HIV and chemokines: implications for therapy and vaccine

The unexpected encounter between the fields of chemokines and HIV has opened new perspectives for understanding the mechanisms of AIDS pathogenesis, as well as for the development of effective therapies and vaccines. An increasing body of evidence supports the concept that the level of CCR5-binding chemokines (i.e., RANTES, MIP-1alpha and MIP-1beta) measured in vivo or ex vivo can provide an accurate correlate of natural or vaccine-induced protection from primate immunodeficiency viruses. In addition, by virtue of their unique immunomodulatory activities, chemokines may represent a new class of "intelligent" vaccine adjuvants, capable of finely tuning both humoral and cellular immune responses by recruiting specific cell types at the site of immunization. Chemokines that bind the major HIV coreceptors (i.e., CCR5 and CXCR4) are potent natural inhibitors of HIV, although a potential limitation to their therapeutic use is the risk of inducing inflammatory side-effects or of interfering with the physiology of the homeostatic chemokine system. However, recent data indicate that the ability of chemokines to block HIV infection can be uncoupled from their signaling activity. Thus, both modified chemokines and small derivative molecules maintaining the HIV-inhibitory function, but devoid of receptor-activating capability, have been generated. Moreover, for the CC chemokine RANTES, the structural determinants of receptor recognition and antiviral function have been elucidated. Altogether, these findings provide a theoretical foundation for the rational design of safe and effective HIV-coreceptor inhibitors.