Targeting the Chemokine Receptor CCR5: Good for HIV, What about Other Viruses?

Abstract

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 individuals. 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 expressed on a variety of immune cells and is responsible for mediating leukocyte chemotaxis and homing to sites of infection. 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 presence of the CCR5Δ32 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 CCR5Δ32 heterozygote and an association of the Δ32 mutation with severe tickborne encephalitis symptoms [5, 6] suggest a broader role for CCR5 in flaviviral infections. Several lines of evidence point to the CCR5Δ32 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+ to the lungs, accompanied by an increased mortality rate [7, 8]. The vicriviroc treatment arms in the Suleiman et al study included 79 participants. 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 attributed 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 untoward effects, especially when the receptor blocked is nonspecific for a given pathogen and has an important role in the general function of cellular immunity against other viruses. In the future, the encouraging results of this trial should be followed up by studying additional patients with specific attention to other viral infections and for a longer follow-up period.