Abstract
Current antivirals effectively target diverse viruses at various stages
of their life cycles. Nevertheless, curative therapy has remained
elusive for important pathogens, such as human immunodeficiency virus
type 1 (HIV-1) and herpesviruses, in large part due to viral latency and
the evolution of resistance to existing therapies. Here, we review the
discovery of viral master circuits: virus-encoded autoregulatory gene
networks that autonomously control viral expression programs (i.e.,
between active, latent, and abortive fates). These circuits offer the
opportunity for a new class of antivirals that could lead to intrinsic
combination-antiviral therapies within a single molecule-evolutionary
escape from such circuit-disrupting antivirals would require
simultaneous evolution of both the viral cis regulatory element (e.g.,
the DNA-binding site) and the trans element (e.g., the transcription
factor) in order for the virus to recapitulate a circuit that would not
be disrupted. We review the architectures of these fate-regulating
master circuits in HIV-1 and the human herpesvirus cytomegalovirus along
with potential circuit-disruption strategies that may ultimately enable
escape-resistant antiviral therapies.
