The “gag sequence” refers to a gene found in retroviruses, a family of viruses that includes the human immunodeficiency virus (HIV). This gene contains the genetic instructions for producing the main structural proteins that form the core of a new virus particle. Understanding this sequence is fundamental to comprehending how these viruses build themselves within an infected cell. While this gene is present in many retroviruses, HIV provides a well-studied example to illustrate its general functions and significance.
The Gag Polyprotein and its Components
The term “Gag” stands for Group-specific antigen, reflecting its historical discovery as a common antigen among retroviruses. Gag is initially produced as a single, large polyprotein, meaning it is a long chain of amino acids that contains several distinct protein segments. This polyprotein is later cut into smaller, functional proteins by viral enzymes. For HIV, the Gag polyprotein, often referred to as Pr55Gag, is composed of four main structural domains: Matrix (MA), Capsid (CA), Nucleocapsid (NC), and p6, along with two short spacer peptides, SP1 and SP2.
The Matrix (MA) protein (p17) targets the entire Gag polyprotein to the inner surface of the host cell’s plasma membrane, anchoring the assembling virus. The Capsid (CA) protein (p24) forms the conical core that encapsulates the viral genome in the mature virus particle, creating its protective shell.
The Nucleocapsid (NC) protein (p7) directly binds to and packages two copies of the viral genomic RNA into the nascent virion. The p6 protein, located at the C-terminus of Gag, recruits host cell factors that facilitate the final pinching off of the new viral particle from the host cell membrane. The spacer peptides, SP1 and SP2, help regulate the precise and sequential cleavage of Gag by the viral protease during maturation.
Role in Viral Assembly and Budding
The formation of new virus particles, a process called assembly, begins in the cytoplasm of an infected cell after the Gag polyprotein is translated from viral RNA. Thousands of newly synthesized Gag polyproteins travel to the inner surface of the host cell’s plasma membrane, where they begin to cluster, driven by interactions between individual Gag molecules and the membrane. The viral genomic RNA is also recruited and packaged into this developing structure, primarily through interactions with the Nucleocapsid (NC) domain of Gag.
As more Gag polyproteins accumulate, they self-assemble into a spherical, immature particle. This immature particle encapsulates the viral RNA and other necessary viral enzymes, such as reverse transcriptase and integrase. The final step of this process is known as budding. During budding, the assembled, immature particle pushes outwards from the host cell membrane, effectively wrapping itself in a piece of the host cell’s outer surface to form its own outer envelope. This process culminates in the complete pinching off of the new, immature virus particle from the host cell.
Viral Maturation Post-Budding
Once the new virus particle has budded from the host cell, it is initially in an immature and non-infectious state. To become capable of infecting new cells, it must undergo maturation. This process is orchestrated by the viral enzyme called protease, which was packaged into the budding particle as part of the Gag-Pol polyprotein.
The activated protease precisely cuts the large Gag polyprotein at specific sites, separating it into its individual functional proteins: Matrix (MA), Capsid (CA), Nucleocapsid (NC), and p6, along with the spacer peptides. This series of cleavages triggers a significant structural rearrangement within the particle. The Capsid (CA) proteins re-form into a condensed, conical core structure. This distinct conical shape is a hallmark of a mature, infectious retrovirus, necessary for the virus to successfully infect a new host cell.
Targeting the Gag Sequence in Medicine
Understanding the Gag sequence and its associated processes is important for developing medical interventions against retroviruses like HIV. The various stages of viral assembly and maturation, which are largely driven by Gag, offer specific targets for antiviral drugs. One major class of HIV drugs, Protease Inhibitors (PIs), directly exploits the maturation process. These drugs work by binding to and blocking the activity of the viral protease enzyme.
When the protease is inhibited, it cannot cleave the Gag polyprotein into its functional components. As a result, the virus particles fail to mature and remain in their non-infectious, immature state. This prevents the virus from establishing new infections, thereby disrupting the viral life cycle. A related therapeutic strategy involves maturation inhibitors, which interfere with the final steps of Gag processing by targeting cleavage sites within the Gag polyprotein itself, rather than the protease enzyme directly. These inhibitors, like PIs, also lead to the production of non-infectious virions.