期刊
CELL
卷 160, 期 5, 页码 990-1001出版社
CELL PRESS
DOI: 10.1016/j.cell.2015.02.009
关键词
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资金
- NSF [1144247]
- NIH [R01-AI109593, DP2-OD006677]
- Center for Synthetic and Systems Biology at UCSF [P50GM081879]
- NIH Delaney CARE Collaboratory of AIDS Researchers for a Cure [U19A1096113]
- UCSF-GIVI CFAR [P30AI027763, S10RR028962-01]
- Alfred P. Sloan Foundation
- Pew Scholar's in the Biomedical Sciences
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR028962] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P30AI027763, R01AI109593, U19AI096113] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [T32EB009383] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P50GM081879, T32GM067547, T32GM008284] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [DP2OD006677] Funding Source: NIH RePORTER
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.
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