Double‐Edged Genetic Swords and Immunity: Lesson from CCR5 and Beyond. Part 3
Second, the possible consequences of infection with WNV or other flaviviruses in HIV‐positive patients who are receiving CCR5 blockers remains unknown, because very little is understood regarding the long‐term effects of CCR5 blockers on immune functions in vivo. A previous study found that Maraviroc, a CCR5 antagonist, did not influence IL‐2 and CD25 levels, whereas germ‐line inactivation of CCR5 and Ab‐mediated blockade of CCR5 did influence IL‐2 and CD25 levels. This may have been due to differences in the receptor configuration and resulting functionality of Ab‐bound and inhibitor‐bound forms of CCR5. Hence, it is conceivable that the effects on immune function secondary to germ‐line absence of CCR5 in humans and mice versus chemical antagonism of CCR5, such as after administration of Maraviroc, are dissimilar. Given that distinct biological responses of CCR5 might be determined through different receptor conformations, presumably the signaling pathways triggered in cells exposed to Maraviroc versus cells genetically lacking CCR5 may be distinct. Highlighting this possibility is the recent observation that CCR5 forms hetero‐oligomeric complexes with at least 2 other chemokine receptors (CCR2 and CXCR4), and specific antagonists of 1 set of receptors (eg, CCR2 and CCR5) lead to functional cross‐inhibition of the other (ie, CXCR4). This has relevance to the full evaluation of the health consequences of CCR5 blockers, because these data suggest that antagonists of 1 chemokine receptor may regulate the functional properties of another to which they do not directly bind [30]. Thus, Act III may reveal that the immune consequences of CCR5 blockers may not be identical to those found in CCR5‐null people.
Third, the studies by the Murphy group pose a dilemma. Is there a threshold of CCR5 expression, albeit low, that promotes WNV disease? At least in the context of HIV infection, there appears to be a threshold of CCR5 surface expression that is permissive for cell entry, such that small changes in CCR5 density are associated with large increases in HIV infectivity and efficacy of CCR5 blockers. The converse may be operative in WNV infection, in that CCR5 expression levels below a certain (low) threshold may enhance the risk of a more aggressive WNV clinical presentation. Whether such a threshold of CCR5 expression exists is a testable hypothesis because subjects bearing one or lacking the CCR5Δ32 allele display a wide range of CCR5 surface expression levels, and this variability may be partly due to CCR5 promoter polymorphisms that influence expression. Additionally, one may also need to consider other factors that result in low CCR5 expression levels. For example, the copy number of CCL3L1, a potent CCR5 agonist, correlates inversely with CCR5 expression. Hence, Act III may clarify this dilemma.
Finally, we anticipate that Act III will continue to be punctuated by additional examples that show the tradeoffs associated with the CCR5 null state. This is already happening: a recent study showed that CCR5Δ32 homozygosity is associated with increased susceptibility to tick‐borne encephalitis virus. These tradeoffs are a reminder of the constant tug of war between host and pathogen and also of the need to be vigilant, because what we find in one context might differ in another.