Social reward: interactions with social status, social communication, aggression, and associated neural activation in the ventral tegmental area.

Nearly all species engage in a variety of intraspecific social interactions, and there is evidence that these interactions are rewarding. Less is known, however, about the factors that influence social reward. Using the conditioned place preference paradigm, we tested whether social interactions are rewarding for male Syrian hamsters. We also tested whether social stimuli increase neural activation in the ventral tegmental area (VTA), a component of the mesolimbic reward system, and how individual differences in social behavior and experience influence neural activation. In the present study, we found that hamsters developed a conditioned place preference for social interactions, but the effects were significantly stronger in dominant animals compared with subordinates. The number of Fos-immunoreactive cells in the VTA was significantly higher in hamsters that had engaged in a direct social encounter compared with hamsters exposed to a caged stimulus hamster or controls. Interestingly, socially experienced males had more Fos-immunoreactive cells in the VTA than socially naive males after exposure to a social stimulus. Surprisingly, the amount of Fos immunoreactivity in the VTA induced by a social stimulus was correlated with the amount of aggressive/dominance behaviors that had been observed during interactions that had occurred 2 months earlier. Our results indicate that social interactions between males are rewarding, and that social dominance increases the reward value. Social interactions stimulate the mesolimbic reward system, and social experience enhances its response to novel social stimuli and may produce long-term changes in the neural mechanisms that mediate the maintenance of dominance over long periods of time.

Targeting the proteolytic processing of the viral glycoprotein precursor is a promising novel antiviral strategy against arenaviruses.

A crucial step in the arenavirus life cycle is the biosynthesis of the viral envelope glycoprotein (GP) responsible for virus attachment and entry. Processing of the GP precursor (GPC) by the cellular proprotein convertase site 1 protease (S1P), also known as subtilisin-kexin-isozyme 1 (SKI-1), is crucial for cell-to-cell propagation of infection and production of infectious virus. Here, we sought to evaluate arenavirus GPC processing by S1P as a target for antiviral therapy using a recently developed peptide-based S1P inhibitor, decanoyl (dec)-RRLL-chloromethylketone (CMK), and the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). To control for off-target effects of dec-RRLL-CMK, we employed arenavirus reverse genetics to introduce a furin recognition site into the GPC of LCMV. The rescued mutant virus grew to normal titers, and the processing of its GPC critically depended on cellular furin, but not S1P. Treatment with the S1P inhibitor dec-RRLL-CMK resulted in specific blocking of viral spread and virus production of LCMV. Combination of the protease inhibitor with ribavirin, currently used clinically for treatment of human arenavirus infections, resulted in additive drug effects. In cells deficient in S1P, the furin-dependent LCMV variant established persistent infection, whereas wild-type LCMV underwent extinction without the emergence of S1P-independent escape variants. Together, the potent antiviral activity of an inhibitor of S1P-dependent GPC cleavage, the additive antiviral effect with ribavirin, and the low probability of emergence of S1P-independent viral escape variants make S1P-mediated GPC processing by peptide-derived inhibitors a promising strategy for the development of novel antiarenaviral drugs.

Site 1 protease is required for proteolytic processing of the glycoproteins of the South American hemorrhagic fever viruses Junin, Machupo, and Guanarito.

The cellular proprotein convertase site 1 protease (S1P) has been implicated in the proteolytic processing of the glycoproteins (GPs) of Old World arenaviruses. Here we report that S1P is also involved in the processing of the GPs of the genetically more-distant South American hemorrhagic fever viruses Guanarito, Machupo, and Junin. Efficient cleavage of Guanarito virus GP, whose protease recognition sites deviate from the reported S1P consensus sequence, indicates a broader specificity of S1P than anticipated. Lack of GP processing of Junin virus dramatically reduced production of infectious virus and prevented cell-to-cell propagation. Infection of S1P-deficient cells resulted in viral persistence over several weeks without the emergence of escape variants able to use other cellular proteases for GP processing.