HIV transactivation: Stochastic modeling for studying the effects of BET inhibitors on the modulation of P-TEFb levels

Abstract

Latency is the major obstacle in eradicating HIV from infected patients. Recent studies have shown that BET protein inhibitors can successfully reverse this latency by inhibiting the binding of BET proteins with positive cellular cofactor P-TEFb. Thus, availability of P-TEFbs plays an important role in HIV transactivation. However, in cells of our immune system which are primarily infected by the virus, number of P-TEFb is very low and is considered as one of the factors in inducing viral latency. At such small numbers of P-TEFb, the internal fluctuations can have a decisive role in the cell fate decision and fluctuations in the P-TEFb levels can switch the HIV to either a state of active replication or to a state of latency. Aimed at quantitative understanding of how BET inhibitors affect the statistics of P-TEFb level, we develop a coarse-grained stochastic model. However, the interaction between P-TEFb and BET proteins makes the problem analytically challenging. To address the nonlinearity arising due to such interactions, we use Langevin equation based approach to study the statistics of steady-state P-TEFb levels and explore the variations of some of the important quantities such as noise and fano factor associated with P-TEFb as well as correlations between BET and P-TEFb levels with model parameters. The analytic results derived exhibit that these quantities, in general, show non-monotonic response with respect to the parameters of the model. The results derived will be helpful in estimating the model parameters as well in identifying the pathways that can be intervened for effective HIV transactivation.

Keywords: BRD4 and P-TEFb regulation; HIV transactivation; Stochastic modeling.