CCR5 antagonism in HIV infection: ways, effects, and side effects

Pierre Corbeau and Jacques Reynes • AIDS • 2009 • Volume 23 - Issue 15

Special Author Introduction
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The discovery that the cell surface CCR5 molecule was used as a main coreceptor by most HIV-1 strains has provided a new target to antiretroviral therapy. Given the roles played by CCR5 in viral replication and cytopathogenicity, small molecules, antibodies and modified ligands binding to CCR5 and thereby inhibiting its interaction with HIV-1 envelope display good antiviral activities. Yet, the use of CCR5 blockers to treat HIV-1-infected individuals raises various concerns discussed in our review. First, they must be prescribed to patients harbouring CCR5-using (R5 strains) virions and not to those infected with virions using the other coreceptor, CXCR4 (X4 strains). Second, there is a concern that hindering R5 strains might favour the development of X4 strains that are associated with a higher cytopathogenicity. Last, but not least, as most CCR5 inhibitors prevent the binding of CCR5 natural ligands, inflammatory CC-chemokines, they hamper the CCR5 function of chemokine receptor, i.e. the capacity of CCR5 expressing immune cells to move towards inflammation sites. The good news is that they might have a beneficial effect in autoimmune diseases, atherosclerosis, and graft rejection in which CCR5 is involved. The bad news is that they might have a detrimental effect on the CCR5-mediated recruitment of immune cells against various infectious agents. Finally, as it is more and more evident that CCR5 is also a coactivation molecule, it is tempting to speculate that it has something to do with the polyclonal immune activation that is a landmark of this disease and potentially its main driver. If this is the case, then CCR5 antagonists might prevent postactivation CD4+ T cell loss, an effect that could account for the fact that they have been associated with a good immunological restoration. 

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