When the human immunodeficiency virus (HIV) infects a cell, it inserts its genetic instructions into the host’s DNA, creating what is called a provirus. At both ends of this provirus are identical sequences of genetic material known as the Long Terminal Repeat, or LTR. The LTR functions as a control panel, dictating whether the virus will actively replicate or remain dormant and hide from the immune system.
This dual capability makes the LTR a central element in the lifecycle of HIV. It contains all the necessary signals to control the expression of the virus’s genes. When cellular conditions are favorable, the LTR initiates the production of new viral components, but it can also shut down this process entirely.
The Structure and Genetic Blueprint
The HIV LTR is composed of three distinct regions, each with a specific role: U3, R, and U5. After the virus converts its RNA into DNA, these regions are duplicated to form a complete LTR at each end of the proviral DNA. The 5′ LTR, located at the beginning of the viral genes, acts as the primary promoter for viral gene expression.
The U3, or Unique 3′, region functions as the command center for initiating viral activity. It contains enhancer and promoter elements that are docking sites for proteins from the host cell. These sites attract transcription factors like Nuclear Factor-kappa B (NF-κB) and Specificity Protein 1 (Sp1), which turn on the transcription of viral genes.
Following U3 is the R, or Repeated, region. This segment serves as the starting point for transcribing viral RNA and contains the Trans-activation response element (TAR). The TAR element forms a stable stem-loop structure in the new viral RNA, which acts as a binding site for a viral protein that enhances the rate of transcription.
The final component is the U5, or Unique 5′, region. This section plays a part in reverse transcription, ensuring the viral RNA is accurately copied into DNA. It also contains sequences involved in the final processing of new viral RNA, preparing the genetic material for packaging into new virus particles.
Driving Viral Replication
In an active HIV infection, the LTR drives the continuous production of new virus particles. The process begins when an infected host cell, such as an immune T-cell, becomes activated. This activation leads to an abundance of host transcription factors like NF-κB, which bind to the LTR’s U3 region and kick off a low level of HIV gene transcription.
This initial transcription is inefficient but produces small quantities of early viral proteins, including Tat (Trans-Activator of Transcription). Tat acts as a potent accelerator by binding to the TAR element in the R region of the newly forming viral RNA strands.
The interaction between Tat and TAR is a turning point in the replication cycle. By binding to TAR, Tat recruits cellular proteins that “supercharge” the RNA polymerase II enzyme, making it highly effective. The result is a massive amplification of viral RNA production, leading to the synthesis of all components needed to assemble thousands of new, infectious virus particles.
The Key to Viral Latency and Persistence
The same LTR that directs viral production is also responsible for HIV’s ability to become dormant. This state, known as latency, occurs when an infected cell is not active. In these quiet cells, the host transcription factors needed to initiate replication are not available, so the LTR’s “on-switch” cannot be flipped.
With the LTR promoter inactive, the HIV provirus remains integrated within the host cell’s DNA but does not produce any viral RNA or proteins. This dormant state makes the infected cell invisible to the immune system, as there are no viral components on the cell surface to signal its presence.
This collection of latently infected cells forms the latent reservoir, which is the primary reason current antiretroviral therapy (ART) cannot cure HIV. ART is effective at stopping active viral replication but has no effect on the silent proviruses. If a resting cell with a dormant provirus is reactivated, the necessary host factors become available, restarting viral replication.
A Target for Future HIV Therapies
The LTR’s control over the switch between replication and dormancy has made it a primary target for HIV cure strategies. Since the latent reservoir is the main barrier to a cure, researchers are developing methods to manipulate the LTR to eliminate these hidden viruses. The most prominent of these strategies is known as “shock and kill.”
The “shock” part of this strategy uses drugs called Latency Reversing Agents (LRAs) to force the LTR to activate. These agents artificially stimulate the host cell pathways that activate transcription factors. By turning the LTR to the “on” position, these drugs awaken the dormant provirus, causing it to begin producing viral proteins.
Once the virus is reactivated, the “kill” phase can begin. The production of viral proteins makes the formerly latent cell visible to the immune system, which can then recognize and destroy it. Researchers are also exploring combining LRAs with other therapies, such as therapeutic vaccines or engineered immune cells, to enhance the clearance of these newly awakened cells. This approach represents a promising path toward a functional cure for HIV.