HIV’s ability to establish a long-lived dormant-like state (called “proviral latency”) is the chief barrier to therapeutic eradication with combination anti-retroviral therapies (ART).  However, latency was thought to play no role in the natural evolutionary history of the virus.  Latency was believed to be an “epiphenomenon” resulting from HIV infection of lymphocytes as they silenced during transitioning from activated to resting-memory cells. Our studies overturned this dogma in the field by showing that HIV latency is not an “epiphenomenon” driven by cellular silencing but is a viral-encoded ‘bet-hedging’ program driven by HIV’s Tat gene-regulatory circuit (Razooky et al. 2015).

Part of the reason latency was thought to be an epiphenomenon for so long was that no evolutionary benefit was proposed for the latent state.  The dogma held that ART, a modern intervention, could not have influenced historic viral evolution and since HIV mutates quickly enough to evade immune responses, unlike herpesviruses, no latent reservoir was needed.  Our studies provided a theoretical basis for why such a viral-encoded ‘bet-hedging’ program might exist: to protect against viral extinction in target poor environments, e.g. the mucosa, during early infection (Rouzine et al. 2015).

For review:  Weinberger and Weinberger Cell 2013.

Papers of note: Razooky, Pai et al. Cell 2015 (linked above) and Rouzine et al. Cell 2015.