Abstract
BackgroundInfectivity of retroviruses such as HIV-1 and MuLV can be abrogated by compounds targeting zinc finger motif in viral nucleocapsid protein (NC), involved in controlling the processivity of reverse transcription and virus infectivity. Although a member of a different viral family (Pneumoviridae), respiratory syncytial virus (RSV) contains a zinc finger protein M2-1 also involved in control of viral polymerase processivity. Given the functional similarity between the two proteins, it was possible that zinc finger-reactive compounds inactivating retroviruses would have a similar effect against RSV by targeting RSV M2-1 protein. Moreover, inactivation of RSV through modification of an internal protein could yield a safer whole virus vaccine than that produced by RSV inactivation with formalin which modifies surface proteins.ResultsThree compounds were evaluated for their ability to reduce RSV infectivity: 2,2'-dithiodipyridine (AT-2), tetraethylthiuram disulfide and tetramethylthiuram disulfide. All three were capable of inactivating RSV, with AT-2 being the most potent. The mechanism of action of AT-2 was analyzed and it was found that AT-2 treatment indeed results in the modification of RSV M2-1. Altered intramolecular disulfide bond formation in M2-1 protein of AT-2-treated RSV virions might have been responsible for abrogation of RSV infectivity. AT-2-inactivated RSV was found to be moderately immunogenic in the cotton rats S.hispidus and did not cause a vaccine-enhancement seen in animals vaccinated with formalin-inactivated RSV. Increasing immunogenicity of AT-2-inactivated RSV by adjuvant (Ribi), however, led to vaccine-enhanced disease.ConclusionsThis work presents evidence that compounds that inactivate retroviruses by targeting the zinc finger motif in their nucleocapsid proteins are also effective against RSV. AT-2-inactivated RSV vaccine is not strongly immunogenic in the absence of adjuvants. In the adjuvanted form, however, vaccine induces immunopathologic response. The mere preservation of surface antigens of RSV, therefore may not be sufficient to produce a highly-efficacious inactivated virus vaccine that does not lead to an atypical disease.
Highlights
Infectivity of retroviruses such as human immunodeficiency virus 1 (HIV-1) and murine leukemia virus (MuLV) can be abrogated by compounds targeting zinc finger motif in viral nucleocapsid protein (NC), involved in controlling the processivity of reverse transcription and virus infectivity
This paper reports that the zinc finger reactive compounds capable of inactivating HIV-1 and other retroviruses by targeting their nucleocapsid protein are capable of inhibiting respiratory syncytial virus (RSV) infectivity, and that this inhibition is accompanied by modification of the RSV zinc finger containing protein M2-1
This paper presents evidence that compounds that inactivate retroviruses by targeting the zinc finger motif in their nucleocapsid proteins are effective against human respiratory syncytial virus
Summary
Infectivity of retroviruses such as HIV-1 and MuLV can be abrogated by compounds targeting zinc finger motif in viral nucleocapsid protein (NC), involved in controlling the processivity of reverse transcription and virus infectivity. Formalin-inactivated respiratory syncytial virus (RSV) vaccine administered to infants and children in the United States in the 1960’s resulted in the enhancement of the disease after subsequent exposure of these children to RSV [4]. While the exact cause of such atypical responses to formalin-inactivated viruses is not known, one possible explanation is that traditional means of viral inactivation, such as formalin or heat treatment can denature virion surface proteins [6]. This would result in altered antigenicity of a virus, accompanied by an atypical and often harmful host response to infection. Viral inactivation with maximal preservation of its original structure may provide a solution for successful vaccine development against diseases currently refractory to vaccination
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