Abstract
Transcription of HIV provirus is a key step of the viral cycle, and depends on the recruitment of the cellular positive transcription elongation factor b (P-TEFb) to the HIV promoter. The viral transactivator Tat can displace P-TEFb from the 7SK small nuclear ribonucleoprotein, where it is bound and inactivated by HEXIM1, and bring it to TAR, which allows the stalled RNA polymerase II to transition to successful transcription elongation. In this study, we designed a chimeric inhibitor of HIV transcription by combining functional domains from HEXIM1 and Tat. The chimera (HT1) potently inhibited gene expression from the HIV promoter, by competing with Tat for TAR and P-TEFb binding, while keeping the latter inactive. HT1 inhibited spreading infection as well as viral reactivation in lymphocyte T cell line models of HIV latency, with little effect on cellular transcription and metabolism. This proof-of-concept study validates an innovative approach to interfering with HIV transcription via peptide mimicry and competition for RNA-protein interactions. HT1 represents a new candidate for HIV therapy, or HIV cure via the proposed block and lock strategy.
Highlights
Treatment with combination antiretroviral therapy leads to efficient suppression of HIV replication, but HIV persistence in latently infected cells remains an obstacle to cure [1]
We developed a new approach to inhibiting HIV transcription with a chimera derived from host and viral proteins involved in the regulation of HIV gene expression
We fused a domain from the viral transactivator Tat to two domains from the host cell transcription regulator HEXIM1
Summary
Treatment with combination antiretroviral therapy (cART) leads to efficient suppression of HIV replication, but HIV persistence in latently infected cells remains an obstacle to cure [1]. Suppressing residual HIV transcription is the goal of the emerging block and lock HIV cure strategies [9,10,11], which aim at deepening HIV latency so that integrated proviruses remains permanently locked in the infected cells. More studies are needed to determine whether a permanent state of latency can be reached after LPA treatment is interrupted This would validate block and lock strategies as a path to a functional cure and/or a faster reservoir decay, a process that is probably delayed by residual replication and cell proliferation [13]
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