Double‐Edged Genetic Swords and Immunity: Lesson from CCR5 and Beyond
Was Shakespeare, that keen observer of human behavior, also an insightful infectious disease epidemiologist? Had he been prompted to pen these thoughts because he had astutely observed that some individuals resisted acquiring some infections or did poorly once infected compared with others? Validating Shakespeare’s crystal ball, 250 years later, it was first postulated that these fortresses are genetic traits, with J. B. S. Haldane and A. C. Allison suggesting that malaria was an evolutionary force that selected for malaria‐resistant genes. However, there is a tradeoff. As illustrated by the results reported by Murphy and colleagues in this issue of the Journal and the vignettes described below, it has become apparent that these genetic variants are oftentimes akin to a double‐edged sword, serving as a fortress against one infection while conferring susceptibility to another. For example, genetic traits that result in hemoglobin and/or red blood cell disorders (eg, sickle cell disease and thalessemia) protect against malaria. The African‐specific allele that results in the null state for Duffy antigen receptor for chemokines (DARC) on erythrocytes protects against Plasmodium vivax malaria. However, the role of DARC null state in infectious diseases is likely to be much more complex, because it may correlate with a blunted inflammatory response to endotoxins, serve as a genetic basis for the ethnic leukopenia that is observed commonly in persons of African ancestry, increase the risk of acquiring human immunodeficiency virus (HIV) infection, and confer a survival advantage to leukopenic HIV‐positive African Americans.
Murphy and colleagues now highlight another genetic tradeoff: the null state of CC chemokine receptor 5 (CCR5) is associated with early symptom development and more pronounced clinical manifestations after infection with West Nile virus (WNV) , whereas this same genetic state is known to confer strong protection against risk of acquiring HIV infection. The CCR5 null state, which is due to homozygosity for the European‐specific 32 base pair (bp) coding deletion mutation (Δ32), propelled the HIV field forward in the mid‐1990s, spawned an explosion of studies that explored the association of CCR5Δ32/Δ32 with a myriad of infectious and noninfectious diseases, and led to the development of CCR5 blockers for the treatment of HIV disease.
In retrospect, defining the link between CCR5 surface expression and HIV pathogenesis appears to be Act I of a 3‐act Shakespearean play on the role of CCR5. Act II is punctuated by scenes that reveal the double‐edged nature of the phenotypes associated with the possession of the CCR5Δ32/Δ32 genotype. From a historical perspective, it is noteworthy that the Murphy laboratory has played a major role in both acts thus far. In Act I, his laboratory was among the first to clone and functionally characterize CCR5 and, along with the Berger laboratory, demonstrate that CCR5 is the major coreceptor required for cell entry of HIV‐1. In Act II, although CCR5‐null mice were found to have immune perturbations following inflammatory challenges, the plot really heated up when the Murphy laboratory challenged these mice with WNV, a mosquito‐borne neurotropic flavivirus. From this point onward, the story resembles Macbeth.