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A hardwired HIV latency program.

TitleA hardwired HIV latency program.
Publication TypeJournal Article
Year of Publication2015
AuthorsRazooky, BS, Pai, A, Aull, K, IM Rouzine, Weinberger, LS
JournalCell
Volume160
Issue5
Pagination990-1001
Date Published2015 Feb 26
ISSN1097-4172
KeywordsCD4-Positive T-Lymphocytes, Cells, Cultured, HIV, Humans, tat Gene Products, Human Immunodeficiency Virus, Virus Latency
Abstract

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.

DOI10.1016/j.cell.2015.02.009
Alternate JournalCell
PubMed ID25723172
PubMed Central IDPMC4395878
Grant ListT32 GM008284 / GM / NIGMS NIH HHS / United States
T32 GM067547 / GM / NIGMS NIH HHS / United States
P50GM081879 / GM / NIGMS NIH HHS / United States
DP2 OD006677 / OD / NIH HHS / United States
P50 GM081879 / GM / NIGMS NIH HHS / United States
P30AI027763 / AI / NIAID NIH HHS / United States
T32 EB009383 / EB / NIBIB NIH HHS / United States
R01-AI109593 / AI / NIAID NIH HHS / United States
DP2-OD006677 / OD / NIH HHS / United States
S10 RR028962 / RR / NCRR NIH HHS / United States
R01 AI109593 / AI / NIAID NIH HHS / United States
P30 AI027763 / AI / NIAID NIH HHS / United States
U19 AI096113 / AI / NIAID NIH HHS / United States
U19AI096113 / AI / NIAID NIH HHS / United States
S10RR028962-01 / RR / NCRR NIH HHS / United States