HIV-1 Viral Entry is Mediated by Chemokine Receptors
For HIV, the first step in its replication cycle is to target and infect its host cell, the CD4+ lymphocyte. It does this using a complex set of interactions with viral proteins displayed on the surface of the viral envelope and receptors on the surface of the CD4+ cell. The viral envelope protein is comprised of two glycoproteins called gp41 and gp120.
Chemokines are cytokines that stimulate leukocyte movement and regulate the migration of leukocytes from the blood to tissues. The two major families of chemokines are:
- CC chemokines, which act mainly on lymphocytes,
monocytes, eosinophils, and basophils
- CXC chemokines, which act mainly on neutrophils
(find image of the CC chemokines and CXC chemokines)
One of the key receptors for CC chemokines is the CCR5 receptor, and a key receptor for CXC chemokines is the CXCR4 receptor. These receptors are relevant to our discussion because the CCR5 and CXCR4 receptors are the primary co-receptors used by HIV -1 to enter a CD4+ T-cell.
Schematic representation for HIV entry into its host cell
CD4 Binding: The gp120 viral envelope protein has an affinity for the CD4 receptor which is expressed on the cell surface of the CD4+ cell. CD4 binding inhibitors such as the experimental drug TNX-355 have been shown to inhibit the gp120 and CD4 receptor interaction and block HIV infection.
Co-receptor Binding: The binding of the gp120 to the CD4 receptor causes a conformational change in the gp120 protein. This change exposes a binding site for a chemokine co-receptor (CCR5 or CXCR4). CCR5 antagonists block the binding of the gp120 protein and block HIV infection.
Virus-Cell Fusion: Once gp120 binds to the co-receptor, this causes a conformational change in the gp41 protein allowing the insertion of a fusion peptide from the gp41 protein into the cell membrane. This insertion of the fusion peptide draws the virus and CD4+ cell close enough together to allow the virus envelope and the cell membrane to fuse. Once this happens, the viral core can enter the CD4+ cell and the infection begins. Enfuvirtide inhibits the conformational change and blocks the insertion of the fusion peptide.