C21orf91 Genotypes Correlate With Herpes Simplex Labialis (Cold Sore) Frequency: Description of a Cold Sore Susceptibility Gene

Kriesel, John D.; Jones, Brandt; Matsunami, Nori; Patel, Milan K.; Pierre, Christine A. St.; Kurt-Jones, Evelyn A.; Finberg, Robert W.; Leppert, M.; Hobbs, Maurine R.

doi:10.1093/infdis/jir633

Cited by 30 publications

(39 citation statements)

References 26 publications

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“…We reported that a series of polymorphic key regulators at the interface of innate and adaptive immunity (i.e., HLA class I molecules, KIR and CD16A) are associated with this clinical variability, strengthening the essential role of cytotoxic lymphocytes in the immune control of HSV-1 (2). Polymorphisms of other genes, including APOE and CSSG-1, were related to susceptibility to recurrences, but their exact roles in HSV-1 control are unknown (1,44,45). In turn, inborn mutations of TLR3-IFN signaling pathway genes predisposing to herpetic encephalitis support a crucial role for TLR3 in the control of HSV-1 primary infection in the CNS (3), but those mutations are apparently not connected with common forms of HSV-1 infection.…”

Section: Discussionmentioning

confidence: 98%

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation

Moraru

Black

Muntasell

et al. 2015

The Journal of Immunology

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HSV-1 latently infects most humans, causing a variable clinical picture that depends, in part, on host genetic factors. Both IgG and its cellular FcRs, CD16A and CD32A–C (encoded by FCGR3A and FCGR2A–C, respectively, on chromosome 1), display polymorphisms that could affect their defensive function. Of potential relevance are a FCGR3A dimorphism resulting in CD16A-valine/phenylalanine-158 allotypes with different IgG affinity, variations conditioning NK cell expression of CD32B or CD32C, and IgG1 H chain (IGHG1) and kappa-chain (IGKC) polymorphisms determining allotypes designated G1m and Km. In this study, we assessed the contribution of Ig genetic variations and their interaction with FcR polymorphism to HSV-1 susceptibility, as well as their impact on NK cell–mediated Ab-dependent cellular cytotoxicity (ADCC). Our results show an epistatic interaction between IGHG1 and FCGR3A such that the higher affinity CD16A-158V/V genotype associates with an asymptomatic course of HSV-1 infection only in homozygotes for G1m3. Furthermore, CD16A-158V and G1m3 allotypes enhanced ADCC against opsonized HSV-1–infected fibroblasts. Conversely, Km allotypes and CD32B or CD32C expression on NK cells did not significantly influence HSV-1 susceptibility or ADCC. NK cells degranulating against immune serum-opsonized HSV-1–infected fibroblasts had heterogeneous phenotypes. Yet, enhanced ADCC was observed among NK cells showing a differentiated, memory-like phenotype (NKG2CbrightNKG2A−CD57+FcRγ−), which expand in response to human CMV. These results extend our knowledge on the importance of immunogenetic polymorphisms and NK cell–Ab interplay in the host response against HSV-1 and point to the relevance of interactions between immune responses elicited during chronic coinfection by multiple herpesviruses.

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Section: Discussionmentioning

confidence: 98%

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation

Moraru

Black

Muntasell

et al. 2015

The Journal of Immunology

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“…In mice, chromosome 6 has been attributed to lethal disease via loci that are linked to the natural killer cell complex and tumor necrosis factor (42). The correlation of specific genetic loci with human disease, however, was reported only recently (36). In humans, mutations in Toll-like receptor 3 (TLR3)/UNC-93B have been linked to sporadic and recurrent cases of herpes simplex encephalitis in isolated families (10).…”

Section: Host Geneticsmentioning

confidence: 99%

“…A confounding observation is that the same region encodes both adenovirus and Coxsackie virus receptors. These efforts represent a first attempt to classify very complex relationships between clinical disease and the host genome (36).…”

Section: Host Geneticsmentioning

confidence: 99%

An Inquiry into the Molecular Basis of HSV Latency and Reactivation

Roizman

Whitley

2013

Annu. Rev. Microbiol.

189

187

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Herpes simplex virus (HSV) evolved an elegant strategy that enables the virus to impact a large fraction of the human population. The virus replicates at the portal of entry (mouth, genitals) and concurrently it is transported retrograde to sensory neurons. In sensory neurons it establishes a silent (latent) infection. A variety of stimuli can reactivate the virus. The reactivated virus is transmitted anterograde to a site at the portal of entry for transmission by physical contact between infected and uninfected tissues to other individuals. The central issue is how a virus that vigorously replicates and successfully blocks the innate immune defenses of the host at the portal of entry into the body remains silent in sensory neurons. The presentation focuses on three key issues: (a) current assessment of the impact of HSV on human health, (b) the mechanisms by which the virus overcomes a key host defense mechanism at the portal of entry into the body and yet is silenced in latently infected neurons, and (c) the mechanisms by which the virus reactivates.

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“…Symptoms that typically define orofacial herpes are an eruption of painful sores in and around the oral cavity. This includes lips (cold sores), cheeks, nose, chin, roof of the mouth, tongue, and gums (51). Symptoms that typically define ocular herpes include a clinically well-documented history of recurrent HSV-1 ocular disease (HSK), such as herpetic lid lesions, herpetic conjunctivitis, dendritic or geographic keratitis, stromal keratitis, decreased corneal sensation, and iritis consistent with HSK.…”

Section: Construction and Verification Of Hsv-1 And Hsv-2 Proteome MImentioning

confidence: 99%

Immunodominant “Asymptomatic” Herpes Simplex Virus 1 and 2 Protein Antigens Identified by Probing Whole-ORFome Microarrays with Serum Antibodies from Seropositive Asymptomatic versus Symptomatic Individuals

Dasgupta

Chentoufi

Kalantari

et al. 2012

J Virol

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cHerpes simplex virus 1 (HSV-1) and HSV-2 are medically significant pathogens. The development of an effective HSV vaccine remains a global public health priority. HSV-1 and HSV-2 immunodominant "asymptomatic" antigens (ID-A-Ags), which are strongly recognized by B and T cells from seropositive healthy asymptomatic individuals, may be critical to be included in an effective immunotherapeutic HSV vaccine. In contrast, immunodominant "symptomatic" antigens (ID-S-Ags) may exacerbate herpetic disease and therefore must be excluded from any HSV vaccine. In the present study, proteome microarrays of 88 HSV-1 and 84 HSV-2 open reading frames(ORFs) (ORFomes) were constructed and probed with sera from 32 HSV-1-, 6 HSV-2-, and 5 HSV-1/HSV-2-seropositive individuals and 47 seronegative healthy individuals (negative controls). The proteins detected in both HSV-1 and HSV-2 proteome microarrays were further classified according to their recognition by sera from HSV-seropositive clinically defined symptomatic (n ‫؍‬ 10) and asymptomatic (n ‫؍‬ 10) individuals. We found that (i) serum antibodies recognized an average of 6 ORFs per seropositive individual; (ii) the antibody responses to HSV antigens were diverse among HSV-1-and HSV-2-seropositive individuals; (iii) panels of 21 and 30 immunodominant antigens (ID-Ags) were identified from the HSV-1 and HSV-2 ORFomes, respectively, as being highly and frequently recognized by serum antibodies from seropositive individuals; and (iv) interestingly, four HSV-1 and HSV-2 cross-reactive asymptomatic ID-A-Ags, US4, US11, UL30, and UL42, were strongly and frequently recognized by sera from 10 of 10 asymptomatic patients but not by sera from 10 of 10 symptomatic patients (P < 0.001). In contrast, sera from symptomatic patients preferentially recognized the US10 ID-S-Ag (P < 0.001). We have identified previously unreported immunodominant HSV antigens, among which were 4 ID-A-Ags and 1 ID-S-Ag. These newly identified ID-A-Ags could lead to the development of an efficient "asymptomatic" vaccine against ocular, orofacial, and genital herpes.

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C21orf91 Genotypes Correlate With Herpes Simplex Labialis (Cold Sore) Frequency: Description of a Cold Sore Susceptibility Gene

Abstract: We evaluated candidate genes in the cold sore susceptibility region using fine mapping with 45 SNP markers. 2 complementary techniques identified C21orf91 as a gene of interest for susceptibility to HSL. We propose that C21orf91 be designated the Cold Sore Susceptibility Gene-1 (CSSG1).

Cited by 30 publications

References 26 publications

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation

An Inquiry into the Molecular Basis of HSV Latency and Reactivation

Immunodominant “Asymptomatic” Herpes Simplex Virus 1 and 2 Protein Antigens Identified by Probing Whole-ORFome Microarrays with Serum Antibodies from Seropositive Asymptomatic versus Symptomatic Individuals

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