The Human Immunodeficiency Virus (HIV) uses a pair of glycoproteins, gp120 and gp41, to enter a human host cell. These two proteins are located on the virus’s surface and function as a coordinated unit to identify, bind to, and fuse with specific cells of the human immune system. This entry process allows the virus to deliver its genetic material into the host cell, beginning the cycle of infection. The functions of gp120 and gp41 are distinct but sequential, with each protein performing a specific job that leads to the next step.
Origin and Structure of HIV’s Entry Machinery
HIV’s entry machinery begins as a single, large precursor molecule named gp160. This polyprotein is produced within an infected host cell’s endoplasmic reticulum, where it assembles into groups of three, known as trimers. The gp160 trimer is then transported to the Golgi apparatus, where host cell enzymes cleave each molecule into two non-covalently associated subunits: the surface protein gp120 and the transmembrane protein gp41.
This cleavage is a necessary step for the virus to become infectious. The resulting structure, a trimer of gp120-gp41 pairs, studs the surface of the new virus particle, forming the viral spike. In this arrangement, gp120 forms the outer cap of the spike, while gp41 acts as the stalk, anchored within the viral membrane. This complete spike complex is metastable, meaning it exists in a state of readiness, waiting for the right signal to initiate a series of irreversible changes that lead to infection.
The Binding Process Initiated by gp120
The process of HIV infection begins with the gp120 protein, which acts as the virus’s targeting system. Its primary function is to locate and attach to a specific receptor on the surface of host immune cells, most notably helper T-cells. This primary receptor is a molecule called CD4. This binding triggers a significant structural rearrangement within the gp120 protein itself.
This initial binding event exposes new regions on the gp120 surface that were previously hidden. These newly exposed sites allow gp120 to engage with a second receptor on the host cell, known as a co-receptor. Depending on the specific strain of HIV, this co-receptor is typically either CCR5 or CXCR4, both of which are chemokine receptors that play roles in normal immune cell function.
This dual interaction induces a final conformational change in the gp120-gp41 complex. The structural shift in gp120 causes it to partially dissociate from gp41, unmasking the fusion machinery of the gp41 protein. This exposure prepares gp41 to execute its role in merging the viral and host membranes.
The Fusion Mechanism Driven by gp41
Once gp120 binding has occurred, the now-exposed gp41 protein undergoes a rapid transformation to execute membrane fusion, a process often compared to a spring-loaded mechanism. Upon activation, a hydrophobic segment at the N-terminus of gp41, known as the fusion peptide, is projected outward and inserts itself into the membrane of the target host cell. This action tethers the virus to the host cell.
Following the insertion of the fusion peptide, gp41 begins to refold into a highly stable structure. Two regions within the gp41 ectodomain, the N-terminal heptad repeat (NHR) and the C-terminal heptad repeat (CHR), collapse onto each other. This refolding process forms a stable structure known as a six-helix bundle.
This folding action is a powerful process that pulls the viral envelope and the host cell membrane into direct contact. The strain caused by this action forces the lipid bilayers of the virus and the cell to merge. This merging creates a fusion pore, an opening through which the viral capsid can pass into the cytoplasm of the host cell, completing the entry process.
Therapeutic and Vaccine Implications
The actions of gp120 and gp41 make them principal targets for the development of antiretroviral therapies. One class of drugs, known as fusion inhibitors, is designed to interfere with the function of gp41. The drug enfuvirtide, for example, is a peptide that mimics a segment of gp41’s CHR region. It works by binding to the NHR region of gp41, blocking the formation of the six-helix bundle and halting the fusion process.
The envelope complex is also the primary focus for developing an HIV vaccine, though this has proven to be a significant scientific challenge. One obstacle is the high mutation rate of the viral gene that codes for gp160. This rapid evolution constantly changes the structure of gp120, allowing the virus to evade antibodies.
An additional complication is the “glycan shield,” a dense layer of sugar molecules that coats the surface of gp120. This shield masks many of the protein’s underlying surfaces from detection by antibodies. The virus uses this shield to protect the conserved regions necessary for receptor binding, making it difficult for the immune system to mount an effective response.