180:Acrylic Resins; D000282:Administration, Intravaginal; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage; D002482:Cellulose / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005260:Female; D005782:Gels; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D011145:Polyvinyls / Q000008:administration & dosage; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D014621:Vagina / Q000276:immunology; D014783:Viscosity
D000180:Acrylic Resins; D000890:Anti-Infective Agents; D005782:Gels; D011145:Polyvinyls; D018894:Reverse Transcriptase Inhibitors; C006912:carboxypolymethylene; D002482:Cellulose; C002283:hydroxyethylcellulose