AEGiS-15IAC: [LbOrA02] PRE-CLINICAL PREDICTION OF THE RISK OF THE OCCURRENCE OF LATENCY DURING VAGINAL AND RECTAL PRE-TREATMENT WITH PRO-2000/5 IN A hu-SCID MUCOSAL MOUSE MODEL

15th International AIDS Conference

Bangkok, Thailand — July 11-July 16, 2004

[LbOrA02] PRE-CLINICAL PREDICTION OF THE RISK OF THE OCCURRENCE OF LATENCY DURING VAGINAL AND RECTAL PRE-TREATMENT WITH PRO-2000/5 IN A hu-SCID MUCOSAL MOUSE MODEL

Int Conf AIDS. 2004 Jul 11-16;15:Abstract No. LbOrA02

S Di Fabio¹, E Germinario¹, A Profy², G Giannini¹, M Spada³, F Carlini¹, C Lapenta³, E Proietti³, A Binelli¹, F Belardelli³, S Vella¹
¹Istituto Superiore di Sanità ISS Department of Drug research and Evaluation, Rome, Italy; ²Indevus Pharmaceuticals, Lexington, United States; ³Istituto Superiore di Sanità ISS , Rome, Italy

BACKGROUND: Sulfonated polymers can be considered as 'first generation' of microbicides that at the moment are considered promising candidate topical agents entering phase II/III clinical trials. Within this group, the naphthalene sulfonate polymer PRO 2000/5 has been shown to inhibit infection by cell-free virus both in vitro and in vivo assays. Few animal models are suitable to ensure the efficacy in preventing transmission across rectal and vaginal mucosa. Our study focuses on the use of a hu-SCID model of cell-associated and free HIV transmission at the vaginal and rectal level.

METHODS: Gels containing PRO 2000/5 at two different concentrations (0.5% and 4%) were evaluated for protective efficacy vs a matched placebo gel. Animals received: i) a single intravaginal application of 25 µl of PRO 2000/5; ii) a single intra-rectal application of 50 µl of PRO 2000/5; iii) or placebo gel 15-20 minutes prior to a non-invasive vaginal challenge with cell-free or 2x10⁶ human peripheral blood lymphocytes (hu-PBL) previously infected in vitro with a dual-tropic laboratory-derived R5X4 strain of HIV-1 (1/BX08). Cell to cell transmission was assessed by p24 determination and by real time PCR.

RESULTS: In our in vivo model 0,5% and 4% PRO 2000/5 gel were able to reduce the rate of sexual (rectal and vaginal) transmission by free and cell-associated HIV by 40-70% as shown by p24 results. All 10 animals receiving the placebo gel became infected. However, real time PCR results indicate that in our in vivo model pre-treatment with doses of PRO 2000/5 gel low as 0.5% were able to reduce rectal and vaginal infection but failed to completely block both free and cell-associated HIV-1 proviral integration.

CONCLUSIONS: Using our hu-SCID model of sexual transmission of HIV we could predict that pre-treatment with PRO2000/5 gel was able to block HIV-replication but did not block the transfer of the virus as indicated by the presence of cells containing an integrated DNA provirus. Therefore, suggesting that the persistence of latently infected resting cells it may occur.

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