CpG methylation and methionine metabolism account for phenotypic bifurcation of HIV transcription: a unique case of a pure epigenetic phenomenon

HIV transcription is characterized by its stochastic nature, which plays a pivotal role in determining the fate of a provirus—active replication or latent infection—and is therefore a critical determinant of the HIV latency establishment. Building upon our previous work, we identified a unique phenotype of stochastic HIV transcription in a Jurkat T cell clonal model harboring a single lentiviral-based vector, herein referred to as the HIV transcription-sensitized model. A defining feature of this cellular model is that the turnover of HIV transcription shows elevated frequency—a phenomenon designated phenotypic bifurcation—suggesting that, under certain conditions, the regulation of stochastic HIV transcription can be a pure epigenetic phenomenon. In continuation of and to further substantiate this premise, the present study characterizes the contributions of epigenetic regulation of CpG methylation, methionine metabolism that coordinates cell cycle events, and HIV antisense transcription to this phenomenon. This work adds direct causal evidence to the hypothesis that a potential lag prior to the entry of the G2 phase in the bifurcated state of low HIV transcription may serve as one of the underlying mechanisms that lead to the high CpG methylation level compared with that measured in the state of high HIV transcription, contributing to the cyclical turnover of phenotypic bifurcation of HIV transcription.