How Do HIV Entry Inhibitor Drugs Work?

Novel Antiretroviral Drugs Block HIV From Entering Vulnerable Cells

Courtesy Pfizer Laboratories

An HIV entry inhibitor (also known as a fusion inhibitor) is a class of antiretroviral drug used in combination therapy to treat HIV. These novel agents prevent HIV replication by blocking a key entry point on host cells. These entry points include such surface proteins as:

  • CD4, a protein receptor found on the surface of "helper" T-cells (CD4+ T-cells)
  • gp120, a protein on the HIV surface
  • CCR5, a receptor found on the surface of CD4 T-cells
  • CXCR4, another receptor found on CD4 T-cells
  • gp41, an HIV protein that penetrates the cell membrane

By blocking one or several of the proteins needed to "unlock" the host's cells "front door," the virus' replication cycle is effectively stopped.

People who have become resistant to other classes of drugs (protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors) will likely benefit from the entry inhibitors as they can generally overcome drug resistance problems. This is particularly good news for anyone whose treatment options are limited, offering high levels of activity in the face of multi-drug resistance.

Currently, there are two entry inhibitor drugs approved by the U.S. Food and Drug Administration for use in the treatment of HIV infection: Selzentry (maraviroc) and Fuzeon (enfuvirtide).

Maraviroc and CCR5 Receptor Antagonists

A CCR5 receptor antagonist is a type of antiretroviral drug that prevents HIV infection by binding to a protein on the surface of the host CD4 T-cell called the CCR5.

The CCR5 receptor is one of the primary entry points for HIV, particularly in early stage infection. By preventing attachment to the CCR5 receptor, HIV is unable to enter and infect the host cell.

Also known as an entry inhibitor, the CCR5 receptor antagonist is different from other classes of antiretrovirals insofar as it doesn't target the virus directly, but instead attaches to the surface of the host cell.

It's important to note that not all HIV binds to a host cell via the CCR5 receptor and, therefore, not everyone will be a candidate for this class of drug. A genetic test called the trofile assay is performed to determine the tropism of your specific virus. If the test is positive for CCR5, the virus is said to be "CCR5 tropic"—meaning that it will be responsive to a CCR5 receptor antagonist class drug.

A number of CCR5 receptor antagonist inhibitor candidates have been developed, although only one has actually reached the market (listed by date of development):

  • Apliviroc (discontinued due to severe liver toxicity)
  • Maraviroc (available under the brand names Selzentry in the U.S. and Celsentri abroad)
  • Vicriviroc (abandoned by the manufacturer in 2010)

Fuzeon and the Development of Fusion Inhibitors

Fusion is a stage in the life cycle of HIV that enables the virus to bind to a host cell prior to entering it. A fusion inhibitor works by binding to the gp41 protein on the surface of the host cell and preventing it from fusing with HIV.

Without this fusion, HIV replication is stopped and cellular infection is averted.

At present, fusion inhibitors have been designed to be delivered by injection rather than as an oral dose. This, combined with the high cost of treatment (approximately $25,000/year), have limited the drug's use to salvage therapy (i.e., when all other treatment options have been exhausted).

A number of fusion inhibitor candidates have been developed, although only one has actually reached the market:

  • Enfurvitide (available under brand name Fuzeon)
  • T-1249 (discontinued by manufacturers due to difficulties in formulation)
  • TRI-1144 (in development)
  • TRI-199 (in development)


Biswas, P.; Tambussi, G.; and Lazzarin, A. "Access denied? The status of co-receptor inhibition to counter HIV entry" (abstract page). Expert Opinion in Pharmacotherapy. 20087; 8(7): 923-933.

U.S. Food and Drug Administration (FDA). "FDA Approves Novel Antiretroviral Drug." Silver Spring, Maryland; press release issued August 6, 2007.

FDA. "Drug Approval Package: Fuzeon (enfuvirtide) for injection." Accessed May 30, 2016.

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