Mechanism of Viral Entry
To understand the sites of drug action, it is necessary to review the natural infection process. The main targets for the virus are macrophages and T-lymphocytes, which bear CD4 receptors on their surface.
The entry process consists of several consecutive steps:
- Primary binding. The viral envelope protein gp120 attaches to the CD4 receptor.
- Co-receptor engagement. This is a critical step. Successful entry requires additional binding to chemokine co-receptors — CCR5 or CXCR4.
- Activation. Only after binding to CD4 and co-receptors does another viral glycoprotein, gp41, acquire functional activity.
- 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, bringing the viral and cellular membranes close together for final fusion.
Dynamics of Viral Tropism
HIV strains can be tropic (have an affinity) for CCR5 receptors, CXCR4 receptors, or both.
- In the early stages of the disease, the virus exhibits tropism primarily for CCR5 receptors located on macrophages.
- As the infection progresses, a shift occurs: the virus begins to bind more actively to CXCR4 receptors on the surface of T-cells.
Clinically, this altered binding is manifested by the accelerated depletion of CD4+ T-lymphocytes (T-helper cells) and the development of severe immunosuppression. Interestingly, the phenomenon of genetic resistance in part of the European population (the CCR5 delta-32 mutation) served as the basis for developing targeted drugs.
Maraviroc: Attachment Inhibitor
Maraviroc disrupts the earliest stage of virus-cell interaction.
- Mechanism of action: The drug blocks CCR5 chemokine receptors on the human cell membrane. As a result, the viral protein gp120 cannot complete the attachment phase.
- Spectrum of activity: The drug is effective only against CCR5-tropic strains. It is ineffective against viruses utilizing the CXCR4 receptor.
- Pharmacokinetics: Administered orally, with a bioavailability of 23–33%. It is metabolized by the CYP3A4 enzyme. When combined with inducers or inhibitors of this enzyme, strict dose adjustments are required (ranging from 150 to 600 mg twice daily).
- Tolerability: Generally well tolerated, though cases of hepatotoxicity have been reported.
Enfuvirtide: 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 protein gp41. It competitively binds to the HR1 region instead of the virus's own HR2 domain. Consequently, fusion of the viral envelope with the cell membrane is blocked.
- Pharmacokinetics: Unlike most other antivirals, it is administered parenterally (subcutaneously). Bioavailability via this route reaches 84%.
- Adverse effects: Local injection-site reactions (pain, induration, erythema, pruritus) are most common. Cysts, abscesses, or cellulitis may develop less frequently.
Indications for Use
Both drugs are prescribed to adult patients with HIV-1 exclusively as part of combination antiretroviral therapy (cART). The primary indication is treatment failure caused by the development of viral resistance to other classes of antiretroviral agents.