HIV, the retrovirus that causes AIDS, has escalated into a global pandemic that currently afflicts nearly 40 million people. Although small molecule antiretroviral therapies for HIV have been developed over the past 20 years, these treatments are unable to eradicate the virus from the host due to latent viral reservoirs in a small fraction of quiescent immune (T) cells. In particularly, post-integration latent reservoirs are composed of inactive viral DNA inserted into the cellular DNA of a long-lived memory T cell population. This reservoir poses the most significant barrier to HIV eradication because a patient's cells are not actively expressing genes in the HIV genome, but it may reactivate at any time to reseed a viral infection, meaning that patients must continue antiretroviral therapies throughout their lives.

The mechanism by which these latent reservoirs are established remains unknown; however, immediately after HIV enters a cell, it appears to face a critical fate choice between either active gene expression (which leads to rapid viral replication and cell death) or low levels of gene expression (which may lead to viral latency). In situations with slow reactions and/or low numbers of molecules (such as a single virus), stochastic or probabilistic effects in gene expression can be important. We hypothesized that stochastic effects in a positive feedback loop of the virus' gene regulation “circuit” could lead to significant delays in viral gene expression along with “flipping” between low and high viral expression levels. A combined experimental and computational system was developed to investigate this hypothesis, and it has yielded insights into the mechanisms by which the cellular signaling state and the viral integration site can combine to influence stochastic effects in viral gene activation, and thereby influence the establishment of latency.

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