Transcriptional and Posttranscriptional Regulation of HIV-1 Gene Expression

Abstract

Control of HIV-1 gene expression depends on two viral regulatory proteins, Tat and Rev. Tat stimulates transcription elongation by directing the cellular transcriptional elongation factor P-TEFb to nascent RNA polymerases. Rev is required for the transport from the nucleus to the cytoplasm of the unspliced and incompletely spliced mRNAs that encode the structural proteins of the virus. Molecular studies of both proteins have revealed how they interact with the cellular machinery to control transcription from the viral LTR and regulate the levels of spliced and unspliced mRNAs. The regulatory feedback mechanisms driven by HIV-1 Tat and Rev ensure that HIV-1 transcription proceeds through distinct phases. In cells that are not fully activated, limiting levels of Tat and Rev act as potent blocks to premature virus production.A fter integration into the host genome, the HIV-1 provirus acts as a transcription template that is regulated at the transcriptional and posttranscriptional levels. Immediately after infection, HIV-1 produces only short completely spliced mRNAs encoding the viral regulatory proteins Tat and Rev. As the infection proceeds, transcription increases sharply, and larger, incompletely spliced mRNAs are produced. These encode Env and the HIV-1 accessory genes Vif, Vpr, and Vpu. Also synthesized late are the full-length unspliced transcripts which act both as the virion genomic RNA and the mRNA for the Gag-Pol polyprotein (Kim et al. 1989;Pomerantz et al. 1990).This complex pattern of gene expression is controlled by the regulatory proteins Tat and Rev. Tat activates viral transcription by stimulating elongation from the viral long terminal repeat (LTR). Rev transports the unspliced and incompletely spliced mRNAs encoding the structural proteins from the nucleus to the cytoplasm. In this article, we review our current understanding of how these unique regulatory proteins orchestrate HIV-1 gene expression through their interactions with the cellular transcription, RNA splicing, and RNA transport machinery.

HIV Pathogenesis: Dynamics and Genetics of Viral Populations and Infected Cells

“…As discussed in other articles in this collection (Hu and Hughes 2011;Karn and Stoltzfus 2011;Malim and Bieniasz 2011), the relative contribution of these mechanisms is a matter of some debate. Whatever the source, the overall single-step point mutation rate for HIV-1 is 3 Â 10 25 mutations per base per replication cycle, and about 10-fold less for transversions than transitions (Mansky and Temin 1995).…”

HIV-1 splicing is controlled by local RNA structure and binding of splicing regulatory proteins at the major 5′ splice site

“…Splicing has to be strictly regulated to allow the balanced production of all viral RNAs and proteins. The HIV-1 transcript contains several SREs to enhance or inhibit splicing at nearby positioned splice sites (Damgaard et al, 2002;Karn & Stoltzfus, 2012;Leblanc et al, 2013;Stoltzfus, 2009;Stoltzfus & Madsen, 2006;Tange et al, 2001;Zahler et al, 2004). Furthermore, usage of HIV-1 splice sites can be influenced by local RNA structure (Abbink & Berkhout, 2008;Jacquenet et al, 2001;Mueller et al, 2014;Zychlinski et al, 2009 59 ), which will allow efficient U1 snRNA annealing and splicing.…”

Cyclin T1 and CDK9 T-Loop Phosphorylation Are Downregulated during Establishment of HIV-1 Latency in Primary Resting Memory CD4+T Cells

“…Studies have shown that various factors operating at the levels of transcription and posttranscription can restrict the expression of the integrated provirus in resting CD4 ϩ T cells (5,6). Transcriptional blocks to productive HIV-1 replication include epigenetic modifications at the viral long terminal repeat (LTR) and inadequate availability of activation-dependent transcription factors such as P-TEFb, NF-B, NFAT, Sp1, AP-1, and C/EBP (7)(8)(9)(10).…”