A Modified Zinc Acetate Gel, a Potential Nonantiretroviral Microbicide, Is Safe and Effective against Simian-Human Immunodeficiency Virus and Herpes Simplex Virus 2 Infection In Vivo

Abstract

We previously showed that a prototype gel comprising zinc acetate (ZA) in carrageenan (CG) protected mice against vaginal and rectal herpes simplex virus 2 (HSV-2) challenge as well as macaques against vaginal simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) challenge. In this work, we modified buffers and cosolvents to obtain a stable, nearly iso-osmolal formulation and evaluated its safety and efficacy against SHIV-RT and HSV-2. In vitro toxicity to lactobacilli and Candida albicans was determined. Macaques were given daily doses of ZA and CG (ZA/CG) or CG alone vaginally for 14 days and challenged with SHIV-RT 24 h later. Mice were challenged vaginally or rectally with HSV-2 immediately after a single gel treatment to measure efficacy or vaginally 12 h after daily gel treatment for 7 days to evaluate the gel's impact on susceptibility to HSV-2 infection. The modified ZA/CG neither affected the viability of lactobacilli or C. albicans nor enhanced vaginal HSV-2 infection after daily ZA/CG treatment. Vaginal SHIV-RT infection of macaques was reduced by 66% (P ‫؍‬ 0.006) when macaques were challenged 24 h after the last dose of gel. We observed 60% to 80% uninfected mice after vaginal (P < 0.0001) and rectal (P ‫؍‬ 0.008) high-dose HSV-2 challenge. The modified ZA/CG gel is safe and effective in animal models and represents a potential candidate to limit the transmission of HIV and HSV-2. S everal recent clinical trials have shown that microbicides containing antiretroviral drugs (ARVs) reduce the sexual transmission of HIV and other sexually transmitted diseases (STIs) (1). The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial (CAPRISA-004) showed that pericoital use (before and after sex) of vaginally applied 1% tenofovir (TFV) gel reduced human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus 2 (HSV-2) acquisition by 39% and 51%, respectively (2). Similarly, three oral pre-exposure trials (iPrex, Partners PrEP, and TDF2) targeting men who have sex with men (MSM) and transgender women, HIV-serodiscordant couples, or heterosexual men and women demonstrated between 44% and 73% efficacy (1). Conversely, a lack of efficacy was seen in two trials (FEM-PrEP and VOICE) in which women received daily oral emtricitabine-TFV and TFV (1, 3). A recent analysis of these two studies suggested that the lack of efficacy could have been due to poor regimen adherence (1, 3, 4).Although ARV-containing topical microbicides will likely be available soon, there are important questions regarding their use. (i) Does topical administration of an ARV in people with an undiagnosed HIV infection lead to resistance development and affect their treatment outcomes? (ii) How accessible will these products be (i.e., will they be available over the counter or by prescription only)? (iii) Can the introduction of an HIV-specific microbicide increase the transmission of other STIs?Given these unanswered questions and the potential limitations of ARV-containing topical microbicides, we are ...

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

“…CG gel does not damage vaginal or rectal epithelial tissue in mice. It does not increase susceptibility to HSV-2 vaginal infection in mice and is nontoxic to Lactobacillus jensenii or Lactobacillus crispatus in vitro (Kenney et al, 2013). Experiments in macaques show that repeated application is safe with no effects on vaginal pH or cytokines and chemokine levels in fluids (Kenney et al, 2011).…”

“…Considering the excellent safety profile, rheological properties, and anti-HPV activity of a 3% CG gel, we have used CG-based gels as delivery vehicles for anti-HIV and anti-HSV-2 APIs (Fernández-Romero et al, 2012; Kenney et al, 2011; Kenney et al, 2013; Kenney et al, 2012; Kizima et al, 2014). …”

Antiviral activity and pathogenetic targets for seaweed sulfated polysaccharides in herpesvirus infections

“…The authors confirmed that the drug could block sexual transmission of the virus, exhibited low toxicity in vitro, caused minimal changes to the vaginal and rectal mucosa, without affecting functions of vaginal epithelial cells and normal vaginal flora. Later, the authors demonstrated the efficacy of the modified gel in experiments in vivo [77]. For example, gel protected 60% of animals from vaginal and 80% of animals from rectal infection with the high dose of HSV 2.…”

Herpes simplex virus 2 infection: molecular association with HIV and novel microbicides to prevent disease

“…This latter compound has been demonstrated to be innocuous for the vaginal tissue and its microflora, as well as preserve its pH in the presence of seminal plasma. Another microbicide with potential is the combination of zinc acetate and carrageenin (AZ/CG) ( Table 2) [182]. AZ/CG decreases up to 80 % infection with HSV-2 in macaques, and its activity would be mediated by the binding of Zn to viral membrane glycoproteins impairing the entry of the virus into target cells [183].…”