Post-attachment Inhibitors

Post-attachment inhibitors are a class of drugs used to suppress HIV in the body. When post-attachment inhibitors are used in combination with other HIV-fighting medications, the treatment regimen is referred to as antiretroviral therapy (ART).

HIV needs to enter human host cells called CD4 cells, or T cells, to replicate. In order to enter into these cells, HIV needs to bind to the host cell surface and then fuse itself with the host cell to get inside. Post-attachment inhibitors block the binding step in the process, preventing HIV from attaching and getting into its target cell to replicate.

How post-attachment inhibitors treat HIV

Viruses like HIV need human host cells to replicate. They cannot multiply on their own without human cells. When HIV particles called virions enter the body after a transmission event, the next main steps of the HIV lifecycle are as follows:¹

1. Binding
2. Fusion
3. Reverse transcription
4. Integration
5. Replication
6. Assembly
7. Budding

Figure 1. Post-attachment inhibitors target binding in the HIV life cycle

The HIV virions have proteins on the outside that recognize receptors on CD4 cells. Once a virion finds a CD4 cell, its outside proteins can bind to the CD4 cell receptor and link the CD4 cell and virion together (step 1: binding). In order for the virus to fully bind and fuse with the CD4 cell and get inside the cell to continue replication (step 2: fusion), other receptors on the CD4 cell surface may get involved. These additional receptors on the CD4 cell include the CCR5 or CXCR4 receptors. The HIV surface receptors involved in the first two steps are called gp120 and gp41. Any of these receptors on the CD4 cell or HIV itself may be targets for HIV medications.¹

Once inside the cell, the virion disassembles itself so that it can begin the replication process. The next three steps represent the replication process of the virus’s genetic material. The last two steps of the process involve HIV re-assembling itself into new, mature virions that can be released from the CD4 cell and enter the bloodstream where they can go on to infect new cells.¹

Blocking CD4 receptors

Post-attachment inhibitors block the CD4 receptor on the outside of CD4 cells. The CD4 receptor is involved in the binding of HIV to its target cell. HIV needs to bind using the CD4 receptor in order to move on to the next step in the life cycle, fusion, and entry into the cell. When the CD4 receptors are blocked by a post-attachment inhibitor, HIV cannot adequately bind to its target cell. This stops the replication process since HIV needs to get inside the human host cells to replicate.

There are other medications that can be used to block the physical merging of HIV and CD4 cells called fusion inhibitors; however, post-attachment inhibitors are different in that they block the step before fusion and binding. When using a post-attachment inhibitor, an HIV virion can still, in theory, fuse with a CD4 cell. However, it has a harder time binding to the host cell in the first place.²

Examples of post-attachment inhibitors

Common post-attachment inhibitors include, but may not be limited to:^2,3

• Ibalizumab-uiyk (IBA)
• Rukobia (fostemsavir)

Things to note

The post-attachment inhibitor ibalizumab may cause diarrhea or rash. Further, post-attachment inhibitors may cause a condition called IRIS (immune reconstitution inflammatory syndrome). IRIS occurs when an individual’s immune system gets stronger after being weak and responds aggressively to previously hidden infections. This heightened response may make the person fighting the infection feel worse.⁴