The use of vaginal microbicides has gained support as a strategy for the protection of women against HIV-1 and other sexually transmitted disease (STD) pathogens. The preclinical Swiss Webster murine model has been developed to specifically measure cervicovaginal tissue integrity and inflammation following application of candidate vaginal microbicides, when potential exposure to an STD pathogen may occur. This model demonstrates both mechanistic and temporal differences in inflammatory responses following microbicide exposure. Currently, specific markers of inflammation, including pro-inflammatory cytokines, are being evaluated in the cervicovaginal mucosa. Safety profiles of polybiguanides (PBGs), which demonstrated significant in vitro efficacy against HIV-1, are being assessed in vivo. Intravaginal application of PEHMB (1%) resulted in little or no cervicovaginal toxicity after shortor long-term exposure. Collectively, these studies support the Swiss Webster model as a valuable tool for the preclinical assessment of toxicity and inflammation associated with exposure to candidate topical microbicides. Furthermore, these results strongly support further development of polybiguanide derivatives as vaginal microbicidal agents. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005
An alternating copolymer of styrene and maleic acid ( alt -PSMA) differs from other polyanionic antiviral agents in that the negative charges of alt -PSMA are provided by carboxylic acid groups instead of sulfate or sulfonate moieties. We hypothesized that alt -PSMA would have activity against human immunodeficiency virus type 1 (HIV-1) comparable to other polyanions, such as the related compound, poly(sodium 4-styrene sulfonate) (PSS). In assays using cell lines and primary immune cells, alt -PSMA was characterized by low cytotoxicity and effective inhibition of infection by HIV-1 BaL and IIIB as well as clinical isolates of subtypes A, B, and C. In mechanism of action assays, in which each compound was added to cells and subsequently removed prior to HIV-1 infection (“washout” assay), alt -PSMA caused no enhancement of infection, while PSS washout increased infection 70% above control levels. These studies demonstrate that alt -PSMA is an effective HIV-1 inhibitor with properties that warrant further investigation.
We previously demonstrated that the biguanide-based compound NB325 inhibits human immunodeficiency virus type 1 (HIV-1) infection by interacting with the CXCR4 viral coreceptor. This interaction also appeared to be persistent, since HIV-1 infection was inhibited even when the virus was introduced subsequent to the removal of NB325 from the cell culture medium. The present studies were conducted to determine the extent and mechanism of this prolonged antiviral activity. Persistent inhibition of HIV-1 infection by NB325 was concentration dependent and was apparent up to 8 h after removal of the compound. Flow cytometric analyses of stimulated CD4(+) T lymphocytes exposed to NB325 demonstrated concentration-dependent reductions in CXCR4 extracellular loop 2 epitope recognition that were maintained up to 24 h after removal of the compound. CXCL12-induced chemotaxis was also persistently inhibited following pre-exposure to NB325. These results demonstrate that persistent inhibition of X4 HIV-1 infection by NB325 involves extended perturbation of the viral coreceptor CXCR4.
Human semen is a complex medium containing high concentrations of cytokines, chemokines, and growth factors that play key roles in orchestrating immune responses during reproduction.These factors are essential to establishing conditions that facilitate fertilization and embryogenesis through modulation of local immune responses in the female reproductive tract.Typically, semen initiates a biphasic process of inflammation that is gradually resolved, leading to immune cell recruitment pivotal to clearing excess sperm and establishing tolerance of the fetal allograft.However, the identity and concentration of factors found in semenmay be altered in the male reproductive tract as a consequence of sexually transmitted infections and infertility conditions.As a result, imbalances in semen content can skew the secretory response of the cervicovaginal epithelium after deposition during heterosexual intercourse, which may distort local immune activity and lead to embryo rejection or enhanced pathogen transmission.Recognizing the array of factors contained in semen and the degree to which they vary is an essential part of understanding the impact of variations in semen content on reproductive biology and the transmission of sexually transmitted disease pathogens.
This study investigated the use of glutathione as a marker to establish a correlation between plasma parameters and the resultant liquid chemistry from two distinct sources to predefined biological outcomes. Two different plasma sources were operated at parameters that resulted in similar biological responses: cell viability, mitochondrial activity, and the cell surface display of calreticulin. Specific glutathione modifications appeared to be associated with biological responses elicited by plasma. These modifications were more pronounced with increased treatment time for the European Cooperation in Science and Technology Reference Microplasma Jet (COST-Jet) and increased frequency for the dielectric barrier discharge and were correlated with more potent biological responses. No correlations were found when cells or glutathione were exposed to exogenously added long-lived species alone. This implied that short-lived species and other plasma components were required for the induction of cellular responses, as well as glutathione modifications. These results showed that comparisons of medical plasma sources could not rely on measurements of long-lived chemical species; rather, modifications of biomolecules (such as glutathione) might be better predictors of cellular responses to plasma exposure.
Recent studies of cellulose-based polymers substituted with carboxylic acids like cellulose acetate phthalate (CAP) have demonstrated the utility of using carboxylic acid groups instead of the more common sulfate or sulfonate moieties. However, the pK(a) of the free carboxylic acid group is very important and needs careful selection. In a polymer like CAP the pK(a) is approximately 5.28. This means that under the low pH conditions found in the vaginal lumen, CAP would be only minimally soluble and the carboxylic acid would not be fully dissociated. These issues can be overcome by substitution of the cellulose backbone with a moiety whose free carboxylic acid group(s) has a lower pK(a). Hydroxypropyl methylcellulose trimellitate (HPMCT) is structurally similar to CAP; however, its free carboxylic acids have pK(a)s of 3.84 and 5.2. HPMCT, therefore, remains soluble and molecularly dispersed at a much lower pH than CAP. In this study, we measured the difference in solubility and dissociation between CAP and HPMCT and the effect these parameters might have on antiviral efficacy. Further experiments revealed that the degree of acid substitution of the cellulose backbone can significantly impact the overall efficacy of the polymer, thereby demonstrating the need to optimize any prospective polymer microbicide with respect to pH considerations and the degree of acid substitution. In addition, we have found HPMCT to be a potent inhibitor of CXCR4, CCR5, and dual tropic strains of human immunodeficiency virus in peripheral blood mononuclear cells. Therefore, the data presented herein strongly support further evaluation of an optimized HPMCT variant as a candidate microbicide.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Pathogenic viruses cause many human, animal, and plant diseases that are associated with substantial morbidity, mortality and socio-economic impact. Although effective strategies for combatting virus transmission and associated disease are available, global outbreaks of viral pathogens such as the virus responsible for the COVID-19 pandemic demonstrate that there is still a critical need for new approaches that can be used to interrupt the chain of viral infection and mitigate virus-associated pathogenesis. Recent studies point to non-thermal plasma (NTP), a partly ionized gas comprised of a complex mixture of reactive oxygen and nitrogen species along with physical effectors, as the potential foundation for new antiviral approaches. A more thorough understanding of the antiviral properties and safety of NTP has stimulated explorations of NTP as the basis for treatments of viral diseases. The recently described immunomodulatory properties of NTP are also being evaluated for potential use in immunotherapies of viral diseases as well as in antiviral vaccination strategies. In this review, we present the current state-of-the-art in addition to compelling arguments that NTP merits further exploration for use in the prevention and management of viral infections and associated diseases.
