SPL7013 Gel as a Topical Microbicide for Prevention of Vaginal Transmission of SHIV_89.6Pin Macaques

Abstract

SPL7013 is a dendrimer with a polyanionic outer surface that allows multiple interactions with target sites. It potently binds and blocks HIV-1 and chimeric simian/HIV-1 viruses (SHIVs) replication in vitro. Gels containing different concentrations of SPL7013 were used as topical microbicides in female pigtailed macaques (Macaca nemestrina) to study their ability to prevent vaginal transmission of SHIV(89,6P). On virus challenge, all untreated macaques (8/8) and seven of eight macaques treated with placebo gel were infected within 2 weeks postinfection (PI) and showed high plasma viremia and dramatic CD4(+) cell decline within 4 weeks PI. In contrast, 6/6 macaques, 5/6 macaques, and 2/6 macaques treated with 5% w/w (50 mg/ml), 3% w/w (30 mg/ml), and 1% w/w (10 mg/ml) SPL7013 gels, respectively, resisted viral challenge. The results showed that animals treated with SPL7013 showed a dose-dependent resistance to virus challenge. Neither SPL7013 nor placebo gels produced any adverse effects following the single application in the study. These results showed that 3-5% w/w SPL7013 gels were effective in blocking vaginal transmission of SHIV in macaques after single gel application followed by single virus challenge. These results suggest that SPL7013 gel may be a promising anti-HIV microbicide formulation for further evaluation.

RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models

“…Another group of four macaques were not pretreated with DMPA prior to virus challenge. Two macaques in each group were inoculated intravaginally with 500 TCID 50 of RT-SHIV; the remaining two macaques in each group received 1,000 TCID 50 as previously described [13,14]. Briefly, 0.5 ml of virus preparation was atraumatically introduced to the vaginal mucosa using a stainless steel animal feeding tube.…”

“…SIVmac239 gag -specific primers were used to amplify virus DNA by PCR as described previously [13,14,46]. …”

Polymeric Anti‐HIV Therapeutics

“…[134] A 3 wt% formulation has shown to possess inhibitory activity against HIV-1 and the herpes simplex virus (HSV) up to 3 h following vaginal administration in women demonstrating long-lived efficacy of the dendritic drug. [135] Although other polymers such as poly(naphthalene sulfonate) (5, PRO2000), [76] carrageenan [136] and cellulose sulfate [137] based microbicides showed promising results in vitro, human trials demonstrated that these gels did not provide protection against HIV-1 infection.…”

Hyperbranched Molecular Structures with Potential Antiviral Activity: Derivatives of 5,6-Dihydroxyindole-2-Carboxylic Acid

“…As far as dendrimers are concerned, their applications in treatment of several human diseases are under critical investigation and looks very promising; these macromolecules serve as targeted drug, carriers and delivery agents as well as imaging agents in human systems [4][5][6]. In particular, polymers having a dendrimer-based structure have emerged from several research programs focused on the development of inhibitors of HIV and other enveloped viruses [7][8][9][10][11][12][13][14][15][16][17][18][19].…”