Abstract
Biological circuits can be controlled by two general schemes:
environmental sensing or autonomous programs. For viruses such as HIV,
the prevailing hypothesis is that latent infection is controlled by
cellular state (i.e., environment), with latency simply an epiphenomenon
of infected cells transitioning from an activated to resting state.
However, we find that HIV expression persists despite the
activated-to-resting cellular transition. Mathematical modeling
indicates that HIV's Tat positive-feedback circuitry enables this
persistence and strongly controls latency. To overcome the inherent
crosstalk between viral circuitry and cellular activation and to
directly test this hypothesis, we synthetically decouple viral
dependence on cellular environment from viral transcription. These
circuits enable control of viral transcription without cellular
activation and show that Tat feedback is sufficient to regulate latency
independent of cellular activation. Overall, synthetic reconstruction
demonstrates that a largely autonomous, viral-encoded program underlies
HIV latency potentially explaining why cell-targeted latency-reversing
agents exhibit incomplete penetrance.
