Novel approaches and challenges to treatment of central nervous system viral infections

Abstract

Existing and emerging viral CNS infections are major sources of human morbidity and mortality. Treatments of proven efficacy are currently limited predominantly to herpesviruses and human immunodeficiency virus. Development of new therapies has been hampered by the lack of appropriate animal model systems for some important viruses and by the difficulty in conducting human clinical trials for diseases that may be rare, or in the case of arboviral infections, often have variable seasonal and geographic incidence. Nonetheless, many novel approaches to antiviral therapy are available including candidate thiazolide and purazinecarboxamide derivatives with potential broad-spectrum antiviral efficacy. New herpesvirus drugs include viral helicase-primase and terminase inhibitors. The use of antisense oligonucleotides and other strategies to interfere with viral RNA translation has shown efficacy in experimental models of CNS viral disease. Identifying specific molecular targets within viral replication cycles has led to many existing antivirals and will undoubtedly continue to be the basis of future drug design. A promising new area of research involves therapies based on enhanced understanding of host antiviral immune responses. Toll-like receptor agonists, and drugs that inhibit specific cytokines as well as interferon preparations have all shown potential therapeutic efficacy. Passive transfer of virus-specific cytotoxic T-lymphocytes have been used in humans and may provide an effective therapies for some herpesvirus infections and potentially for progressive multifocal leukoencephalopathy. Humanized monoclonal antibodies directed against specific viral proteins have been developed and in several cases evaluated in humans in settings including West Nile virus and HIV infection and in pre-exposure prophylaxis for rabies.

Viral diseases of the central nervous system

“…The IFN-I pathway, for example, plays an important role in the CNS defense against most viral infections [136], and modulation of this pathway might provide a therapeutic means to control the magnitude of CNS inflammatory responses. Many advances in our understanding of neurotropic viruses have been made thus far, but more research is required to improve our ability to rapidly diagnose and then treat CNS infections [137], especially for viruses like JCV that have no animal model. Viral diseases of the CNS represent a significant burden to the global community, and the only way to lessen this burden is through a concerted research effort that involves pathogen discovery, animal model and therapeutic development, and intervention studies.…”

Therapeutic antiviral T cells noncytopathically clear persistently infected microglia after conversion into antigen-presenting cells

“…A primary challenge in the biomedical research community is devising efficacious strategies to purge viral infections. Prevention of infection through vaccination has yielded a myriad of successes ( Plotkin, 2009 ; Koff et al, 2013 ), but therapeutic elimination of viruses has proven more difficult to accomplish, particularly during states of persistence ( Nath and Tyler, 2013 ). One approach that is gaining considerable momentum is referred to as adoptive immunotherapy or immunocytotherapy ( Volkert, 1962 , 1963 ; Oldstone et al, 1986 ).…”

Dendritische Nanostrukturen zur rezeptorvermittelten Aufnahme von siRNA in neurale Zellen

“…Schließlich sollte untersucht werden, ob die neuartigen dendritischen siRNA‐Nanopartikel eine medizinisch relevante Funktion in primären Neuronen, die mit herkömmlichen Methoden kaum zu transfizieren sind, erfüllen können 3f. 14 Als Ziel wählten wir dabei das neurotrope Tollwutvirus (RABV). Tollwut verursacht mehr als 55 000 Todesfälle pro Jahr und kann nach dem Einsetzen klinischer Symptome nicht mehr behandelt werden 15.…”