Box 1. Virus-host interactions as a paradigm for systems analysis

Researchers at the Institute for Systems Biology (ISB, Seattle, WA) have nicely summarized the properties of biological systems that make them attractive for systems-level exploration—emergent properties, robustness and modularity⁵⁷. Emergence is a trait in which the whole is greater than the sum of the parts; robustness is characteristic of resilience to fluctuations in the immediate environment resulting from redundancy and control mechanisms; modularity is a phenomenon that explains the 'clustering' of parts into a functional or structural entity. That said, certain features of virus-host interactions make them particularly interesting for global investigations. A case in point for emergent properties is the discovery of aberrant innate immune responses in macaques lethally infected by the 1918 influenza virus¹⁶. Robustness of HIV through latency and rapid low-fidelity turnover is widely recognized as a factor for continued infection and resistance. Modularity in predicted varicella zoster virus–human and KSHV-human networks was seen in Uetz's work²⁶, although the intraviral interactomes lacked clustering and were tightly connected. Taken together, these examples demonstrate that virus-host interplay provides a rich opportunity for large-scale analyses (see main text for a variety of illustrative studies).