What ART Drugs Prevent HIV Entry into the Human Immune Cell?

Antiretroviral therapy (ART) is a complete treatment regimen for human immunodeficiency virus (HIV) infection, with a combination of three or more classes of drugs. Each drug class targets the virus at a different stage in its replication cycle, which improves the chances of controlling the infection.

HIV infection has no cure but ART can contain the viral growth and keep the patient healthy and active for many years. ART also helps minimize the chances of transmission. Interrupting or stopping ART can lead to increase in viral load, and virus mutations that develop resistance to treatment.

HIV infection is caused by a virus that infects human immune cells known as T-cells. HIV infection spreads through certain bodily fluids such as blood, semen, vaginal fluids or breast milk. The virus enters into the T-cell and uses its cell machinery to replicate itself, destroying the host cell in the process.

In its later stages, HIV infection can lead to acquired immune deficiency syndrome (AIDS), when the immune system is so weakened that it is unable to fight even common infections.

HIV goes through several stages in its life cycle. It enters the T-cell and releases certain enzymes which enable its integration with the host cell, and creation of more viral particles.

Most of the drugs developed in the early days of ART act on the virus after it enters into the T-cell by interfering with the integration and replication activities.

The newest drugs attack the virus at the stage when it binds to the T-cell and prevent it from penetrating the cell membrane. There are three classes of drugs which attack the virus in different ways, before it enters the immune cell (extracellular):

• Fusion inhibitor: Introduced in 2003, the fusion inhibitor stops the HIV from fusing with the immune cell’s membrane, preventing entry.
• Chemokine receptor antagonist (CCR5 antagonist): Developed in 2007, the chemokine receptor antagonist blocks entry of certain specific strains of HIV, which attach to a particular protein on the immune cell’s surface known as chemokine receptor 5 (CCR5).
• Post-attachment inhibitor (Entry inhibitor): The latest ART drug to be approved by FDA in 2018, the post-attachment inhibitor prevents the viral envelope fusion with the cell membrane after it binds to the cell.

HIV is a microscopic particle that has a single strand of genetic matter known as RNA, which cannot reproduce on its own. The RNA is covered in an envelope known as capsid which has two glycoproteins (a kind of protein molecule that incorporates a sugar molecule), gp120 and gp41, embedded in its surface.

The essential steps for the HIV to fuse its capsid with the T-cell membrane and enter into the cell are:

• The HIV glycoprotein gp120 binds to the CD4 receptor on the T-cell’s surface.
• The CD4-gp120 complex undergoes a structural change with a loop that attaches to one of the other two receptors (CCR5 or CXCR4) found on the T-cell surface.
• The second glycoprotein gp41 inserts itself into the cell membrane.
• The capsid merges with the cell membrane and the RNA emerges from the capsid and enters the fluid inside the T-cell (cytoplasm).

The three classes of entry inhibitor drugs block the viral fusion and entry process in different ways.

• Fusion inhibitor: The fusion inhibitor binds to the HIV glycoprotein gp41, alters its structure and prevents the completion of fusion.
• Chemokine receptor antagonist: The chemokine receptor antagonist binds to the CCR5 receptor and stops the HIV’s gp120 from attaching to it. This drug class works selectively on certain HIV strains such as R5 that attach to chemokine receptor CCR5 (CCR5-tropic virus). The chemokine receptor antagonist is ineffective against those virus strains that bind with CXCR4. The patient undergoes a test to determine the virus type before taking this drug class.
• Post-attachment inhibitor: The post-attachment inhibitor binds to the T-cell’s CD4 receptor and alters its structure. The structural change in the CD4 stops further chain reactions which would otherwise lead to the HIV’s fusion and entry into the T-cell.

Currently, one FDA-approved drug is available in each class of drugs that work at the fusion and entry stage of the HIV. Following is the list of the drugs with some of their side effects.

Fusion inhibitor

Enfuvirtide (Fuzeon)

Taken as an injection in the skin tissue (subcutaneous) twice daily, approved only for antiretroviral treatment-experienced patients with drug resistance.

Side effects include:

• Injection-site reactions such as:
  • Pain
  • Discoloration of the skin (ecchymosis)
  • Lump in the skin (induration)
  • Nodules
  • Itching (pruritus)
• Diarrhea
• Nausea
• Fatigue
• Hypersensitivity reactions (rare)

Chemokine receptor antagonist (CCR5 antagonist)

Maraviroc (Selzentry)

Available as tablets only for patients with CCR5-tropic virus resistant to multiple antiretroviral medications.

Side effects include:

• Cough
• Fever
• Constipation
• Abdominal pain
• Dizziness
• Rash
• Upper respiratory tract infection
• Musculoskeletal symptoms
• Liver toxicity
• Orthostatic hypotension (low blood pressure that occurs during change of posture, when standing up from sitting or lying down)

Post-attachment inhibitor

Ibalizumab (Trogarzo)

Administered as IV infusions every two weeks, approved only for antiretroviral treatment-experienced patients with drug resistance.

Side effects include:

• Diarrhea
• Dizziness
• Nausea
• Rash
• Immune reconstitution syndrome: (Rare) Development of inflammatory symptoms caused by the response of the immune system that has recovered with antiretroviral therapy, which starts attacking other pre-existing, latent bacterial or viral infections. These symptoms usually resolve in a few weeks.