Only later did scientists realize that the reason these chemokines have an inhibitory effect on viral replication is that HIV not only has to engage the CD4 molecule to enter the cell, but also it has to dock with one of the 2 other receptors, namely CCR5 or CXCR4, to enter the target cell. If these chemokines are present in sufficient quantities, they engage all the CCR5 and CXCR4 receptors and HIV cannot complete its entry. Attachment to the CD4 molecule then is merely a preliminary step in the whole entry procedure. A subsequent attachment either to CCR5 or CXCR4 is required as a second step in the process of entry. Help from Mother Nature.
Uncertainties still underlie the blocking or manipulation of coreceptors.
After all, these coreceptors have natural functions besides mediating HIV entry into the cell. Coincidently, one reassuring observation emerged that encouraged scientists to pursue blocking CCR5. In the course of studying individuals who had multiple exposures to HIV but never became productively infected, researchers noted that these subjects had natural mutations that blocked the full expression of CCR5 receptors. Individuals with one mutation in their CCR5 receptors had slower disease progression than individuals without this mutation. Individuals with a double mutation in their CCR5 receptors appeared to have a great degree of protection from HIV infection.