Chemokines, cytokines and HIV: a complex network of interactions that influence HIV pathogenesis

The important role of chemokine receptors in HIV pathogenesis is becoming increasingly apparent. The level at which certain chemokine receptors that serve as HIV co-receptors are available influences the susceptibility of a CD4(+) cell to viral infection and to certain HIV envelope-induced alterations in cellular function. Numerous pathogens, including HIV can stimulate the production of chemokines and cytokines from a variety of cell types. Both cytokines and chemokines modulate CCR5 and CXCR4 availability, resulting in differential replication potentials for R5 and X4 HIV strains depending on the milieu in the microenvironment. In addition, differential expression of CCR5 and CXCR4 on activated memory T cells appears to play an important role in preferential replication of R5 HIV strains in vivo. However, expression of HIV co-receptors and CD4 may not be sufficient for effective HIV entry and replication. Intracellular signaling events, triggered by interaction between chemokine receptors and chemokines or HN envelope, are important for efficient entry and completion of early replication events. Envelope proteins of different HN isolates vary in their ability to transduce these signals, a characteristic that may play a role in determining the ability of a virus to productively infect certain cell types. Finally, the interaction between chemokine receptors and chemokines or HIV envelope has significant effects on cellular functions which likely play a role in HIV pathogenesis.