15 JANUARY Correspondence Targeting the Chemokine Receptor CCR5: Good for HIV, What about Other Viruses? To the Editor—We read with interest the report by Suleiman et al [1] on the encouraging results of the VICTOR-E1 Phase 2 Trial, demonstrating vicriviroc’s good and sustained antiretroviral and immunologic activity over 48 weeks in treatment-experienced HIV-infected in- dividuals. These promising results need to be balanced with caution against the possibility that treatment could lead to more severe manifestations of other viral infections; this is due to the mechanism of action of vicriviroc and the significant role of CCR5 in the response to viral infections other than HIV. CCR5 is a chemokine receptor ex- pressed on a variety of immune cells and is responsible for mediating leukocyte chemotaxis and homing to sites of in- fection. Until recently, understanding of the role of CCR5 was limited to its role in HIV cell entry and the protection from HIV afforded by its absence. More recent evidence is mounting to link CCR5 receptor deficiency (ie, the pres- ence of the CCR5D32 allele) with an increased risk of symptomatic and fatal West Nile virus infection [2–4]. Additionally, a severe adverse reaction to the yellow fever virus vaccine in a CCR5D32 heterozygote and an associ- ation of the D32 mutation with severe tickborne encephalitis symptoms [5, 6] suggest a broader role for CCR5 in flaviviral infections. Several lines of evidence point to the CCR5D32 allele being important in determining disease severity of other viral infections, albeit in animal models. In a mouse model, challenge of CCR5-deficient animals with influenza virus was associated with impaired recruitment of CD8 1 to the lungs, accompanied by an increased mortality rate [7, 8]. The vicriviroc treatment arms in the Suleiman et al study included 79 partic- ipants. Four deaths were reported in the study, including 2 subjects in the placebo group and 2 in the vicriviroc 20 mg treatment group; the latter 2 were at- tributed to bilateral atypical pneumonia and presumed disseminated tuberculosis, complicated by multiple organ failure. The concept of targeting a human receptor has numerous advantages but is also accompanied by concerns for un- toward effects, especially when the re- ceptor blocked is nonspecific for a given pathogen and has an important role in the general function of cellular immu- nity against other viruses. In the future, the encouraging results of this trial should be followed up by studying ad- ditional patients with specific attention to other viral infections and for a longer follow-up period. Yoav Keynan, 1,2 Jennifer Juno, 2 Ken Kasper, 1,2 Ethan Rubinstein, 1,2 and Keith R. Fowke 2 1 Department of Internal Medicine and 2 Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada References 1. Suleiman J, Zingman BS, Diaz RS, et al. Vi- criviroc in combination therapy with an op- timized regimen for treatment-experienced subjects: 48-week results of the VICTOR-E1 phase 2 trial. J Infect Dis 2010; 201:590–9. 2. Lim JK, Louie CY, Glaser C, et al. Genetic deficiency of chemokine receptor CCR5 is a strong risk factor for symptomatic West Nile virus infection: a meta-analysis of 4 co- horts in the US epidemic. J Infect Dis 2008; 197:262–5. 3. Glass WG, Lim JK, Cholera R, Pletnev AG, Gao JL, Murphy PM. Chemokine receptor CCR5 promotes leukocyte traffick- ing to the brain and survival in West Nile virus infection. J Exp Med 2005; 202: 1087–98. 4. Lim JK, McDermott DH, Lisco A, et al. CCR5 deficiency is a risk factor for early clinical manifestations of West Nile virus infection but not for viral transmission. J Infect Dis 2010; 201:178. 5. Pulendran B, Miller J, Querec TD, et al. Case of yellow fever vaccine–associated viscerotropic disease with prolonged viremia, robust adap- tive immune responses, and polymorphisms in CCR5 and RANTES genes. J Infect Dis 2008; 198:500–7. 6. Kindberg E, Mickiene A, Ax C, et al. A de- letion in the chemokine receptor 5 (CCR5) gene is associated with tickborne encephalitis. J Infect Dis 2008; 197:266–9. 7. Kohlmeier JE, Miller SC, Smith J, et al. The chemokine receptor CCR5 plays a key role in the early memory CD81 T cell response to respiratory virus infections. Immunity 2008; 29:101–13. 8. Dawson TC, Beck MA, Kuziel WA, Henderson F, Maeda N. Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to in- fluenza A virus. Am J Pathol 2000; 156: 1951–9. Received 25 January 2010; accepted 23 August 2010. Potential conflicts of interest: none reported. Reprints or correspondence: Dr Yoav Keynan, Departments of Internal Medicine and Medical Microbiology, University of Manitoba, Rm 539, 745 Bannatyne Ave, Winnipeg, Manitoba MB R3E 0J9, Canada (keynany@ yahoo.com). The Journal of Infectious Diseases 2011;203:292 Ó The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com 1537-6613/2011/2032-0001$15.00 DOI: 10.1093/infdis/jiq032 292 d JID 2011:203 (15 January) d CORRESPONDENCE View publication stats View publication stats