A hardwired HIV latency program.
Biological circuits can be controlled by two general schemes: environmental sensing or autonomous programs. For viruses such as HIV, the prevailing hypothesis is that latent infection is controlled by cellular state (i.e., environment), with latency simply an epiphenomenon of infected cells transitioning from an activated to resting state. However, we find that HIV expression persists despite the activated-to-resting cellular transition. Mathematical modeling indicates that HIV's Tat positive-feedback circuitry enables this persistence and strongly controls latency. To overcome the inherent crosstalk between viral circuitry and cellular activation and to directly test this hypothesis, we synthetically decouple viral dependence on cellular environment from viral transcription. These circuits enable control of viral transcription without cellular activation and show that Tat feedback is sufficient to regulate latency independent of cellular activation. Overall, synthetic reconstruction demonstrates that a largely autonomous, viral-encoded program underlies HIV latency—potentially explaining why cell-targeted latency-reversing agents exhibit incomplete penetrance.
The Gladstone Institutes (Virology and Immunology), San Francisco, California Institute of Quantitative Biosciences, University of California, San Francisco, 94158; Biophysics Graduate Group, California Institute of Quantitative Biosciences, University of California, San Francisco, 94158.
Brandon S
BS
Razooky
The Gladstone Institutes (Virology and Immunology), San Francisco, California Institute of Quantitative Biosciences, University of California, San Francisco, 94158; Department of Biochemistry and Biophysics, California Institute of Quantitative Biosciences, University of California, San Francisco, 94158.
Anand
A
Pai
Biophysics Graduate Group, California Institute of Quantitative Biosciences, University of California, San Francisco, 94158.
Katherine
K
Aull
The Gladstone Institutes (Virology and Immunology), San Francisco, California Institute of Quantitative Biosciences, University of California, San Francisco, 94158.
Igor M
IM
Rouzine
The Gladstone Institutes (Virology and Immunology), San Francisco, California Institute of Quantitative Biosciences, University of California, San Francisco, 94158; Department of Biochemistry and Biophysics, California Institute of Quantitative Biosciences, University of California, San Francisco, 94158; QB3, California Institute of Quantitative Biosciences, University of California, San Francisco, 94158. Electronic address: leor.weinberger@gladstone.ucsf.edu.
Leor S
LS
Weinberger
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D006678:HIV / Q000502:physiology*; D006801:Humans; D017735:Virus Latency; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
D054322:tat Gene Products, Human Immunodeficiency Virus