Brandon S. Razooky

Nanofabrication Research Laboratory Group & Center for Nanophase Materials Sciences

Oak Ridge National Laboratory

Regulation of HIV persistence: a stochastic, virally controlled process

Proviral latency is the main persistence mechanism that precludes eradication of human immunodeficiency virus, HIV, from infected patients.  Although latency is a viral phenotype, current theories posit that HIV latency is not 'hardwired' into viral circuitry but directly under cell-state control.  Therefore, latency is thought to be a deterministic epiphenomenon with no role in the natural history of the virus.  Here, we synthetically reconstruct HIV regulatory circuitry to define the role of viral gene circuitry and cellular state in regulating latency.  The reconstructed circuits demonstrate that latency is largely autonomous to cellular state in both minimal circuits and full-length replicating viruses.  Strikingly, in primary cells, cell-driven silencing of viral transcription - the prevailing hypothesis for latency establishment - is averted by tuning viral feedback strength.  Overall these results argue that HIV latency is an intrinsic, stochastic feature of the virus that most likely occurs early in the viral lifecycle.  Given the rapid mutation rate of HIV, selection for and conservation of the latency phenotype suggests it has a fitness role in the natural history of the virus.