RESUMEN
Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) strategies with proven in vivo efficacy rely on antiretroviral drugs, creating the potential for drug resistance and complicated treatment options in individuals who become infected. Moreover, on-demand products are currently missing from the PrEP development portfolio. Griffithsin (GRFT) is a non-antiretroviral HIV entry inhibitor derived from red algae with an excellent safety profile and potent activity in vitro. When combined with carrageenan (CG), GRFT has strong activity against herpes simplex virus-2 (HSV-2) and human papillomavirus (HPV) in vitro and in vivo. Here, we report that GRFT/CG in a freeze-dried fast dissolving insert (FDI) formulation for on-demand use protects rhesus macaques from a high dose vaginal SHIV SF162P3 challenge 4 h after FDI insertion. Furthermore, the GRFT/CG FDI also protects mice vaginally against HSV-2 and HPV pseudovirus. As a safe, potent, broad-spectrum, on-demand non-antiretroviral product, the GRFT/CG FDI warrants clinical development.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/prevención & control , Antivirales/uso terapéutico , Carragenina/uso terapéutico , Herpes Genital/prevención & control , Infecciones por Papillomavirus/prevención & control , Lectinas de Plantas/uso terapéutico , Administración Intravaginal , Animales , Antivirales/química , Carragenina/química , Modelos Animales de Enfermedad , Composición de Medicamentos/métodos , Evaluación Preclínica de Medicamentos , Femenino , Liofilización , Herpes Genital/virología , Herpesvirus Humano 2/patogenicidad , Humanos , Macaca mulatta , Masculino , Infecciones por Papillomavirus/virología , Lectinas de Plantas/química , Lectinas de Plantas/genética , Lectinas de Plantas/aislamiento & purificación , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismo , Profilaxis Pre-Exposición/métodos , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Nicotiana/genética , Nicotiana/metabolismo , Resultado del Tratamiento , Vagina/virologíaRESUMEN
All pre-term newborns and a high proportion of term newborns develop neonatal jaundice. Neonatal jaundice is usually a benign condition and self-resolves within few days after birth. However, a combination of unfavorable complications may lead to acute hyperbilirubinemia. Excessive hyperbilirubinemia may be toxic for the developing nervous system leading to severe neurological damage and death by kernicterus. Survivors show irreversible neurological deficits such as motor, sensitive and cognitive abnormalities. Current therapies rely on the use of phototherapy and, in unresponsive cases, exchange transfusion, which is performed only in specialized centers. During bilirubin-induced neurotoxicity different molecular pathways are activated, ranging from oxidative stress to endoplasmic reticulum (ER) stress response and inflammation, but the contribution of each pathway in the development of the disease still requires further investigation. Thus, to increase our understanding of the pathophysiology of bilirubin neurotoxicity, encephalopathy and kernicterus, we pharmacologically modulated neurodegeneration and neuroinflammation in a lethal mouse model of neonatal hyperbilirubinemia. Treatment of mutant mice with minocycline, a second-generation tetracycline with anti-inflammatory and neuroprotective properties, resulted in a dose-dependent rescue of lethality, due to reduction of neurodegeneration and neuroinflammation, without affecting plasma bilirubin levels. In particular, rescued mice showed normal motor-coordination capabilities and behavior, as determined by the accelerating rotarod and open field tests, respectively. From the molecular point of view, rescued mice showed a dose-dependent reduction in apoptosis of cerebellar neurons and improvement of dendritic arborization of Purkinje cells. Moreover, we observed a decrease of bilirubin-induced M1 microglia activation at the sites of damage with a reduction in oxidative and ER stress markers in these cells. Collectively, these data indicate that neurodegeneration and neuro-inflammation are key factors of bilirubin-induced neonatal lethality and neuro-behavioral abnormalities. We propose that the application of pharmacological treatments having anti-inflammatory and neuroprotective effects, to be used in combination with the current treatments, may significantly improve the management of acute neonatal hyperbilirubinemia, protecting from bilirubin-induced neurological damage and death.