- The reservoir of HIV latently infected cells is the major obstacle for complete eradication of HIV. Cells harboring latent HIV are undetectable to the immune system.
- Latency and its transactivation in HIV-infected cells are controlled by the intracellular HIV Tat gene circuit. By reconstructing the probability landscape of the circuit, computing the exact solution of the underlying chemical master equation, the authors examined the detailed mechanism of probabilistic intracellular control of latency and transactivation.
- They also suggested that the genetic switch, which causes latent HIV inside cells to begin to replicate, can be manipulated to completely eradicate the virus from the human body.
During infection, the DNA of HIV integrates itself into the host genome. The Tat gene circuit is a key piece of HIV DNA that controls the HIV gene transcription and activation. When activated, it initiates a takeover of the cell's machinery to churn out new copies of the HIV virus, which infect neighboring cells. HIV-specific immune effector cells kill cells infected with HIV, but only when the cells are being used to produce many copies of the virus (Tat gene circuit on). In cells that are latently infected, the Tat gene circuit is off, and HIV is quiescent.
By targeting the Tat gene circuit with drugs or small molecules to activate it, it would be possible to cause latently-infected cells to start producing more virus to make them a target for the immune system.
Techniques developed to reactivate latent HIV-infected cells (known as «shock and kill») have had mixed results, mostly because it relies on histone deacetylase (HDAC) inhibitors that come with severe adverse effects.
The Tat gene circuit has a random probability of being active or inactive. The switch from inactive to active can happen spontaneously. In HIV-infected cells, reactivation of the Tat gene circuit is still a very rare event.
The authors developed advanced computational algorithms to study the Tat gene circuit under different conditions. They were able to map a probability landscape of the cellular reactions that can impact Tat gene circuit reactivation, suggesting ways to manipulate the circuit to make the «shock and kill» technique more effective. They also tested a «block and lock» strategy, where viral particles are locked into latency by permanently blocking activation of the Tat gene circuit.
The results suggest that controlling HIV latency through manipulation of the Tat gene circuit could be an effective therapeutic strategy to eradicate the infection.
Funding: US Department of Energy, National Institutes of Health; Center for Nonlinear Studies at the Los Alamos National Laboratory.