Medical Hypotheses (2000) 54(6), 1003–1004 © 2000 Harcourt Publishers Ltd doi: 10.1054/mehy.1999.1017, available online at http://www.idealibrary.com on
Plague as HIV vaccine adjuvant E. L. Altschuler Brain and Perception Laboratory, University of California, San Diego, USA
Summary Individuals homozygous for a 32-basepair deletion mutation (null mutation) in CCR5, a chemokine receptor, are nearly immune to developing HIV infection. Recently based on molecular dating evidence it has been proposed that the bacterium Yersinia pestis, cause of plague, may have been the selective pressure which selected for a high prevalence of the 32-basepair null mutation. An association of a robust chemokine response with HIV vaccine efficacy has recently been shown. I suggest that Y. pestis may be a useful adjuvant in an HIV vaccine protocol by stimulating a vigorous chemokine response. © 2000 Harcourt Publishers Ltd
DISCUSSION A paradigm shift in our understanding of the pathogenesis of HIV was had when Gallo and colleagues (1) showed the importance of chemokines in the immune system’s defense against HIV. This was followed quickly by the discovery of human chemokine receptors which served as co-receptors for HIV along with CD4. The CCR5 chemokine receptor was shown to be important in mediating early infectivity of HIV, and interestingly, individuals homozygous for a 32-basepair deletion mutation (null mutation) in CCR5 seemed nearly immune to developing HIV infection, even when repeatedly exposed to the virus (2). The geographic distribution of the 32-basepair deletion was intriguing: the prevalence was particularly high in Iceland, Britain and Askenazi Jews, and declined as one moved east in Europe (3). The striking inhomogeneity of this distribution led to the thought that there may have been some infectious agent in the past that selected for the 32-basepair deletion allele, perhaps a virus or parasite. O’Brien and colleagues have recently suggested that it was not a virus or parasite which selected for the CCR5 null mutation, but a bacterium, Yersinia pestis, cause of
Received 28 June 1999 Accepted 18 October 1999 Correspondence to: E. L. Altschuler, Brain and Perception Laboratory, University of California, 9500 Gilman Drive, 0109 La Jolla, CA 92093-0109, USA. Phone: +1 619 534 7907; Fax: +1 619 534 7190; Email:
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the bubonic plague which ravaged Europe in the Middle Ages (4). They support this contention by flanking marker studies of the mutation showing that it probably occurred only a single time approximately 600 years ago. Now, part of the protection of the CCR5 deletion might derive not only from the absence of an important HIV surface co-receptor, but also from an increased production of inflammatory chemokines in CCR5 –/– individuals in a vain attempt by the body to bind the non-existent receptor. Production of inflammatory chemokines may also have been important in fighting off the agent that selected for the 32-basepair deletion. While there has been no work on Y. pestis and chemokines, one paper working with another Yersinia species, Y. enterocolitica, showed that Y. enterocolitica infection in an in vitro system led to an elaboration of CC-chemokines (5). Recent work has shown that the association of a robust chemokine response with vaccine efficacy (6). I suggest that plague might be a useful adjuvant for an HIV vaccine by causing a large chemokine response. This could be tested in animal HIV vaccine models. Furthermore, it might be possible to see whether military and other individuals who had received plague vaccine, or exposed to wild plague, might have a lower incidence of HIV than in appropriately matched controls. REFERENCES 1.
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