More than 20 years after the discovery of combination antiretroviral therapy (ART), complete eradication of HIV infection has not yet been achieved. While ART controls viral replication, it is not a cure. This is due to HIV latency, in which the virus is hidden in an inactive state in the genomes of long-living host cells (such as memory CD4 T cells). This allows the virus to evade immune surveillance. As ART acts on the viral replication machinery, latent HIV that is not actively replicating can escape ART. Thus, a cure for HIV requires the ability to either eliminate the latent reservoir or to permanently silence the provirus in the reservoir (or a combination of both).
To improve our understanding of what host genes are require forHIV to emerge from latency, ina newstudy published inViruses, researchers from the Emerman lab in the Human Biology and Basic Sciences Divisions reported that the host factor Cyclin T1 is required for promoting HIV reactivation under a large variety of conditions that would otherwise activate it.
Terry Hafer, the lead author of the study and a graduate student in the Emerman lab, performed a latency HIV-CRISPR screen to identify host factors required for HIV to come out of latency in the presence of small molecule latency reactivation agents (LRAs). Cyclin T1 (CCNT1) was the top hit on the screen.It has been shown previously that Cyclin T1 and Cyclin-dependent kinase 9 (CDK9) form a complex with the positive transcription elongation factor b (P-TEFb) to promote HIV transcription elongation. Cyclin T1 and its role in viral transcription elongation is not novel, said Hafer.But what was striking for us was that Cyclin T1 has always been implicated as an essential gene for its role in transcription elongation as part of the P-TEFb complex, he added. Knockouts of Cyclin T1 showed that cyclin T1 loss impacted HIV gene transcription far more than any other host gene, however, Cyclin T1 knockout did not have noticeable effects on host cell function, Hafer explained.
The latency HIV-CRISPR screen was performed on infected Jurkat T cells (J-Lats 10.6 and 5A8) using a HIV dependency factor gene library (HIV-Dep). Here is the catch, the guide RNAs have been modified to be incorporated into the newly produced virions of the infected cells after LRA treatment. The idea behind this was that if a cell lacks a gene that is essential for latency, HIV will not reactivate. Consequently, the specific guide RNA (targetinga gene essential for reactivation) will not be packaged into newly formed virions.By performing deep sequencing, the team was able to identify guide RNA sequences that are underrepresented in the pool of released viruses. One of the top hits on the screen was Cyclin T1 (CCNT1). To validate the screen, the team knocked out CCNT1 in J-Lats cells, followed by treatment with several LRAs. In all treatments, wild-type (WT) CCNT1 cells were able to reactivate HIV, but KO CCNT1 cells failed to reactivate HIV in the presence of LRAs, indicating that Cyclin T1 is essential for HIV reactivation from latency. Moreover, loss of CCNT1 did not affect the expression of CCNT2, a paralog of CCNT1 that also binds to CDK9 as part of complex p-TEFb, suggesting that CCNT1 plays a unique role. Furthermore, CCNT1 KO did not affect cell proliferation in the J-Lat model. The findings were validated in primary CD4 T cells (the primary target of HIV in infected individuals) as well as the loss of CCTN1 did not affect the activation of primary CD4 T cells.
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