The human immunodeficiency virus (HIV) targets specific cells of the immune system, initiating an infection that can lead to acquired immunodeficiency syndrome (AIDS). Understanding how HIV enters host cells is a fundamental aspect of the virus’s life cycle. This initial step, known as viral entry, involves precise interactions between viral and cellular structures. Gaining insight into this mechanism is important for developing prevention and treatment strategies.
The Viral Attacker: HIV’s Envelope Proteins
The surface of the HIV virus is adorned with specialized structures called envelope proteins, essential for initiating contact with host cells. These proteins are organized into complexes, each consisting of three gp120 subunits and three gp41 subunits, collectively known as the Envelope (Env) protein. The Env protein is initially synthesized as a larger precursor, gp160, which is then cleaved by cellular enzymes into gp120 and gp41.
The gp120 subunit is positioned on the outer surface of the viral envelope and is responsible for recognizing and binding to host cell receptors. It contains variable regions, including the V1/V2 and V3 loops, which play roles in co-receptor binding. The gp41 subunit is a transmembrane protein embedded within the viral envelope. While gp120 handles initial attachment, gp41 mediates the fusion of the viral and cellular membranes, allowing the virus to enter the cell.
The Cellular Gatekeepers: Host Cell Receptors
Human host cells possess specific molecules on their surface that HIV exploits for entry. The primary receptor for HIV-1 is the CD4 protein, predominantly found on the surface of immune cells like CD4+ T lymphocytes and macrophages. HIV’s gp120 protein has a high affinity for CD4, making this initial interaction a defining step for infection.
CD4 alone is not sufficient for HIV entry; the virus also requires a co-receptor. The two main co-receptors are CCR5 and CXCR4, both chemokine receptors. Different HIV strains exhibit tropism, preferring either CCR5 (R5-tropic) or CXCR4 (X4-tropic) for entry, or sometimes both (dual-tropic). CCR5-using viruses are found in early infection, while CXCR4-using viruses emerge later in disease progression and are associated with a more rapid decline in CD4+ T-cells.
The Docking Mechanism: How HIV Binds to the Host Cell
HIV binding to a host cell is a multi-step process, beginning with the viral gp120 protein. The initial attachment occurs when gp120 on the HIV surface binds to the CD4 receptor on the host cell membrane. This specific, high-affinity interaction tethers the virus to the target cell. The binding of gp120 to CD4 induces significant conformational changes within the gp120 protein.
These conformational changes in gp120 expose a previously hidden binding site for the co-receptor. The V1/V2 loops of gp120 shift, unmasking the co-receptor binding site. Following CD4 binding, gp120 then engages with either the CCR5 or CXCR4 co-receptor, depending on the viral strain’s tropism. This second binding event further stabilizes attachment and brings the viral and host cell membranes into closer proximity. The sequential engagement of CD4 and a co-receptor triggers additional structural rearrangements, preparing the virus for entry.
Opening the Door: Membrane Fusion and Viral Entry
After HIV docks to the host cell surface, membrane fusion allows the viral contents to enter the cytoplasm. The binding of gp120 to both CD4 and a co-receptor initiates conformational changes within the associated gp41 protein. In its resting state, gp41 is in a metastable, non-fusogenic conformation, requiring a trigger to change shape.
Co-receptor binding acts as this trigger, causing gp41 to undergo structural rearrangements. A hydrophobic region of gp41, the fusion peptide, is exposed and inserts into the host cell membrane. This insertion is followed by refolding of gp41, forming a stable six-helix bundle structure. This structural change pulls the viral envelope and the host cell membrane together. The membranes eventually merge, creating a pore through which the viral core, containing genetic material (RNA) and enzymes, is released into the host cell’s cytoplasm, completing the entry process.
Why Understanding Entry is Crucial
Understanding HIV binding and entry has significantly influenced the development of antiviral therapies. This knowledge allowed scientists to identify specific targets for drugs designed to block the virus at its initial stage of infection. A class of antiretroviral medications, known as entry inhibitors, directly interferes with this process.
These inhibitors work by targeting different steps of viral entry. Attachment inhibitors prevent the initial interaction between gp120 and CD4. Co-receptor antagonists block gp120 binding to CCR5 or CXCR4. Fusion inhibitors, such as enfuvirtide, directly target gp41, preventing the merging of viral and cellular membranes. This targeted approach provides additional treatment options and continues to inform research into new preventative strategies and potential vaccines.