The Human Immunodeficiency Virus (HIV) relies on specific proteins to invade human cells and establish infection. Glycoprotein 41 (gp41) is a significant component, playing a direct role in the virus’s ability to fuse with and enter host cells. Its involvement in the initial stages of the viral life cycle makes it a focal point in understanding HIV infection and disease progression.
What gp41 Is
Gp41 is a transmembrane glycoprotein embedded within the HIV viral envelope. It is part of a larger precursor protein, gp160, which is cleaved by host cellular proteases (e.g., furin) to yield two distinct subunits: gp120 and gp41. While gp120 resides on the exterior surface of the viral envelope, gp41 is the transmembrane portion, with a segment anchored within the viral membrane.
Structurally, gp41 contains several functional segments within its ectodomain, the part extending outside the viral membrane. These include an N-terminal fusion peptide, heptad repeat regions (HR1 and HR2), a loop region, and a membrane proximal external region (MPER). The arrangement of these regions, particularly the helix-rich domains, allows gp41 to undergo significant conformational changes, which are necessary for its function in membrane fusion.
How gp41 Enables Viral Entry
HIV entry begins with gp120 binding to the CD4 receptor on target cells. This attachment facilitates gp120’s binding to a co-receptor (CCR5 or CXCR4) on the host cell membrane. This sequential binding triggers conformational changes within the gp120-gp41 complex.
These changes expose the gp41 subunit, which extends and inserts its N-terminal fusion peptide into the host cell membrane. This creates an intermediate pre-hairpin structure that bridges the viral and host cell membranes. Following this insertion, gp41 undergoes refolding, forming a stable six-helix bundle structure. This refolding draws the viral and host cell membranes into close proximity, leading to membrane fusion.
The close proximity of the membranes, facilitated by gp41’s conformational changes, leads to the formation of a fusion pore. This pore allows the viral contents, including its genetic material, to pass from the virus into the host cell’s cytoplasm, initiating the infectious cycle. This complex, stepwise mechanism highlights gp41’s direct involvement in merging the viral and cellular membranes, a necessary step for successful HIV infection.
gp41 as a Therapeutic Target
Given its important role in facilitating HIV entry, gp41 is a key target for antiviral therapies. Drugs designed to interfere with gp41’s function prevent the virus from infecting new cells. This approach led to the development of a class of drugs known as fusion inhibitors.
Enfuvirtide (T-20) is a fusion inhibitor. It is a synthetic peptide that mimics a part of gp41’s heptad repeat 2 (HR2) region. By binding to gp41’s heptad repeat 1 (HR1), enfuvirtide prevents the interaction between HR1 and HR2. This binding blocks the conformational changes in gp41 that are required for the fusion of the viral and host cell membranes, thereby inhibiting viral entry.
Fusion inhibitors like enfuvirtide offer a distinct mechanism of action compared to other antiretroviral drugs, which target viral enzymes such as reverse transcriptase or protease. This difference is valuable for patients who have developed resistance to other classes of HIV medications. Enfuvirtide is administered by subcutaneous injection and is well-tolerated, though injection site reactions are common. Its ability to disrupt the viral entry process makes it a significant component in combination antiretroviral therapy regimens, especially for those with limited treatment options.