HIV entry inhibitors

Mechanism of viral entry into the cell

To understand the sites of action of the drugs, it is necessary to examine the natural infection process. The main targets for the virus are macrophages and T-lymphocytes bearing CD4 receptors on their surface.

The entry process consists of several consecutive steps:

1. Initial binding. The viral envelope protein gp120 attaches to the CD4 receptor.
2. Co-reception. This is a critical stage. For successful entry, the virus requires additional binding to chemokine co-receptors — CCR5 or CXCR4.
3. Activation. Only after binding to CD4 and co-receptors does another viral glycoprotein, gp41, acquire functional activity.
4. Fusion. A conformational change occurs in gp41. Its "fusion peptide" inserts into the target cell membrane. Regions of this protein (HR1 and HR2) interact with each other, ensuring the approximation and final fusion of the viral and cellular membranes.

Viral tropism dynamics

HIV strains can be tropic (have an affinity) for CCR5 receptors, CXCR4 receptors, or both types simultaneously.

• At early stages of the disease, the virus exhibits tropism predominantly for CCR5 receptors located on macrophages.
• With further disease progression, a shift occurs: the virus begins to bind more actively to CXCR4 receptors on the surface of T-cells.

Clinically, this change in binding manifests as accelerated destruction of CD4 lymphocytes (T-helper cells) and the development of pronounced immunosuppression. Interestingly, the phenomenon of genetic resistance in part of the European population (the CCR5 gene mutation) formed the basis for the development of targeted drugs.

Maraviroc (Selzentry): adsorption blocker

Maraviroc disrupts the earliest stage of virus-cell interaction.

• Mechanism of action: The drug blocks chemokine receptors CCR5 on the human cell membrane. Because of this, the viral protein gp120 cannot complete the adsorption stage.
• Spectrum of activity: The drug is effective only against CCR5-tropic strains. It does not work against viruses that use the CXCR4 receptor.
• Pharmacokinetics: Taken orally, bioavailability is 23–33%. Metabolized by the CYP3A4 enzyme. When combined with inducers or inhibitors of this enzyme, strict dose adjustment is required (from 150 to 600 mg twice daily).
• Tolerability: Generally well tolerated, though cases of hepatotoxicity have been reported.

Enfuvirtide (Fuzeon): fusion inhibitor

Enfuvirtide acts at a later stage, preventing membrane fusion.

• Mechanism of action: Structurally, the drug mimics the peptide sequence of the HR2 region of the viral gp41 protein. It competitively binds to the HR1 region instead of the virus's own HR2. As a result, the fusion of the viral envelope with the cell membrane is blocked.
• Pharmacokinetics: Unlike other antiviral agents, it is administered parenterally (subcutaneously). Bioavailability with this route of administration reaches 84%.
• Side effects: Local injection site reactions (pain, induration, erythema, pruritus) occur most frequently. Cysts, abscesses, or cellulitis may develop less commonly.

Indications for use

Both drugs are prescribed to adult HIV-1 patients exclusively as part of combination therapy. The main indication is treatment failure caused by the development of viral resistance to other classes of antiretroviral drugs.

Class and exam questions

What else to study on this topic

• Molecular structure and functions of viral glycoproteins gp120 and gp41
• Mechanisms of HIV resistance development to antiretroviral therapy
• The role of the CYP3A4 isoenzyme in drug metabolism
• Pathogenesis of CD4 lymphocyte depletion during shifts in viral tropism
• Principles of designing combination antiretroviral therapy regimens

Other topics in the "Antivirals" section

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.