DEVELOPMENT AND PRE-CLINICAL EVALUATION OF A NEW MICROBICIDE GEL FOR THE PREVENTION OF HIV-1 AND HIV-2 INFECTION

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Entry inhibitors and Carbosilane dendrimers are potent inhibitors of cell-associated HIV-2 infection

Publication . Diniz, A. R.; Briz, V.; Borrego, P.; Palladino, C.; Rodés, C.; De la Mata, F. J.; Gómez, R.; Muñoz-Fernández, M. A.; Taveira, N.

"Pre-exposure prophylaxis with topical microbicides formulated with antiviral agents can prevent HIV-1 acquisition. The ideal microbicide should prevent both cell-free and cell-associated HIV-1 and HIV-2 infections in the vaginal or rectum mucosa. So far, few candidate microbicides have been tested against HIV-2. Previously, we have shown that anionic carbosilane dendrimers 2G-S16 (sulphonate), G2-NF16 (naphthylsulfonated) and G3-S16 (sulphated-end groups) have potent antiviral activity against HIV-1. In this work, we evaluated the activity of these dendrimers and the fusion inhibitors T-1249 and T20 in preventing cell-free and cellassociated HIV-2 infection."

2015-03-22Conference object

Open access

Development of water-soluble polyanionic carbosilane dendrimers as novel and highly potent topical anti-HIV-2 microbicides

Publication . Briz, Verónica; Sepúlveda-Crespo, Daniel; Diniz, Ana Rita; Borrego, Pedro; Rodes, Berta; Javier de la Mata, Francisco; Gómez, Rafael; Taveira, Nuno; Muñoz-Fernández, Mª Ángeles

"The development of topical microbicide formulations for vaginal delivery to prevent HIV-2 sexual transmission is urgently needed. Second- and third-generation polyanionic carbosilane dendrimers with a silicon atom core and 16 sulfonate (G2-S16), napthylsulfonate (G2-NS16) and sulphate (G3-Sh16) end-groups have shown potent and broad-spectrum anti-HIV-1 activity. However, their antiviral activity against HIV-2 and mode of action have not been probed. Cytotoxicity, anti-HIV-2, anti-sperm and antimicrobial activities of dendrimers were determined. Analysis of combined effects of triple combinations with tenofovir and raltegravir was performed by using CalcuSyn software. We also assessed the mode of antiviral action on the inhibition of HIV-2 infection through a panel of different in vitro antiviral assays: attachment, internalization in PBMCs, inactivation and cell-based fusion. Vaginal irritation and histological analysis in female BALB/c mice were evaluated. Our results suggest that G2-S16, G2-NS16 and G3-Sh16 exert anti-HIV-2 activity at an early stage of viral replication inactivating the virus, inhibiting cell-to-cell HIV-2 transmission, and blocking the binding of gp120 to CD4, and the HIV-2 entry. Triple combinations with tenofovir and raltegravir increased the anti-HIV-2 activity, consistent with synergistic interactions (CIwt: 0.33–0.66). No vaginal irritation was detected in BALB/c mice after two consecutive applications for 2 days with 3% G2-S16. Our results have clearly shown that G2-S16, G2-NS16 and G3-Sh16 have high potency against HIV-2 infection. The modes of action confirm their multifactorial and non-specific ability, suggesting that these dendrimers deserve further studies as potential candidate microbicides to prevent vaginal/rectal HIV-1/HIV-2 transmission in humans."

2015-07Journal article

Open access

Inhibition of HIV cell-to-cell fusion by antiretroviral drugs and neutralizing antibodies

Publication . Diniz, A. R.; Borrego, P.; Bártolo, I.; Taveira, N.

"Inhibition of HIV cell entry by antiretroviral drugs and neutralizing antibodies (NAbs) is typically measured in assays where cell-free virions enter reporter cell lines. However, direct Env-mediated cell-to-cell transmission is a major mechanism of HIV infection that also needs to be targeted. In this work we aimed to determine the ability of anti-HIV compounds in clinical or research use to inhibit HIV mediated cell-to-cell fusion (syncytia formation)."

2015-07-15Conference object

Open access