The human immunodeficiency virus (HIV) presents a challenge to global health due to its sophisticated method of replication, which involves a complex series of interactions with an infected person’s cellular machinery. The virus relies on its own set of regulatory elements to take control of the host cell’s functions. A deeper look into how HIV manipulates the host cell reveals a system of remarkable efficiency.
Understanding the HIV Rev Protein
The Regulator of Virion Expression (Rev) is a small, regulatory protein produced from HIV’s genetic material. Its primary job is to control the expression of other viral genes, and its production signals a shift in the virus’s strategy inside the infected cell. Once produced, the Rev protein is transported into the cell’s nucleus. Inside the nucleus, Rev accesses the viral RNA transcripts that will be used to build new virus particles. The function of this protein is required for the virus to complete its replication cycle and produce new, infectious virions.
Rev’s Crucial Role in HIV RNA Export
The primary function of the Rev protein is to move specific HIV genetic blueprints, in the form of RNA, out of the cell’s nucleus. A cell normally has quality control systems that prevent incompletely processed RNA from leaving the nucleus, ensuring only mature messenger RNAs (mRNAs) are transported for protein production. HIV’s genetic material must bypass this rule to replicate.
HIV produces long, unspliced and shorter, singly spliced RNA transcripts that contain instructions for building the virus’s structural components. These transcripts are also the genetic material that will be packaged into new virus particles.
Without a way to exit the nucleus, these RNAs would be trapped and degraded by the host cell, halting viral production. Rev acts as a molecular escort for these viral RNAs. By binding to them, Rev signals the cell’s transport machinery that these specific RNAs are approved for export, overriding the cell’s normal quality control. This allows the unspliced and singly spliced viral RNAs to reach the cytoplasm for the production of new virions.
The Molecular Mechanism of Rev Action
Rev’s function lies in its ability to recognize and bind to a specific target. This target is a highly structured 351-nucleotide sequence within the viral RNA known as the Rev Response Element (RRE). The RRE is present only on the unspliced and singly spliced HIV RNAs, ensuring that Rev specifically selects the transcripts needed for the late phase of viral production. The protein itself has distinct domains that enable its function.
A nuclear localization signal (NLS) directs the newly made Rev protein from the cytoplasm into the host cell’s nucleus. Once inside, an arginine-rich motif on the protein binds directly to the RRE sequence on the viral RNA. Multiple Rev proteins can form a complex on a single RRE.
This Rev-RRE complex then uses the nuclear export signal (NES) on the Rev protein. The NES is recognized by a host cell protein, CRM1, which is a primary receptor for nuclear export. By latching onto the NES, the CRM1 system treats the entire viral RNA complex as cargo and guides it through the nuclear pore complex into the cytoplasm.
Consequences of Rev Function for HIV Propagation
The activity of the Rev protein creates a switch in the HIV life cycle, dividing it into an early and a late phase. In the early phase, without Rev, only small, completely spliced viral mRNAs can exit the nucleus. These early transcripts code for regulatory proteins, including Rev itself and another protein called Tat, which amplifies viral transcription. This initial phase sets the stage for viral assembly.
Once enough Rev protein accumulates in the nucleus, it triggers the transition to the late phase. By exporting the unspliced and singly spliced mRNAs, Rev enables the production of structural proteins. These include Gag proteins that form the viral core, Pol which includes enzymes for replication, and Env proteins that make up the viral envelope.
A non-functional Rev protein would halt this process. The structural and enzymatic proteins would not be synthesized, and the viral genomes would remain trapped in the nucleus. This stops the production of new virions and halts viral propagation.
Targeting Rev for Antiviral Therapies
Since the HIV replication cycle depends on Rev’s function, the protein is a potential target for antiviral drugs. The goal of such therapies is to block Rev’s mechanism, trapping the genetic blueprints for new viruses inside the nucleus. This strategy differs from many existing antiretroviral drugs that target viral enzymes.
Researchers have explored several ways to inhibit Rev. One focus is developing molecules that block the interaction between the Rev protein and the RRE on the viral RNA. If Rev cannot bind to the RRE, it cannot initiate the export process. The challenge is creating a specific drug that does not interfere with the host cell’s own proteins, which could cause side effects.
Another approach targets the interaction between Rev’s nuclear export signal and the host’s CRM1 export protein. A substance known as Leptomycin B, for example, binds to CRM1 and prevents Rev from using this pathway. However, developing safe CRM1 inhibitors for clinical use has been difficult because this pathway is also important for normal cellular functions. Despite these challenges, Rev’s function continues to make it a target for developing new HIV therapies.