Pathogens often utilize molecular mimicry to hijack host proteins for their own benefit. These processes can involve mechanisms for gaining entry into host cells, or manipulating the immune response and silencing molecular alarms designed for host defense. Interestingly, it appears that HIV-1 and the protozoan parasite Toxoplasma gondii (T. gondii) have evolved in parallel to utilize CCR5, the natural receptor for chemokine family members that include RANTES/CCL5, MIP-1 alpha/CCL3, and MIP-1 beta/CCL4.1-3 Both HIV-1 and T. gondii express proteins that bind CCR5, and a recent study reveals a potential competition between these pathogens for access to the receptor.
T. gondii is an intracellular protozoan parasite causing toxoplasmosis, an infection in humans that can result in lymphadenopathy, myocarditis, pulmonary necrosis, and encephalitis.4 Fortunately, for most immunocompetent individuals, the disease rarely manifests itself.4 Host cells recognize T. gondii infection, likely via toll-like receptors (TLRs), and mount an immune response that includes MyD88 signaling and the induction of IL-12 and IFN-gamma.5,6 Additionally, researchers have shown that the T. gondii protein cyclophilin 18 (C18) binds the chemokine receptor CCR5 and mediates TLR/MyD88-independent IL-12 production (Figure 1).2 Why T. gondii would develop a mechanism that appears to enhance the immune response is at present unclear, although protecting the host from serious infection could have potential benefits in parasitic transmission.2
|Figure 1. Host cells recognize T. gondii infection, likely via toll-like receptors (TLRs), and mount an immune response that includes MyD88 signaling and the induction of IL-12. IL-12 is also produced in response to T. gondii infection via a TLR/MyD88-independent mechanism involving T. gondii protein cyclophilin 18 (C18) binding to the chemokine receptor CCR5. Recently, it was shown that the T. gondii protein C18 not only binds CCR5, but also inhibits HIV-1 interaction with CCR5.|
HIV-1 utilizes the chemokine receptors CXCR4 or CCR5 as co-receptors for gaining access to host cells.7 CCR5, in particular, represents an attractive target for HIV-1 therapy. Several molecules have been described, including natural chemokines and their derivatives, that compete with HIV-1 for the co-receptor and suppress infection.7 Furthermore, CCR5 appears to be dispensable for overall health, as individuals homozygous for a 32 base-pair deletion (Δ32/CCR5) that results in receptor downregulation exhibit no significant health problems.8 These individuals do, however, appear to have a resistance to HIV-1 infection.9 Observations such as these have led to ongoing clinical studies to examine whether CCR5 might represent a therapeutic target for HIV-1.
Recently, it was shown that the T. gondii protein C18 not only binds CCR5, but also inhibits HIV-1 interaction with CCR5 (Figure 1). C18 blocks HIV-1 envelope-mediated fusion and protects human peripheral blood mononuclear cells from infection by HIV-1 R5 strains.10 Unfortunately, simply infecting individuals with T. gondii in order to offer protection from HIV-1 is likely not a viable therapeutic option. Toxoplasmic encephalitis, exacerbated by a compromised immune system, is a common AIDS complication.11 However, further assessments of the molecular structure of C18 and the mechanisms underlying its inhibition of HIV-1 infection could provide important information regarding the blockade of HIV-1 access to human cells.