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Virus infections in humans are characterized by a broad spectrum of the course and outcomes ranging from acute to chronic and lethal variants. Experimental and clinical studies of the pathogenesis of virus infections are based on the use of the high-throughput technologies for quantitative characterization of the system behavior at the molecular-, cellular-, tissue and systemic levels of regulation. Understanding of the multilayer regulatory mechanisms underlying the observed spectrum of the dynamics of infectious and the response to antiviral and immunomodulatory therapies represents a fundamental task requiring the application of systems approaches for their mathematical modelling. The infection is viewed as a trajectory of a dynamical system in the state space of the quantifiable characteristics of disease. The unfavorable course of infection is interpreted as abnormal systems dynamics. Some key issues and recent results in the development of integrative mathematical models of immune responses to experimental and human infections, such as LCMV and HIV are presented.