In vitro and in vivo evaluation of two carrageenan-based formulations to prevent HPV acquisition

Rodríguez, Aixa; Kleinbeck, Kyle; Mizenina, Olga; Kizima, Larisa; Levendosky, Keith; Jean-Pierre, Ninochka; Villegas, G.; Ford, Brian E.; Cooney, Michael L.; Teleshova, Natalia; Robbiani, Melissa; Herold, Betsy C.; Zydowsky, Thomas M.; Romero, José A. Fernández

doi:10.1016/j.antiviral.2014.05.018

Cited by 57 publications

(87 citation statements)

References 40 publications

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“…In support of earlier data demonstrating that anti-HIV-1 (cellbased assays), anti-SHIV-RT (macaque vaginal explants), and anti-HSV-2 (murine model) activity of PC-1005 and anti-HPV activity (murine model) of CG is maintained in the presence of biological fluids (SP) (14,20,22,23;Kenney et al,unpublished), PC-1005 was active against HIV-1 BaL and HSV-2 in human ectocervical explants in the presence of vaginal fluids. Infection levels were inversely correlated with MIV-150 levels (HIV-1) and CG (HSV-2) levels in the CVLs.…”

Section: Figsupporting

confidence: 67%

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In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa

Villegas

Calenda

Zhang

et al. 2016

Antimicrob Agents Chemother

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Our recent phase 1 trial demonstrated that PC-1005 gel containing 50 μM MIV-150, 14 mM zinc acetate dihydrate, and carrageenan (CG) applied daily vaginally for 14 days is safe and well tolerated. Importantly, cervicovaginal lavage fluid samples (CVLs) collected 4 or 24 h after the last gel application inhibited HIV-1 and human papillomavirus (HPV) in cell-based assays in a dose-dependent manner (MIV-150 for HIV-1 and CG for HPV). Herein we aimed to determine the anti-HIV and anti-herpes simplex virus 2 (anti-HSV-2) activity of PC-1005 in human cervical explants afterin vitroexposure to the gel and to CVLs from participants in the phase 1 trial. Single HIV-1BaLinfection and HIV-1BaL–HSV-2 coinfection explant models were utilized. Coinfection with HSV-2 enhanced tissue HIV-1BaLinfection.In vitroexposure to PC-1005 protected cervical mucosa against HIV-1BaL(up to a 1:300 dilution) in single-challenge and cochallenge models. CG gel (PC-525) provided some barrier effect against HIV-1BaLat the 1:100 dilution in a single-challenge model but not in the cochallenge model. Both PC-1005 and PC-525 at the 1:100 dilution inhibited HSV-2 infection, pointing to a CG-mediated protection. MIV-150 and CG in CVLs inhibited HIV (single-challenge or cochallenge models) and HSV-2 infections in explants in a dose-dependent manner (P< 0.05). Stronger inhibition of HIV-1 infection by CVLs collected 4 h after the last gel administration was observed compared to infection detected in the presence of baseline CVLs. The anti-HIV and anti-HSV-2 activity of PC-1005 gelin vitroand CVLs in human ectocervical explants supports the further development of PC-1005 gel as a broad-spectrum on-demand microbicide.

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Section: Figsupporting

confidence: 67%

“…Kenney Zydowsky, and N. Teleshova, submitted for publication), and its activity is not affected by SP (20). Furthermore, PC-1005 gel provides CG-mediated activity against HPV, and this activity is not compromised in the presence of SP (22,23).…”

mentioning

confidence: 95%

In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa

Villegas

Calenda

Zhang

et al. 2016

Antimicrob Agents Chemother

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“…On the contrary, the MZC gel or MZCL IVR (Table 1) combines carrageenan (CG) and zinc (in addition to MIV-150, an anti-HIV non-nucleoside RTI) showed potent and durable synergistic anti-HSV-2 activity [20-22]. This MPT formulation retains antiviral activities when virus is added in seminal plasma [23]. …”

Section: Hsv-2: Major Cofactor In the Hiv Epidemicmentioning

confidence: 99%

“…CG, however, was by far the most potent, with an IC 50 of 2 ng/ml, and it was active against a broad spectrum of genital HPV types. Importantly, it retains high activity in the presence of seminal plasma [23]. Interestingly, several commercial sexual lubricants are formulated using carrageenan as the primary gelling agent.…”

Section: Hpv Prevention Strategies: Learning From Success and Moving mentioning

confidence: 99%

Multipurpose prevention technologies: the future of HIV and STI protection

Fernández-Romero

Deal

Herold

et al. 2015

Trends in Microbiology

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Every day, more than 1 million people are newly infected with sexually transmitted infections (STIs) that can lead to morbidity, mortality, and an increased risk of human immunodeficiency virus (HIV) acquisition. Existing prevention and management strategies, including behavior change, condom promotion, and therapy have not reduced the global incidence and prevalence, pointing to the need for novel innovative strategies. This review summarizes important issues raised during a satellite session at the first HIV R4P conference, held in Cape Town, on October 31, 2014. We explore key STIs that are challenging public health today; new biomedical prevention approaches including multipurpose prevention technologies (MPTs); and the scientific and regulatory hurdles that must be overcome to make combination prevention tools a reality.

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“…Consequently, heparin and other polyanionic compounds have been reported to act as HSPG antagonists, binding and sequestering HPV in the extracel-lular environment and thus hampering the cell surface attachment of HPV and hence infection (references 11 and 12 and references therein). The in vivo effectiveness of this anti-HPV strategy was demonstrated recently using the polyanionic sugar carrageenan (13,14).…”

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confidence: 99%

The Agmatine-Containing Poly(Amidoamine) Polymer AGMA1 Binds Cell Surface Heparan Sulfates and Prevents Attachment of Mucosal Human Papillomaviruses

Cagno

Donalisio

Bugatti

et al. 2015

Antimicrob Agents Chemother

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The agmatine-containing poly(amidoamine) polymer AGMA1 was recently shown to inhibit the infectivity of several viruses, including human papillomavirus 16 (HPV-16), that exploit cell surface heparan sulfate proteoglycans (HSPGs) as attachment receptors. The aim of this work was to assess the antiviral activity of AGMA1 and its spectrum of activity against a panel of lowrisk and high-risk HPVs and to elucidate its mechanism of action. AGMA1 was found to be a potent inhibitor of mucosal HPV types (i.e., types 16, 31, 45, and 6) in pseudovirus-based neutralization assays. The 50% inhibitory concentration was between 0.34 g/ml and 0.73 g/ml, and no evidence of cytotoxicity was observed. AGMA1 interacted with immobilized heparin and with cellular heparan sulfates, exerting its antiviral action by preventing virus attachment to the cell surface. The findings from this study indicate that AGMA1 is a leading candidate compound for further development as an active ingredient of a topical microbicide against HPV and other sexually transmitted viral infections. Human papillomaviruses (HPVs) are members of the Papillomaviridae family of double-stranded DNA nonenveloped viruses (1). The 8-kb HPV genome is enclosed in a capsid shell comprising major (L1) and minor (L2) structural proteins. Most of the HPVs belonging to the Alphapapillomavirus genus are sexually transmitted and infect the anogenital mucosa. For the great majority of immunocompetent individuals, HPV infections are transient, causing asymptomatic epithelial infections or benign epithelial hyperplasia. Genital warts are the most common lesions, caused mainly by HPV-6 and HPV-11. Small proportions of men and women fail to control viral infections and develop HPV-related malignancies, including carcinoma of the cervix, vulva, vagina, penis, anus, or oropharynx. Several HPV types belonging to HPV species 7 (HPV-18, HPV-39, HPV-45, HPV-59, and HPV-68) or species 9 (HPV-16, HPV-31, HPV-33, HPV-35, HPV-52, HPV-58, and HPV-67) can confer high oncogenic risk. HPV-16 and HPV-18 cause about 70% of all cases of invasive cervical cancer worldwide (followed by HPV-31, HPV-33, and HPV-45) (2).It has been estimated that more than 528,000 new cases of cervical cancer occur every year, and cervical cancer caused 266,000 deaths worldwide in 2012 (3, 4). Eighty-five percent of cervical cancer cases occur in women living in low-socioeconomic settings, primarily due to a lack of access to effective cervical cancer screening programs. No anti-HPV drugs are available to cure HPV lesions; therefore, the current treatments are ablative and directed at the abnormal cells associated with HPV, rather than at the virus itself. The development of new ways to prevent genital infections is essential in order to reduce the burden of HPV diseases. Two prophylactic vaccines, Gardasil and Cervarix, are currently available. The first is designed to protect against oncogenic HPV types 16 and 18 and low-risk HPV types 6 and 11 and therefore is preventive against both cancer and genital warts (5); the ...

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In vitro and in vivo evaluation of two carrageenan-based formulations to prevent HPV acquisition

Cited by 57 publications

References 40 publications

In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa

In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa

Multipurpose prevention technologies: the future of HIV and STI protection

The Agmatine-Containing Poly(Amidoamine) Polymer AGMA1 Binds Cell Surface Heparan Sulfates and Prevents Attachment of Mucosal Human Papillomaviruses

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