In their everyday fight for survival, germs must face not only the sophisticated immunologic weaponry developed by their natural hosts, but also the potential interfering effects of other microorganisms. As illustrated by a growing number of examples, such interference cannot be simply ascribed to competition for space or vital substrates (including receptor molecules), but it is often mediated by the microbial manipulation of the host immune system, in particular of soluble mediators such as cytokines and chemokines.1 Golding and colleagues (page 3280) provide a new paradigm of this concept by showing that a protein encoded by the parasite Toxoplasma gondii, the cyclophilin C-18, blocks the infectivity and fusogenic activity of HIV. This study is a natural extension of the observation reported in May of this year by some of the same authors2 who identified C-18 as the principal parasite component that mediates the immunomodulatory effects of Toxoplasma, demonstrating that this cyclophilin directly binds and activates CCR5, a chemokine receptor that represents a critical entry gateway for HIV on the surface of human cells. At this stage, the potential clinical implications of this observation remain uncertain. On one side, it is conceivable that Toxoplasma infection, while representing one of the most threatening complications of AIDS, might paradoxically induce a temporary abatement of HIV replication, as seen for example during acute measles3 ; on the other side, however, there are no clinical data, at present, to support this concept. In fact, the in vivo interactive network is likely to be more complex, as suggested by experiments in mice bearing a full-length HIV-1 transgene, in which infection with Toxoplasma was shown to induce a significant increase in proviral transcription.4
While interference with HIV presumably represents a purely accidental side-effect for Toxoplasma, the question arises as to how the parasite might benefit from activation of CCR5. In this respect, it is noteworthy that diverse microbial pathogens have evolved strategies to modulate chemokine functions.1 Some viruses, such as human herpesvirus 6 (HHV-6) and human T-cell lymphotropic virus I (HTLV-I) or HTLV-II, are potent inducers of host chemokines, while others, including various herpesviruses and poxviruses, encode functional chemokine agonists that were ancestrally hijacked from the host genome.5 Even though the mechanism selected by Toxoplasma (a cyclophilin with no sequence homology to cellular chemokines) may be unique, this emerging pattern suggests that control of the chemokine system may provide a key to survival for invading microorganisms.
An interesting perspective stemming from the present findings is the possibility of exploiting Toxoplasma C-18 for developing novel CCR5-targeted HIV entry inhibitors. Several such inhibitors have been identified in recent years, with a few already under clinical evaluation. Why then consider an additional lead molecule, particularly one derived from a pathogenic parasite? One good reason could be that none of the compounds currently under scrutiny has yet attained a proven record of safety and clinical effectiveness. But another argument that is difficult to refute is that “natura artis magistra” (“nature is the master of art”). Since CCR5 is a member of the 7-transmembrane-domain receptor family, obtaining atomic-level structural information remains a challenging task. However, we can learn about the structure of a receptor by observing it from the ligand perspective. Naturally selected CCR5-binding molecules, including Toxoplasma C-18 and chemokines, may teach us a precious lesson, courtesy of aeons of evolution, on how to effectively block one of the essential gateways of HIV.
