The first common cold sore susceptibility gene.

The outcome of any interaction between a virus and host is determined by genetic and environmental factors and is manifest as either susceptibility to or chronicity of infection or severity of disease [1]. This interplay between host genetics and viral strain genomic sequence has been well defined in murine models of different viral infections, such as murine cytomegalovirus, retroviruses (Friend leukemia virus), and influenza virus [2–4]. In some human viral infections, eg, human immunodeficiency virus (HIV) infection, the effects of various host genes on viral acquisition, disease, and survival have been well defined. For example, homozygosity for a large deletion in the HIV coreceptor chemokine (C-C motif) receptor 5 (CCR5) is highly protective against viral acquisition [5]. KIR, CCR5, CCR2, and HLA-B57 variants delay HIV disease progression in white persons through immunologic mechanisms, whereas HLA-B35 accelerates it [6–8]. To date, however, only some of the variation in disease progression has been explained by genetic studies. In human infectionswith herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) there is added complexity in that both are shed asymptomatically in the saliva and genital secretions, respectively. Clinical lesions develop in only a portion of the shedding population. Worldwide, 50%–100% and 10%–90% of populations are infected with HSV-1 and HSV-2, respectively, but only a minority of infections present with disease, which varies remarkably in frequency and severity, eg, 20%–30% for herpes simplex labialis [8, 9]. In animal models, the viral strain, size of inoculum, and strain of animal help determine initial disease severity and latent viral burden in the spinal ganglia that, in turn, influences frequency of reactivation. Therefore, it is not surprising that a range of human genes might influence different phenotypes of herpes labialis, including initial disease severity, frequency and severity of recurrences, and/or frequency and extent of viral shedding (a determinant of spread or infectiousness).In mice and humans, several genes predisposing to severe initial disease and mortality have been identified. In mice, these include 3 loci on chromosome 6, 1 linked to the natural killer cell complex, and 2 near the tumor necrosis factor a gene locus, 1 of which is sex linked [10]; in humans, deficiency of Tolllike receptor (TLR) 3/UNC-93B has been linked to herpes simplex encephalitis [11]. In mice, such genetic resistance varies according to the route of inoculation and is eliminated by intracerebral inoculation. These findings are consistent with the observation that resistance to infection of the dorsal routeganglion, establishmentof viral latency, and subsequent reactivation involves multiple genetic loci [11, 12]. Mice are poor models of recurrent herpes. However, in human recurrent herpes caused by HSV-2, older studies linked HLA-A1 and HLA-B27 deficiency to increased frequency of genital herpes. More recently, certain TLR2 polymorphisms were shown to predispose to more frequent genital herpes and genital HSV-2 shedding [13]. In the past, human studies have been restricted to single candidate genes suggested by pathogenetic studies or to a single chromosomal region (chromosome 6) encoding the HLA system, often not explaining the strong genetic predispositions suggested by familial or twin studies. Until recently, geneticists have been frustrated in their ability to localize familial traits to specific regions of the human genome and then to genes andprecise genetic sequences. The sequencing of the human genome, the availability of dense genotyping primers across the genome, and powerful analytic methods have led to routine genome-wide analyses for a number of multigenic diseases, including infectious diseases. Perhaps unsurprisingly, the most common region affecting host response to viruses and other pathogens is still the HLA region. However, non–major histocompatibility complex regions have also been identified [14], most notably for spontaneous clearance and drug response to the hepatitis C virus [15–17]. Here a single genetic variant of interleukin (IL) 28B was found to predict viral clearance. This discovery has been translated directly into clinical practice, so that patient genotyping is already widely used by clinicians to predict who Received and accepted 19 April 2011. Correspondence: Anthony L. Cunningham, PhD, MBBS MD, Westmead Millennium Institute, Darcy Road, PO Box 412, Westmead, NSW Australia 2145 (tony.cunningham@ sydney.edu.au). The Journal of Infectious Diseases 2011;204:1645–7 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. [email protected] 0022-1899 (print)/1537-6613 (online)/2011/20411-0001$14.00 DOI: 10.1093/infdis/jir635